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Neurobiology
of Behaviour
Visual Summary Issue
University of Toronto
Winter
2015
HMB300H1F 2015 University of Toronto
Table of Contents
Summaries by:
1. Vaisny Balamurali 4 41. Catherine Matolcsy 84
2. Saadia Esat 6 42. Lucy McPhee 86
3. Xin Yue Kou 8 43. Arinda Muntean 88
4. Soonji Kwon 10 44. Yuki Nishimura 90
5. Alexandra Kubica 12 45. Miranda Nong 92
6. Daniel Derkach 14 46. Hyun Park 94
7. Vanessa Ferlaino 16 47. Maryna Pilkiw 96
8. Floriana Ferri 18 48. Joravir Singh Riar 98
9. Sonja Ing 20 49. Ashkan Salehi 100
10. Ricky Ng 22 50. Husain Shakil 102
11. Jessica Gosio 24 51. Arman Shekari 104
12. David Giang 26 52. Jaclin Simonetta 106
13. Akua Obeng-Dei 28 53. Olivia Singh 108
14. Mie Andersen 30 54. Eugene Tang 110
15. Madli Vahtra 32 55. Jiawei Zhang 112
16. Pranay Siriya 34 56. Yidong Zhan 114
17. Alana Brown 36 57. Nimara Dias-Karunaratne 116
18. Chuqi Sandy Wang 38 58. ZiTeng Li 118
19. Vanessa Bracaglia 40 59. Man Lai Ho 120
20. Vivian Liu 42 60. Sylvia Jennings 122
21. Bernie Longange 44 61. Melissa Colaluca 124
22. Dong-Eun (Raquel) Lee 46 62. Divya Mamootil 128
23. Vonny Pui Ying Wong 48 63. Padmanabhan Ramanujam 130
24. Ola Taji 50
25. Ashima Agarwal 52
26. Ariba Alam 54
27. Samin Alikhanzadeh 56
28. Megan Cabral 58
29. Sammy Cai 60
30. Chun-Chi Chu 62
31. Chantel George 64
32. Patrick Hornlimann 66
33. Shikha Kuthiala 68
34. Shonali Rajesh Lakhani 70
35. Victor Lee 72
36. Ella Lew 74
37. Yi Xuan Li 76
38. Rose Ly 78
39. Tong Mai 80
40. Fazila Malek 82
4
Summary of:
Accumulation of amyloid in cognitive impairment after mild

traumatic brain injury
Authors: Shun-Tai Yang, Ing-Tsung Hsiao, Chia-Ju Hsieh, Tung-Hsiao Chiang, Tzu-Chen Yen,
Wen-Ta Chiu, Kun-Ju Lin, Chaur-Jong Hu
Background/Introduction:
Mild traumatic brain injury (mTBI) can occur after mechanical force/ impact is applied
to the head, usually occurring in accidents and/or sports related injury. Biochemical and
physical changes occur within the brain as a result of mTBI, these changes can result in a
semi-permanent or permanent decline in cognitive, physical and/or psychological function.
Many studies analyzing the consequences of mTBI have shown patients having Alzheimer’s
Disease (AD) like pathology; patients showed increased accumulation of Aβ plaque
formation, tau proteins and neurofibrillary tangles (NFTs). This study aims to examine the
effects of mTBI and look at the role of the APOE4 gene in Aβ plaque formation as well as
the effectiveness of using amyloid positron emission tomography (PET) as a diagnostic tool.
Materials and Methods:
A total of 37 participants were used in this study, there were 10 controls. 27
participants were former mTBI patients found in the Taiwan TBI Database, 6 of the 27
mTBI subjects were former mTBI patients with obvious cognitive impairment/ dementia.
All study participants underwent questionnaire screening to assess cognitive function.
Participants were administered the AD8 questionnaire and Mini Mental Status Examination
(MMSE). Apoliprotein E genotyping was done on all participants using the PCR-PFLP
method. Aβ plaque, tau proteins and neurofibrillary tangles (NFTs) accumulation was
analysed through amyloid PET and normalizing images to an MRI template. MRI images
where then used to examine brain volumes of following 7 regions: cerebellum, bilateral
frontal, occipital, temporal, precuneus, striatum and posterior cingulate.
Major Results:
Amyloid accumulation scores of 1.83± 0.75 (mTBI with dementia),0.86± 0.65 (mTBI without
dementia), 0.60 ± 0.52(control) demonstrated increased amyloid presence in mTBI patients
with dementia. Patient’s cognitive function scores through the AD8 tests showed similar trends
to that of the amyloid accumulation scores as increased dementia showed increased AD8
scores (0.3 control, 1.6 mTBI without dementia and 3.3 mTBI with dementia). While compiling
AD8 scores and amyloid accumulation scores with patient’s other information including
Initial Loss of Consciousness (ILOC) researchers found ILOC was a risk factor to increased AD
pathology. Odds Ratio of ILOC was 12.5 for patients to acquire dementia. Amyloid PET analysis
showed the amyloid burden in participants. mTBI participants with dementia showed the most
uptake of radioactivity in brain regions ( bilateral striatum, temporal, frontal and parietal lobes)
thus they had the highest amyloid burden, amyloid burden were very low to absent in controls
and mTBI participants without dementia. Genotype comparison to amyloid accumulation and
post mTBI consequences showed that the APOE4 allele was associated with higher incidence
of amyloid plaque formation and dementia. A significant correlation was seen in participants
upon a linear regression anaylysis of APOE4 genotype and their amyloid burden.
Conclusions:
This study’s findings are consistent with existing literature as it demonstrated that
mTBI does have a role in increasing risk in developing AD like pathology resulting in
cognitive decline. It was also able to confirm that the APOE4 allele increases risks to
develop Aβ plaque formation. Most importantly this study successfully uses a novel
technology (amyloid PET) to demonstrate these findings. This should open pathways to
increasing amyloid PET use in a variety of other neurological studies as well as for a
more indepth analysis of AD pathology specifically in mTBI patients on a larger scale.
Further examination in the pathology/biochemistry of how mTBI increases AD pathology
on a larger scale can be very helpful to finding a preventative or curative treatment.
5
Sources for images: http://www.autoaccidentattorneyinfo.com/category/brain-injuries/, https://mybiomedart.wordpress.

com/tag/beta-amyloid-plaques/, http://www.nature.com/news/dna-data-storage-breaks-records-1.11194
Yang, S.T. et al. (2015). Accumulation of amyloid in cognitive impairment after mild traumatic brain
injury. Journal of Neurological Sciences, 341, 99-104.
Summary by: Vaisny Balamurali
6
Summary of:
Hippocampal Neurogenesis Regulates Forgetting During
Adulthood and Infancy
Authors: Katherine G. Akers,Alonso Martinez-Canabal, Leonardo Restivo, Adelaide P. Yiu,
Antonietta De Cristofaro, Hwa-Lin (Liz) Hsiang, Anne L. Wheeler, Axel Guskjolen,
Yosuke Niibori, Hirotaka Shoji, Koji Ohira, Blake A. Richards, Tsuyoshi Miyakawa,
Sheena A. Josselyn, Paul W. Frankland
During adulthood and infancy, it is evident that as neurogenesis occurs, memory
persistence decreases. The presence of neurogenesis was monitored using GFP tagging in
the dentate gyrus and CA3 neurons. When adult and infant mice were fear conditioned,
then tested 1 day later, there was equal freezing time. However as the delay increased
up to 28 days (and increased neurogenesis in infant mice) the infant mice showed less
freezing time, indicating that the initial conditioning was being forgotten. The reason
that infant mice were compared to adult was due to the high amount of neurogenesis
occurring in infants, allowing for more visible results, if any. It is hypothesized that if
neurogenesis occurs, then other hippocampus-dependent memories will be forgotten to
accommodate for the new neuronal connections.
Multiple versions of the method to test the hypothesis were carried, however a large
focus was on two sections with two subsections of experimentation. The first was with
mice who had the option of voluntary running compared to a control who did not have
that option. GFP was administered after 4 weeks, and further ZnT3 was used as a
counter-stain to compare the presence of new and old neurons in the dentate gyrus and
CA3. Additionally a comparison was done between transgenic TK+ mice to wild type,
who were administered GAN to prevent neurogenesis. On both groups fear conditioning
through foot shocks was done, and they were tested against controls weeks later to see if
the contextual fear conditioning had remained. This was done with both adult and then
with infant mice.
Major Results:
With the first set of experiments mentioned above, it was evident with the counter-stain
that new and old neurons were found in close proximity to each other. Additionally, after fear
conditioning had occurred, 1 day later the mice were tested and both groups showed equal
amounts of freezing. However, after four weeks when mice were tested, those who had access
to a running wheel showed a reduction in the conditioned fear context. In the second set of
experiments, after the first day, both sets of mice displayed equal freezing during the test.
Although, after six weeks, the TK+ transgenic mice showed the same reaction as WT mice
who did not has access to a running wheel (they had not forgotten the fear). The WT mice
that had access to a running wheel froze less than the TK+ mice at this time.
Conclusions:
The study suggests that not only is the hippocampus required for consolidating
memories, but the presence of neurogenesis there suggests that it also plays a role in the
forgetting of information through rewiring the DG-CA3 circuits as new memories arise.
This suggestion is evidence for long term degradation in the hippocampos, a concept
necessary to balance long term potentiation. The most frequently activated patterns of
activity is remembered, where older contexts are forgotten.
7
Fig. 2 Voluntary running increases neurogenesis and promotes forgetting in adult mice.
http://www.sciencemag.org.myaccess.library.utoronto.ca/content/344/6184/598/F2.large.jpg
Akers, K. (2014), et al. Hippocampal Neurogenesis Regulates Forgetting During Adulthood and
Infancy. Science, 344(6184), 598-602. Retrieved February 9, 2015, from http://www.sciencemag.org.
myaccess.library.utoronto.ca/content/344/6184/598.full
Summary by: Saadia Esat
8
Summary of:
Sleep deprivation impairs memory, tau metabolism, and synaptic
integrity of a mouse model of Alzheimer’s disease with plaques
and tangles
Authors: Antonio Di Meco, Yash B. Joshi, Domenico Pratico

Increasing cases of Alzheimer’s disease (AD) in the elderly, and with no definite cure,
is becoming a serious public health issue worldwide. From previous understandings, the
development of AD is due to a combination of genetic and environmental factors, where
one of the potential environmental risk factor is chronic stress. Chronic stress can cause
widespread effects within body systems, one of them being the sleep cycle. Interestingly
sleep deprivation (SD) have been found in previous studies to play a role in many
neurodegenerative diseases, including AD. Studies have shown that in AD transgenic mouse
model where it seems that the disease related plaque caused by amyloid-beta is associated
with SD. However no further studies have looked at the relationships between SD and other
AD features, hence this study is set to examine the correlation between chronic SD and AD
phenotypes such as tau metabolism and other causes of cognitive impairments.
This experiment examined several aspects of AD using 3xTg mice that expresses
mutant amyloid precursor protein, the human mutant PS1 knockin as well as the
transgeneic form of tau. At age 8month, the 18 mice were divided into two random
groups, where one group was introduced to SD, and the other group had normal light/
dark cycle as control. During the protocols the mice were assessed behaviourally
using the Y-maze (to measure the mice’s spontaneous will to explore new areas), fear
conditioning through foot shock and sound cues, as well as the Morris water maze. After
scarification at 10month of age, the mice brain were dissected for examination, half for
biochemistry assays, and the other half for immunohistochemistry studies.
Major Results:
For results on cognitive function, SD mice showed no difference on Y-maze activity, an
insignificant decrease of freezing in cued recall for fear conditioning and an significant
decrease in remembering the target platform zone, as well as longer travel distance in
the Morris water maze. Biochemically, amyloid-beta peptides did not differ significantly.
In terms of tau metabolism, SD mice exhibited a decrease in phosphorylation at several
epitopes, potentially due to an significant decrease of the kinase, cdk-5 activity in the
brain. There was also a significant increase in insoluble tau as compared to control, this
also corresponded to the increase in immunoreactivity of the MC-1 antibody, which is a
marker for tau conformation change in AD brain.
Western blot and immunohistochemistry shows that PSD95 in SD mice decreased
significantly, indicating decreased post-synaptic integrity. SD mice also showed a greater
expression of the astrocytosis marker, glial fibrillary acidic protein (GFAP), as microglia
and astrocytes are typically active in AD brains. Lastly, even though there was no change
in the total CREB level, but its phosphorylated form p-CREB was significantly reduced in
SD mice, and this change did not affect any other related factors such as BDNF and cFos.
Conclusions:
We see that sleep deprivation in AD mouse model definitely correlate to cognitive
impairments such as spatial memory deficits, as well as changes biochemically in tau
metabolism. Tau protein is typically found hyperphosphorylated in the AD brain, in this
paper the results of decreased tau phosphorylation and cdk5 activity infer that there may be
other kinases responsible for the phosphorylation of tau in the AD phenotype, although body
temperature could have acted as a confound which was not acknowledged for. The correlation
between increase in MC-1 and insoluble tau suggesting that tau conformation change could
mark initiation of AD progression, however still controversial as previous studies suggests
otherwise. Overall this study demonstrates that SD causes chronic stress that are not only
associated to AD as a progressive marker but in fact likely contribute to the development of AD.
9
Di Meco, A., & Joshi, Y. B., & Pratico, Domenico. (2014). Sleep deprivation impairs memory, tau
metabolism, and synaptic integrity of a mouse model of Alzheimer’s disease with plaques and tangles.
Neurobiologi of Aging, 35, 1813-1820.
Summary by: Xin Yue Kou
10
Summary of:
Endogenous adenosine A3 receptor activation selectively
alleviates persistent pain states.
Authors: Little JW, Ford A, Symons-Liguori AM, Chen Z, Janes K, Doyle T, Xie J, Luongo L,
Tosh DK, Maione S, Bannister K, Dickenson AH, Vanderah TW, Porreca F, Jacobson
KA, & Salvemini D.
Most effective treatments of chronic pain typically involve endogenous opioids, adrenergic and
calcium channels. These clinical treatment methods however, have detrimental side effects. This
study highlights the potential of using an agonist of a G protein-coupled adenosine receptor
(AR) subtype A3 in reversing pathogenic pain. Although there have been developments in the
analgesic uses of other AR subtype agonists, specifically A1AR and A2AAR agonists, there
were cardiovascular side effects. Interestingly, A3AR is highly expressed in cells important in
carrying out neuroprotective effects, such as inflammatory cells and peripheral sensory nerves.
Additionally, there are already clinical trials using A3AR agonist IB-MECA [N6-(3-iodobenzyl)-
adenosine-50-N-methyluronamide] as a means to decrease pain caused by chemotherapeutic
agents and constriction of sciatic nerve without serious side effects. However, activation of A3AR
at spinal and supraspinal (rostral ventromedial medulla (RVM)) sites show promising signs of
becoming a more effective treatment of chronic pain without side effects.
A total of 301 rats and 63 mice were used to test various neuropathic pain models, such as
chronic constriction injury (CCI), spared nerve injury, spinal nerve ligation, chemotherapy-
induced peripheral neuropathy, and cancer-induced bone pain. The mice were classified into
two major groups: wild-type and A3AR -/- mice. Dosage effects and motor coordination were
tested using the Rotarod motor test. Tail flick and hot-plate latency were used to test if normal
nociception was affected by administration of A3AR agonist, MRS5698. Instinctual behaviours
such as flinching and guarding were examined in animals with cancer-induced bone pain. Since
an important site of A3AR activation is the RVM, various systemic microinjections were employed
to test for any differential effects. Additionally, the second important site of A3AR activation is the
spinal cord, specifically L4-L5 segments, where post-spinal nerve ligation was conducted.
Major Results:
CCI neuropathic pain model involved systemic administration of ABT-702, a selective adenosine
non-nucleoside kinase inhibitor. This elicited a long-lasting decrease in flinching and guarding
behaviors, indicative of reversing cancer-induced bone pain. Conversely, both pre- and post-
administration of MRS1523, a selective A3AR antagonist, diminished the anti-nociceptic effects
of ABT-702. The results are similar in A3AR -/- mice. The most effective treatment of neuropathic
pain is the administration of MRS5698, a highly selective A3AR agonist. As a result of higher
selectivity over A1AR and A2AAR, its effects are fast and even comparable to morphine and IB-
MECA. Unlike morphine, MRS5698 does not lead to tolerance upon repeated administration.
However, it is most effective when given in different types of systemic injections: intraperitoneal,
subcutaneous, intravenous. Mechano-allodynia is a specific type of pain induced by stimulation
of a low-threshold afferent nerve that is mechano-sensitive. Not only does MRS5698 alleviate
mechano-allodyna, it reverses many other pain models, such as spared nerve injury, spinal
nerve ligation and cancer-induced pain. Future implications of MRS5698 treatment method
may most notably be due to the fact that it is already in its clinical use as an anti-cancer agent.
Additionally, endogenous opioid and cannabinoid pathways were entirely independent of the
effects of this A3AR agonist. To ensure normal nociception is not compromised, the tail flick
and hot-plate methods were used. To locate the optimal injection sites, A3AR mRNA transcript
and protein levels were measured and compared by Western blot. Thus, the spinal cord and
supraspinal (RVM) sites were both found to be important sites for A3AR activation and therefore,
nociception processing as well.
Conclusions:
Recent advancements have developed A3AR agonist IB-MECA as anti-nociception treatment
however, there were some side effects associated with its use. Alternatively, the use of the highly
selective A3AR agonist, MRS5698, did not lead to the development of side effects to date. The
most exciting implication of MRS5698 is the possible dual treatment of cancer as well as chronic
neuropathic pain.
11
Little JW, Ford A, Symons-Liguori AM, Chen Z, Janes K, Doyle T, Xie J, Luongo L, Tosh DK, Maione
S, Bannister K, Dickenson AH, Vanderah TW, Porreca F, Jacobson KA, & Salvemini D. (2014).
Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states. Brain. doi:
10.1093/brain/awu330.
Summary by: Soonji Kwon

12
Summary of:
Decoding Neural Circuits that Control Compulsive Sucrose
Seeking
Authors: Edward H Nieh, Gillian A Matthews, Stephen A Allsop, Kara N Presbrey, Christopher A
Leppla, Romy Wichmann, Rachael Neve, Craig P Wildes, & Kay M Tye
Lateral hypothalamus (LH) has been found to be responsible for inducing

feelings of hunger. Ventral tegmental area (VTA) has been found to be a part
of the reward centre of the brain. This LH-VTA pathway has been found
electrically and optically, however, how the pathway works corresponding
to food reward and addiction has not. The researchers wanted to show that
the pathway existed for specifically compulsive sucrose eating, and not just
a pathway for eating in general, to the point of addictions like drugs where
the substance is still sought after even through negative consequences. The
neurons of the pathway that projected from the LH to the VTA and the ones
that were received by the LH from the VTA were found using optogenetic-
mediated phototagging while observing neural activity during reward seeking
behaviours. Once these neurons were identified, the mice had an optic fibre
inserted over the VTA that shone either blue or yellow light. Then the mice
were injected in their LH with either ChR2 which activated the loop with
blue light, NpHR which inhibited the loop with yellow light or a control of
eYFP. Conditioned mice learned to go to a port when they saw a cue in order
to obtain sucrose. The port was on the other side of a shock grid. Then the
mice went through 3 different trials each one having 20 cues and was either
paired with no shocks, shocks, or shocks but the optic fibres were used at
the same time. They also wanted to show that the GABA neurons were not
what was causing the compulsive sucrose seeking or an increase in hunger.
Vivo patch-clamp experiments were used to identify the glutamate and
GABA neurons projecting from the LH to the VTA. The same sucrose-shock
experiment was used to understand the role of activation and inhibition of
these neurons and their effects on feeding behaviour. As well the researchers
wanted to see that the activation of the pathway was not inhibiting the
feelings of pain by comparing inhibited and activated mice in hot water tail
withdrawal reaction times. By finding how this pathway affects behaviour it
can lead to therapies and techniques to deal with high sucrose cravings that
lead to obesity and food addictions.
13
Cell (2015) doi: http://dx.doi.org/10.1016/j.cell.2015.01.003 Published online January 29, 2015
Summary by: Alexandra Kubica

14
Summary of:
Transient Maternal IL-6 Mediates Long-Lasting Changes in
Neural Stem Cell Pools by Deregulating an Endogenous Self-
Renewal Pathway
Authors: Denis Gallagher, Andreea A. Norman, Cameron L. Woodard, Guang Yang, Andrée
Gauthier-Fisher, Masashi Fujitani, John P. Vessey, Gonzalo I. Cancino, Nadia Sachewsky,
Knut Woltjen, Michael P. Fatt, Cindi M. Morshead, David R. Kaplan, Freda D. Miller
Current research is unable to explain the mechanism controlling the formation or size of adult stem
cell pools. However, it is known that variations in neural precursor cells (NPCs) directly influence
neurogenesis in adult mammalian brains. Moreover, human gestational stresses have long-term
effects on cognitive function of offspring, possibly correlating to disturbances in the formation of adult
NPC pools. This study examines this prospect by analyzing a maternal cytokine surge of interleukin-6
(IL-6) during gestation. IL-6, which is upregulated in infected mothers, is believed to be responsible
for certain behavioral aberrations in mice, such as autism spectrum disorder and schizophrenia.
Maternal IL-6 enters the fetal circulation and crosses the blood-brain barrier, possibly affecting long-
term neural function. This study hypothesizes that this maternal cytokine surge causes long-term
changes in NPC pools and seeks to probe into the mechanism responsible for such changes.
IL-6 was injected intraperitoneally in pregnant mice on gestational day 13.5 (G13.5) in experimental
groups. Negative controls included mice with no maternal IL-6 infection, or infection with interferon-γ
(IFNγ) or IgG. Other experimental groups included mice with IL-6 receptor (IL6R) knockdown via
IL6R siRNA and IL-6-/- (knockout) mice, with wild-type positive controls. BrdU and Ki67 were used
as proliferation markers. Sox2 was used as a precursor marker. Satb2 was used as a marker for
newborn (differentiated) neurons. Hoechst stained for DNA (less toxic than DAPI). BIII-tubulin was
used to label neurons. GFAP was used to label astrocytes.
Enhanced GFP (EGFP) was transfected in either cortical or ventral ganglionic eminence cells (ventral GE)
of embryos using the piggyBac transfection method to track location of these precursor cells in adults.
Other techniques used include culturing and passaging of neurospheres, RT-PCR, Western blot analyses,
cytokine antibody arrays, as well as various culturing/clonal programs and software for imaging.
Major Results:
Intraperitoneal injection of IL-6 into pregnant mice resulted in ~2 times more BrdU-positive subventricular
zone (SVZ) cells (Fig. 1A/B) and ~1.5 times more SVZ neurosphere-initiation (Fig. 1H) in 2 month-old (adult)
mice. Maternal IL-6 injection also resulted in ~1.5-fold more olfactory bulb neuron birth in adult mice (Fig. 1J).
Postnatal (2 weeks-old) EGFP-positive SVZ cells were Sox2-positive (representing proliferation)
after electroporation of embryonic cortex with EGFP reporter (Fig. 2B/D), and newborn
neuroblasts in the rostral migratory stream (RMS) of adult mice continued to be EGFP-positive
(Fig. 2E), illustrating persistence of NPCs from embryo to adulthood.
In addition to an increase in BrdU-positive cells (signifying proliferation; Fig. 3C), maternal IL-6
injection resulted in an almost 2-fold increase of embryonic cortical precursors (Fig. 3E) and ventral
GE precursors (Fig. 3M) that formed neurospheres at clonal densities 2 days after injection.
IL-6 treatment resulted in larger multicellular clonal bodies (Fig. 5A-C), showing enhancement of
self-renewal (i.e. cloning). IL-6 treatment also resulted in a ~2-fold increase in mixed clones (BIII-
tubulin + other, Fig. 5E; GFAP + other, Fig. 5F), as opposed to uniform clones. In vivo analysis
showed a significant increase in SVZ neurosphere initiation (Fig. 5G).
IL-6 knockout mice (IL-6-/-) showed greatly reduced proliferation of embryonic cortical precursors
compared to WT controls (Fig. 6G/H). 3 days after EGFP transfection in IL6R knockdown mice,
embryonic cortical radial cells exhibited a composition of fewer precursors (Sox2-labeled) and
increased quantities of differentiated neurons (Satb2-labeled; Fig. 7D-G). Similarly, 3 days after
BrdU injection in IL-6-/- mice, embryonic cortical radial cells exhibited a composition of fewer
BrdU-positive precursors and increased quantities of differentiated neurons (Fig. 7J-M).
Conclusions:
This study shows that gestationally increased maternal IL-6 levels increases proliferation and
size of adult forebrain NPC pools. The evidence outlined in this study elucidates this conclusion in
2 ways. Firstly, increased embryonic IL-6 exposure enhances SVZ NPC self-renewal and preserves
clonal multipotency in these precursor cells. Secondly, this study establishes that IL-6 interacts with
its receptor IL6R to uphold NPC levels and to defer neuronal differentiation. This evidence is valuable
to neuroscience research because it adds to the foundation for understanding the mechanisms that
control the size of NPC pools and their multipotency.
15
Figures adapted from Gallagher et al., 2013, p. 566, 572, 574.

Gallagher, D., Norman, A. A., Woodard, C. L., Yang, G., Gauthier-Fisher, A., Fujitani, M., Vessey, J. P.,
Cancino, G. I., Sachewsky, N., Woltjen, K., Fatt, M. P., Morshead, C. M., Kaplan, D. R., & Miller, F. D.
(2013). Transient maternal IL-6 mediates long-lasting changes in neural stem cell pools by deregulating
an endogenous self-renewal pathway. Cell Stem Cell, 13(5), 564-576. doi:10.1016/j.stem.2013.10.002
Summary by: Daniel Derkach
16
Summary of:
Increased Cerebral Metabolism After 1 Year of Deep Brain
Stimulation in Alzheimer Disease
Authors: Gwenn S. Smith, PhD; Adrian W. Laxton, MD; David F. Tang-Wai, MDCM, FRCPC;
Mary Pat McAndrews, PhD; Andreea Oliviana Diacomescu, PhD; Clifford I. Workman,
BS; Andres M. Lozano, MD, PhD, FRCSC.
PET imaging studies suggest that neural circuitry changes correlated with decreased
cerebral glucose metabolism leads to cognitive defects and neuropsychiatric symptoms
associated with Alzheimer’s Disease patients. A recent study investigating alternative
treatment methods based on this discovery used deep brain stimulation (DBS) to
stimulate the Fornix for 1 year resulting in sustained, increased cerebral glucose levels.
The authors investigated this study and predicted that increased glucose levels in
parietofrontal and hippocampal/parahippocampal-parietal networks would result from
DBS after 1 year, and that this increased glucose metabolism would be associated with
better clinical outcomes.

The sample consisted of 5 patients, who had all been taking a steady dose of
cholinesterase inhibitors for a minimum of 6 months. Two weeks after surgical
implantation of an electrode into the fornix, stimulators were activated, with settings
remaining constant for one year. PET was used to measure the functional connectivity
of the hippocampal and cortical networks, as well as to correlate changes in cerebral
glucose metabolism with patients’ cognitive and neuropsychiatric outcomes at baseline,
1 month and 12 months after DBS. ADAS-cog and QOL-AD assessed cognitive and
neuropsychiatric changes.
Major Results:
Both the mean and standard deviation of ADAS-cog and QOL-AD scores appeared
to worsen over time. PET scans identified a frontal-temporal-parietal-striatal-thalamic
network and a frontal-temporal-parietal-occipital-hippocampal network after 1 year of
DBS. High baseline metabolism in brain regions commonly affected by AD indicated
less global cognitive decline. These brain regions were also correlated with increased
metabolism after 1 year of DBS and less decline in ADAS-cog and QOL-AD scores. Low
baseline metabolism in brain regions less commonly affected by AD indicated less global
cognitive decline. These brain regions were also correlated with decreased metabolism
after 1 year of DBS and less decline in ADAS-cog and QOL-AD. Correlations with the
change in metabolism after 1 month of DBS were not significant.
Conclusions:
Increased cerebral metabolism was identified in cortical-subcortical and cortical-
hippocampal networks after 1 year of DBS, which correlated with increased cognitive
function and quality of life in patients. Activation of the frontal-temporal-parietal-striatal-
thalamic network suggests memory and other cognitive functions are affected by DBS
of the fornix. Improved functional activity in the frontal-temporal-parietal-occipital-
hippocampal network may be important for hippocampal input into the default mode
network that is often affected in AD patients. Since different baseline levels of glucose
metabolism in brain regions commonly or less commonly associated with AD were
observed, cerebral glucose metabolism measures could be used to predict DBS response
in patients or even as a technique for patient selection.
17
Smith, G.S., Laxton, A.W., Tang-Wai, D.F., McAndrews, M.P., Diaconescu, A.O., Workman, C.I.,
Lozano, A.M. (2012). Increased Cerebral Metabolism After 1 Year of Deep Brain Stimulation in
Alzheimer Disease. Archives of Neurology, 69, 1141-1148. doi:10.1001/archneurol.2012.590
Summary by: Vanessa Ferlaino

18
Summary of:
Neurofeedback and standard pharmacological intervention in
ADHD: A randomized controlled trial with six-month follow-up
Authors: Victoria Meisel, Mateu Servera, Gloria Garcia-Banda, Esther Cardo, Inmaculada Moreno
This study examined the efficacy of neurofeedback (NF) training in treating Attention
Deficit Hyperactivity Disorder (ADHD) in children and adolescents by comparing it to the
standard pharmacological intervention. Neurofeedback is an operant-conditioning technique
that trains participants to regulate their inattention and hyperactivity through feedback of
their neurophysiological signals, that are measured using EEG. Many studies have reported
that children with ADHD show abnormalities in electrophysiology such as increased frontal
theta activity and decreased beta activity, thus, NF primarily focuses on training participants
to regulate their theta and beta activity. As existent studies regarding NF and ADHD have
shown to be methodologically inadequate, this study was designed to overcome previous
limitations by including randomization, teacher and parent reports and follow-up data.
The study began with 63 recruited children that were of ages 7 to 14; as those with
comorbid disorders, IQ in ranges below 80, unwillingness to undergo randomization,
and taking medication were excluded, the final sample consisted of 23 children. Through
random selection, 12 of the children were chosen to participate in 40 sessions of NF
treatment, attending two 35-minute sessions per week, while 11 received a dosage of 1mg/
kg methylphenidate (standard ADHD pharmacological treatment) per day. The NF sessions
were presented as games such as puzzles or races, and participants were rewarded as
they increased their theta activity and decreased beta activity. Behavioural changes were
assessed at pre-treatment (PRE), post-treatment (POST), two-month (FU1) follow-up and
six month (FU2) follow-up using the following measures: ADHD rating scale, Oppositional
defiant disorder rating scale, Likert scale, and Weiss Functional Impairment Rating Scale.
Major Results:
As there were no significant differences in age, sex, IQ and subtype of ADHD, data
analysis was focused on comparing the results from the pre-assessment phase to the
three other assessments. The group that received the NF training showed significant
improvement in ADHD symptoms, functional impairment, academic performance,
and inattention according to parental reports; the teachers only reported medium
improvements in those categories, that were not considered significant. Hyperactivity and
oppositional defiant behaviour, however, showed less significant change as according to the
mothers and teachers. The methylphenidate group also showed significant improvements
in ADHD symptoms, hyperactivity, and inattention. Teachers also reported significant
reduction in oppositional defiant behaviour. The methylphenidate group, however, did not
show significant improvement in academic performance as reported by the mothers and
teachers. Thus, the most significant difference between the two groups was the change in
academic performance. The two and six-month post-treatment assessments showed that
the NF group maintained the achieved improvements, however, since not all participants
remained free of medication after treatment and because of the small sample size, these
results should be interpreted carefully until more advanced studies replicate the results.
Conclusions:
This study shows through practice and through learning how to change our brains,
it can be possible to rewire the neural circuits in our brain without the need of
pharmacological interventions. Once learned, these changes can be long lasting and
provide benefits in the long term. Although, it is not yet understood how neurofeedback
produces these long-lasting changes in the brain, and what molecular mechanisms
are involved, future research that is able to study the underlying mechanism of
neurofeedback might help us gain an even better understanding of the brain functioning.
19
Meisel, V., Servera, M., Garcia-Banda, G., Cardo, E., & Moreno, I. (2013). Neurofeedback and
standard pharmacological intervention in ADHD: A randomized controlled trial with six-month
follow-up. Biological Psychology, (94): 12-21.
Summary by: Floriana Ferri
20
Summary of:
Transient activation of specific neurons in mice by selective
expression of the capsaicin receptor
Authors: Güler, A. D., Rainwater, A., Parker, J. G., Jones, G. L., Argilli, E., Arenkiel, B. R.,
Ehlers, M. D., Bonci, A., & Palmiter, R. D.
The ability to remotely induce activity in neurons is essential in elucidating how a neuronal
population might interact within complex circuits. Manipulating neural activity in vivo in a precisely
controlled manner allows one to directly correlate behavioural responses. Various techniques have
been developed to this effect, such as optogenetics and genetically engineered receptors. However,
while these techniques have been incredibly successful in controlling neural activity in vivo, they
are not without their limitations – the former is both labour-intensive and invasive, and the latter
often has either low temporal resolution or lack of cellular specificity. In this paper, Güler et al
present a non-invasive model, where neural activity in genetically defined populations can be
induced directly, rapidly and reversibly by selective expression of capsaicin receptor TRPV1.
Triple transgenic mice lines DAT-TRPV1 and ePet-TRPV1 were created by crossing Trpv1
knockout mice (B6.129X1-Trpv1tm1Jul/J) to Gt(ROSA)26Sor-stopflox-Trpv1-ires-ECFP,
Slc6a3Cre or ePet–Cre mice. To confirm selective expression of TRPV1 and capsaicin-dependent
activity in DA neurons, whole-cell patch-clamp recordings were performed on VTA slices. DA
neurons were identified by their spontaneous firing rate and following 8 min of stable baseline
recordings, capsaicin was applied for 8 min. To measure electrophysiology in freely moving
mice, four-tetrode microdrives were implanted and, after two weeks recovery, recordings were
taken through Cheetah acquisition software (Neuralynx); baseline recordings identified putative
DA neurons, and capsaicin was administered following 10 min of stable baseline recordings.
Three tests for characteristic DA activity were performed. First, to monitor locomotor behaviour
following capsaicin administration, mice were placed in an arena and video-recorded via
Ethovision video analysis software (Noldus Information Technology) to track travelled distances
and consecutive beam breaks in activity chambers. Second, food consumption following 4 days
habituation, blocked access to food and then drug or vehicle administration was measured with
BioDAQ food monitoring system (Research Diets). Third, in a two-bottle capsaicin preference
test, mice were presented with two solutions with either almond or vanilla flavouring, where one
flavour was paired with capsaicin and the other with vehicle. Mice were first allowed access to
only one of the solutions during an 8 day association phase, and then they were given free access
to both solutions for 4 days; vehicle and capsaicin solution consumption were monitored.
Major Results:
Güler et al created a triple transgenic mouse line where the capsaicin receptor TRPV1 was
expressed under the control of dopamine transporter promoter (DAT-TRPV1). The authors
demonstrated that the receptor was selectively expressed in dopaminergic neurons and that
DA neural activity was capsaicin-dependent. Peripheral or oral delivery of capsaicin was
sufficient to rapidly and reversibly induce the characteristic DA locomotion and behavioural
responses in vivo. Further, Güler et al created a second transgenic line using R26-TRPV1
mice, expressed under the control of serotonergic enhancer region gene Pet1. Similarly,
TRPV1 was specifically expressed in 5-HT neuronal populations and capsaicin-dependent
activity induced rapid and reversible behaviours characteristic of 5-HT neurons. Successful
application of the genetic remote control technique to two distinct populations suggests that
this model is translatable across neural systems.
Conclusions:
Güler et al have presented a new non-invasive technique by which neural activity can be
specifically, reversibly and rapidly induced through selective activation of TRPV1, thereby
addressing some of the limitations of recent techniques. Since Güler et al demonstrated that
capsaicin could successfully induce transient activity in two neural populations, TRPV1
expression is a technique with the potential for widespread application. Addition of this
method to the repertoire of neural effectors may prove instrumental in elucidating complex
neural circuits.
21
Güler, A. D., Rainwater, A., Parker, J. G., Jones, G. L., Argilli, E., Arenkiel, B. R., ... & Palmiter, R.
D. (2012). Transient activation of specific neurons in mice by selective expression of the capsaicin
receptor. Nature communications, 3, 746.
Summary by: Sonja Ing
22
Summary of:
Blood Biomarkers for Brain Injury in Concussed Professional
Ice Hockey Players
Authors: Pashtun Shahim, MD; Yelverton Tegner,MD, PhD; David H. Wilson, PhD; Jeffrey
Randall, PhD; Tobias Skillback, MD; David Pazooki, MD, PhD; Birgitta Kallberg, BSc;
Kaj Blennow, MD, PhD; Henrik Zetterberg, MD, PhD
Current concussion evaluation protocols require physicians to determine a patient’s
recovery based on symptoms that only offer subjective information, and may not truly
reflect the extent of damage done to the brain. Therefore, a need for objective evaluation
of concussion and recovery assessment arises in sports with high rates of concussion
such as hockey. T-tau and neurofilament light were previously shown to indicate
neuronal damage in cerebrospinal fluid, but the invasive nature of lumbar punctures
would be incompatible with sports participation. T-tau, along with neuron-specific
enolase (NSE) and S-100 calcium-binding protein B (S-100B), previously shown to
increase in Olympic boxers after bouts with high rates of head strikes, were tested for in
the blood contents of athletes.
Professional ice hockey players in the Swedish Hockey League were included in the
study during the 2012-2013 season. In the preseason before a game, players from two
teams had blood samples taken before a friendly game, while one of the two teams also
had samples taken after a game without occurrence of head injury. During the season,
concussed players had blood samples taken 1, 12, 36, 48 and 144 hours after injury (most
concussions show observed recovery after 6 days), then when players were given return to
play status. Plasma and serum were separated. Plasma t-tau was measured using a novel
immunoassay while S-100B and NSE were measured on a modular E170 instrument. All
samples were measured using the same batch of reagents at the same time.
Major Results:
Plasma t-tau levels were shown to increase in hockey players who sustained a
concussion; up to 10 times the levels recorded in the preseason baseline sample, with the
highest levels being recorded 1 hour after the concussion incident. Serum S-100B levels
increased 1 hour post-concussion, but dropped back to baseline levels within 12 hours.
Serum NSE did not significantly increase after concussion in the players. Additionally,
serum S-100B and NSE, not plasma t-tau, increased after a game in which no head
injury occurred. These findings indicate that increases S-100B and NSE are not specific
to brain injury, especially in the case of NSE. Effect size was also analyzed in the study.
In more severe cases of concussion (those lasting 7 to 10 days, 10 days or more, and
those with loss of consciousness), t-tau 1 hour after concussion was higher compared to
individuals who returned to play within 6 days; this trend was insignificant, but 1 hour
t-tau measurements showed strong correlation with the length of concussive symptoms.
Additionally, individuals whose concussive symptoms lasted longer than 6 days had
greater concentrations of t-tau at 144 hours post-injury compared to those who returned
to play in under 6 days.
Conclusions:
In cases of sports-related concussion, blood t-tau measurements may serve as a
practical method of concussion diagnosis as well as determining return to play status
in athletes. However, other factors should also be taken into account for concussion
evaluation, and research on t-tau outside of neurodegenerative disease is still
preliminary, with this particular study also limited by low sample size and a high rate
of unpaired measurements. As some mechanisms of concussion are still unknown
and varied, subjective evaluation of symptoms is still required, and there may be other
potential biomarkers for concussions – the authors mention that neurofilament light,
which is CNS-specific like t-tau, may merit future investigation.
23
Shahim, P., Tegner, Y., Wilson, D.H., Randall, J., Skillbäck, T., Pazooki, D., Kallberg, B., Blennow,
K., & Zetterberg, H. (2014). Blood biomarkers for brain injury in concussed professional ice hockey
players. JAMA Neurology, 71(6), 684-692. doi: 10.1001/jamaneurol.2014.367
Summary by: Ricky Ng

24
Summary of:
Loss of mTOR-Dependent Macroautophagy Causes Autistic-like
Synaptic Pruning Deficits
Authors: Guomei Tang, Kathryn Gudsnuk, Sheng-Han Kuo, Marisa L. Cotrina, Gorazd
Rosoklija, Alexander Sosunov, Mark S. Sonders, Ellen Kanter, Candace Castagna, Ai
Yamamoto, Zhenyu Yue, Ottavio Arancio, Bradley S. Peterson, Frances Champagne,
Andrew J. Dwork, James Goldman, and David Sulzer.
Autism spectrum disorders (ASD) has no known origin and includes deficits in cognitive
abilities including communication skills, social interactions, and emotional control.
One common characteristic of the disorder is aberrant excessive cortical dendritic spine
growth and reduced pruning of postsynaptic glutamatergic synapses. Researchers
hypothesize mutations in genes that inhibit the mammalian target of rapamycin (mTOR)
kinase to be linked to ASD, as overactive mTOR is thought to lead to excessive synaptic
protein synthesis. mTOR also acts downstream to inhibit macroautophagy (autophagy) –
a process involved in neuronal pruning. They predict that the over activity of mTOR leads
to reduced autophagy contributing to ASD.
Representative Golgi images were used for postmortem human temporal lobe images.
Linear regressions, ANOVA and other statistical models were used for comparing
pruning over different time spans or between multiple groups. Novel object recognition
tests were used for social tests of mice, with more sniffing of a novel object representing
more social behaviors, as well as other social tests like three-chamber testing paradigm.
Confocal imaging was performed using Dil-labeled neurons that were labeled using a
Helios gene gun system. Mouse and human brain tissue were lysed with 1X RIPA buffer
supplemented with protease and phosphatase inhibitors and subject to western blot.
Mice strains were obtained from other labs and crossed to obtain desired mice ASD
phenotypes.
Major Results:
Researchers showed greater dendritic spine density and reduced spine pruning in
ASD patients in layer V pyramidal neurons in the superior middle temporal lobe, an
area associated with ASD due to its influence on social and communication networks in
the brain. By using Tsc2+/+ mice, mice with a functional Tsc2 gene that inhibits mTOR
activity, compared to Tsc2+/- mutated mice, ASD social phenotypes were observed as
well as greater spine density and reduced spine pruning, suggesting mTOR hyperactivity
is related to these ASD characteristics. When Tsc2+/- mice were given rapamycin,
a substance blocking mTOR kinase, spine pruning was corrected and spine density
was brought to control levels. mTOR hyperactivity was found to be related to reduced
autophagy activity, and activity could also be restored to control levels once rapamycin
was given. Finally, researchers tested Tsc2+/- mice that also had a loss of autophagy
proteins and therefore no autophagy (Atg7CKO) with rapamycin and found no correction
of pruning and dendrite density of these Tsc2+/-:Atg7CKO mice or just Ast7CKO mice,
like the corrections observed with Tsc2+/- mice.
Conclusions:
From these results, researchers concluded that hyperactivity in mTOR is related to
reduced downstream autophagy and both are found in mice with social ASD deficit
phenotypes. They determined that mTOR-regulated autophagy is required for postnatal
developmental spine pruning and that ASD spine density phenotypes can be corrected
with activation of autophagy. These results provide great insight into the relation of
dendritic spine pruning and autism, and may suggest ways of correcting these structural
differences in ASD patients.
25
Guomei, T., et al. (2014). Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic
Pruning Deficits. Cell Press, 83, 1131-1143
Summary by: Jessica Gosio
26
Summary of:
Locus-specific epigenetic remodelling controls addiction- and
depression-related behaviors
Authors: Elizabeth A Heller, Hannah M Cates, Catherine J Peña, Haosheng Sun, Ningyi Shao, Jian
Feng, Sam A Golden, James P Herman, Jessica J Walsh, Michelle Mazei-Robison, Deveroux
Ferguson, Scott Knight, Mark A Gerber, Christian Nievera, Ming-Hu Han, Scott J Russo,
Carol S Tamminga, Rachael L Neve, Li Shen, H Steve Zhang, Feng Zhang & Eric J Nestler.
Previous studies have been unable to show the mechanisms involved with the relationship
between chromatin modification and its regulation on drug- or stress-evoked plasticity for
behaviour. This study attempts to resolve this issue using the transcription factor FosB
residing in the nucleus accumbens, which is a key reward brain area for drug addiction and
stress. A specific methylation on histone H3 lysine 9 (H3K9me2 by histone methyltransferase
G9a) is a repressive histone modification that is crucial in the regulation of drug and stress
behaviour. However, the previous studies were limited to only show widespread effects of this
H3K9me2 at multiple loci. This study aims to develop stronger proof of linking epigenetic
modifications with one specific, using engineered transcription factors.
Two engineered transcription factors, zinc-finger proteins (ZFPs) or transcription activator-like
effectors (TALEs) made in silico to build to specific locus in the genome, allowing for strict regulation
of its transcription activity. This allows for the investigation for the gene of interest and a causal
observation between turning on a locus and possible plastic changes observed in drug or stress
behaviour. ZFPs and TALEs have also been applied in vitro for investigating epigenetic remodeling
associated with chromatin-modifying enzyme, as well as the investigation of cocaine-evoke and stress-
evoked epigenetic changes in vivo of the Fosb locus in the nucleus accumbens. Methods consist
of Western blotting, Immunohistochemistry, locomotor sensitization, viral-mediated gene transfer
and nucleus accumbens RNA isolation and qRT-PCR. For discovery of the regulation from these
transcription factors, cocaine doses and training to cause social avoidance was also conducted.
Major Results:
From the generation of the ZFPs transcription factors targeting the the specific locus of the
Fosb gene in vivo, the overall indicates the histone post-translational modification on the Fosb
promoter was controlled by ZFPs. Also, they were able to show bi-directional control of the Fosb
gene expression, which was found to be evident when acetylation on the Histone 3 Lysine 9
and 14 (H3K9/K14) promoted gene transcription activation, while H3K9me2 repressed gene
expression when looking at mRNA levels. Specificity of the locus was also evident, since there was
no other location of methylation enrichment in other parts of the nucleus accumbens extract.
After establishing the mechanism, regulation of reward behaviour by ZFPs demonstrated that the
mice that had the methylation H3K9 had the locomotor sensitization blocked, while the activation
epigenetic changes (e.g. acetylation) shown an accentuation of the sensitization effects from their
locomotion. On the other hand, mice that have the H3K9 methylation enrichment, analogous to
ones in depressed humans, shown to have less social interaction and higher anxiety compared to
the control mice that underwent the same subthreshold stimulus. This was shown through less
exploration time in the maze and conducting a chronic social defeat procedure.
Conclusions:
Two main engineered transcription factors were able to create epigenetic changes on the
Fosb promoter site, where Fosb-ZFP35-p65 was found to be associated to create acetylation
on the promoter site, thus allowing an increase in transcription and presented possible
correlation of this acetylation and cocaine-enhanced behaviour related to this Fosb gene.
On the other hand, repressive methylation by the Fosb-ZFP35-G9a was able to block
cocaine locomotion in mice, representing a dysregulation in cocaine sensitization. From
previous studies, Fosb gene was known for its role in pathophysiology in drug addiction for
both rodents and humans. By being able to study this gene and its epigenetic changes of it,
possible future treatment may become available once the foundation of epigenetic changes
is established for the understanding of its association with depression and addiction.
27
Heller, E.A. et al. (2014). Locus-specific epigenetic remodeling controls addiction- and depression-
related behaviour. Nat Neurosci, 17(12), 1720-1727. Received from http://www.nature.com/neuro/
journal/v17/n12/abs/nn.3871.html
Summary by: David Giang
28
Summary of:
Sleep deprivation prevents stimulation-induced increase of

levels of P-CREB and BDNF: Protection by caffeine
Authors: Ibrahim A. Alhaider, Abdulaziz M. Aleisa, Trinh T. Tran, Karim A. Alkadhi
Previous evidence has shown that sleep deprivation either before or after learning
impairs memory formation through the reduction of hippocampal activity and impaired
late long-term potentiation (L-LTP). The expression and activation of cAMP response
element binding protein (CREB) as well as other transcription factors are required for
protein synthesis to occur during L-LTP. The influx of calcium through the binding of
glutamate to the NMDA receptors will allow for the activation of calcium-calmodulin-
dependent protein kinase IV (CaMKIV), that will go on to activate CREB by way of
phosphorylation. In sleep-deprived individuals, CREB and brain-derived neurotrophic
factor (BDNF) expression levels are reduced in the hippocampus that will therefore
have implications to synaptic plasticity involving spatial learning task and induction of
LTP. In previous studies caffeine has been shown to have protective properties relating
to symptoms that correlate with neurodegenerative diseases. The researchers wanted
to investigate the protective properties of caffeine on learning and memory impairment
induced in sleep-deprived rats.
The researchers used radial arm water maze (RAWM), which is a spatial test that is a
combination of the radial arm task and the Morris water maze, in order to measure long-
term memory. Rats that were treated with caffeine were given the same dose that matched
the daily human intake; this treatment lasted for 4 weeks. Electrophysiological recordings
were obtain by way of population spike (pSpike) at the CA1 area in the hippocampus,
multiple high frequency stimulation (MHFS) was done to the Schaffer collaterals were used
in order to induce L-LTP. Five hours after L-LTP was induced in the hippocampal region,
the right hippocampus was removed to examine the molecular levels of P-CREB and BDNF
in the CA1 area of the hippocampus by way of an immunoblot analysis.
Major Results:
The number of error committed by the rats that were treated with caffeine before
the onset of sleep deprivation in RAWN task was reduced, showing that the caffeine
treatments lessen the impairment of long-term spatial memory in rats with sleep
deprivation. When L-LTP was induced, it was found that the magnitude of the sleep-
deprived rats treated with caffeine was similar to that of the rats that were not sleep-
deprived, showing that the caffeine may have some protective effect in sleep-deprived
rats. When examining the molecular expression of P-CREB, it was shown that the sleep-
deprived rats treated with caffeine had increase levels of P-CREB compared to the just
sleep-deprived rats not treated with caffeine, suggesting that a decrease of P-CREB could
be an explanation to the reduction of L-LTP in sleep deprivation. The levels of BDNF in
the sleep-deprived rats treated with caffeine were similar to the levels seen when no sleep
deprivation occurred
Conclusions:
The researchers showed that impaired learning and memory in sleep-deprived animals
can be due to the reduced levels of P-CREB and BDNF that are important in L-LTP. They
showed that caffeine was able to maintain the levels of P-CREB and BDNF, in sleep-
deprived rats, similar to that of rats that were not sleep-deprived. When A1 receptors
are activated through adenosine binding, they will block the release of glutamate
thereby preventing the induction of L-LTP. Caffeine is thought to block the A1 receptors,
explaining the neuroprotective effects as well as suggesting that adenosine have a
potential key role in sleep.
29
Ibrahim A. Alhaider, Abdulaziz M. Aleisa, Trinh T. Tran, Karim A. Alkadhi. “Sleep deprivation prevents
stimulation-induced increase of levels of P-CREB and BDNF: Protection by caffeine “ Molecular and
Cellular Neuroscience 46 (2011) doi:10.1016/j.mcn.2011.02.006 Published online 19 Feburary 2011
Summary by: Akua Obeng-Dei

30
Summary of:
Investigating the long-term effect of subchronic phencyclidine-
treatment on novel object recognition and the association
between the gut microbiota and behavior in the animal model of
schizophrenia
Authors: B. Pyndt Jørgensen, L. Krych, T.B. Pedersen, N. Plath, J.P. Redrobe, A.K. Hansen, D.S.
Nielsen, C.S. Pedersen, C. Larsen, D.B. Sørensen
Phencyclidine (PCP) is an NMDA receptor antagonist that results in a schizophrenia-
like phenotype in rodents when subjected to subchronic PCP (subPCP) treatment. subPCP
treated rats are thus used as a model for studying schizophrenia, showing cognitive
deficits and increased locomotor sensitivity in response to acute PCP (aPCP) treatment –
traits characteristic for schizophrenia. Variance has been reported in this model and may
be resulting from variations in gut microbiota (GM) due to modulation of the microbiota-
gut-brain axis (mGBA). Accordingly, GM has been associated with memory performance
and locomotor activity.
The purpose of this study was to examine the duration of subPCP-induced cognitive
impairment and furthermore to study the effect of subPCP on gut microbiota in
association with behavior.
Rats were treated with PCP for one week (and control group with saline water) followed
by one week of washout. The rats were then tested in novel object recognition test (NOR)
to study their spatial memory at 0, 3, or 6 weeks after washout. Fecal samples were
obtained after NOR for genetic analysis. Next, the rats (the control group inclusive) were
administered aPCP prior to testing in locomotor activity assay (MOTR) to study their
locomotor sensitivity. These experiments were repeated with rats that were additionally
administered ampicillin in order to monitor any variance caused by differences in GM.
Major Results:
It was found that subPCP had a negative impact on memory performance in NOR, and
this effect lasted for 3 weeks. After 6 weeks, the effect had subsided and the memory
performance was similar to the control group. Consistent with earlier studies, the subPCP
increased locomotor activity in response to aPCP, and this increased activity was still
evident 6 weeks after washout.
GM analysis showed a difference between subPCP treated and control groups when
restricted to bacteria present in at least 50% of the samples. A significant correlation
between GM profile and memory performance was evident. Interestingly, antibiotic
reduction of GM rescued the cognitive deficits in subPCP treated rats and their memory
performance were similar to the control group, while the performance of the vehicle
treated group was not affected by antibiotics. Ampicillin treatment did not affect
locomotor activity.
Conclusions:
- Loss of cognition in subPCP-treated rats was evident for 3 weeks, why it is
recommended that the schizophrenic rat model is used up to 3 weeks after subPCP
when studying the effects of novel drugs on NOR.
- GM profiles correlates to cognition, and antibiotic reduction of GM neutralizes the
subPCP induced loss of memory. A difference was observed in the GM of rats
subjected to subPCP. Together these data indicate that the changes in GM is caused
by the subPCP-treatment, and that the subPCP-induced memory deficits are
mediated through changes in GM.
These findings are relevant in regarding to development of new drugs in treating

schizophrenia, as it allows researchers to make better use of the schizophrenic rat model
as well as taking the variance caused by GM into account.
31
Jørgensen, B. P., Krych L., Pedersen T. B., Plath N., Redrobe J. P., Hansen A. K., … Sørensen D. B.
(2015) Investigating the Long-term Effect of Subchronic Phencyclidine-treatment on Novel Object
Recognition and the Association between the Gut Microbiota and Behavior in the Animal Model of
Schizophrenia. Physiology & Behavior, 141, 32-39.
Summary by: Mie Andersen

32
Summary of:
Schizophrenia Susceptibility pathway Neuregulin 1-ErbB4

Suppresses Src Upregulation of NMDA receptors
Authors: Graham M Pitcher, Lorraine V Kalia, David Ng, Nathalie M Goodfellow, Kathleen T Yee,
Evelyn K Lambe & Michael W Salter
NMDA glutaminergic receptors associated with synaptic plasticity may also play an
important role in the development of Schizophrenia. Previous research suggests that
hallucinations and cognitive dysfunction in Schizophrenic patients stem from the
reduced activity of these receptors. At a cellular level, NMDA receptors involved in
synaptic plasticity depend on Src tyrosine kinase mediated phosphorylation to enhance
receptor activity. Schizophrenic patients display reduced levels of phosphorylated NMDA
receptors compared to normal individuals. Hyperactive Nrg and Erbb4 genes, potential
hallmark genes for schizophrenia, are hypothesized to suppress NMDA receptor activity
and block LTP. Nrg produces the ligand NRG1, Erbb4 produces the receptor ErbB4, and
the two couple to elicit downstream signaling pathways. This study attempted to link
reduced NMDA receptor activity to the presence of these genes.
Adult rat and mouse brain slices from the hippocampus and prefrontal cortex were
studied. In the hippocampus, Schaffer Collateral fibers were stimulated and whole cell
recordings were observed in the CA1 region. In the prefrontal cortex, corticocortical
neurons in layers II and III were stimulated, and whole cell recordings were observed
in pyramidal neurons of layer V. Antagonists were used to block AMPA and GABAa
receptors in order to isolate EPSC recordings only from the NMDA receptors. To
determine specific effects of NRG1-ErbB4 ligand-receptor signaling on NMDA receptors,
both Src-enhanced NMDA receptors and Src-independent NMDA receptors (controls
cells) were compared. To activate Src in the tyrosine kinase-dependent NMDA receptors,
phosphopeptide, EPQ(pY)EEIPIA was administered intracellularly. NRG1beta, a soluble
form of NRG1, was then added in excess to both receptor samples.
Before adding the NRG1beta, cells with NMDA receptors and active Src tyrosine
kinase displayed markedly higher levels of EPSPs compared to NMDA receptors without
active Src. When NRG1beta was added to these neurons, the activity levels of the Src-
independent neurons remained the same while the Src-dependent cells displayed levels
of activity that matched the control cells. NRG1beta did not, however, reduce the activity
of Src-dependent NMDA receptors below the level of activity observed in control cells.
The presence of the ErbB4 receptors already in the cells was necessary for NRG1 to
facilitate its suppressive effect. When investigating knockout mice without the Erbb4
gene, NRG1beta did not have a place to bind, and did not elicit an effect on the Src-
dependent NMDA receptors. Similar results were found in neurons of the hippocampus
and prefrontal cortex.
Elevated activity of Src tyrosine kinase-dependent NMDA receptors appeared to

be a critical component in proper cognitive function. This study concluded that excess
NRG1 suppresses this process. The proposed mechanism of this suppression included
NRG-1/ErbB4 signaling inhibiting the catalytic activity of the Src kinase, thus preventing
phosphorylation of the NMDA receptor and reducing downstream pathways including
long-term potentiation. This could explain some of the positive symptoms, such as
cognitive disarray and hallucinations displayed by Schizophrenic patients, but mapping
out the precise molecular pathway requires additional research. Understanding the
physiological mechanism for Schizophrenic symptoms can help provide further insight
into more effective treatment methods. This study suggests that seeking ways to
counteract the suppressed Src-dependent NMDA receptor activity should be the target of
future research.
33
Sources for images: http://www.nature.com/nm/journal/v17/n4/images/nm0411-425-F1.jpg

Pitcher G.M, Kalia L.V, Ng D, Goodfellow N.M, Yee K.T, Lambe E.K, Salter M.W. (2011).
Schizophrenia susceptibility pathway neuregulin 1-erbb4 suppresses Src upregulation of NMDA
receptors. Nature Medicine. 17, 470-478.
Summary by: Madli Vahtra
34
Summary of:
Dopamine D1 and D5 Receptors Modulate Spike Timing-
Dependent Plasticity at Medial Perforant Path to Dentate
Granule Cell Synapses
Authors: Kechun Yang and John A. Dani
Previous studies have shown a dopaminergic influence on the dentate gyrus facilitating
synaptic plasticity in the hippocampus—specifically in spatial learning and memory. However,
the actual mechanism of how dopamine regulates spike timing-dependent LTP (tLTP) is
unknown. Previous attempts have used whole cell patch-clamp protocols that have disturbed the
intracellular environment rendering it difficult to understand downstream mechanisms initiated
by dopamine receptors. It is known DA1 and DA5 receptors are found in the hippocampus, which
Yung and Dani showed are central to tLTP. Yung and Dani suggest that since tLTP is the synaptic
strengthening between pre and postsynaptic neurons dependent on time delay between firing,
understanding the role of dopamine—a neurotransmitter important in detecting salient events
and reward—and the hippocampus—important for spatial information—are important in linking
reward and salience to the external environment, mediated by DA1 and DA5 receptor activation.
Hippocampal slices of genetically variant mice (either DA1, DA5 or Kv4.2 (potassium channel) knockouts)
and wild type mice were used. Using perforated patch-clamp techniques, the intracellular composition of cells
could be maintained, allowing Yang and Dani to look at cellular mechanisms. It also provided a baseline
recording, important in STDP ratio. A bipolar electrode inserted into the perforant pathway caused EPSPs
in presynaptic neurons, either before or after postsynaptic action potentials (at 100 Hz) with variable
time delays in between. This allowed for calculation of the STDP ratio—the “average peak amplitude of 40
consecutive EPSPs…divided by average peak of 20 consecutive EPSPs during baseline”. The role of DA1
was studied using DA1 receptor inhibitors or agonists, which bathed the granule cells. The STDP ratio was
calculated in both scenarios implicating the role of DA1 and DA5 receptors in tLTP.
Major Results:
The DA1 receptor inhibitor showed a negative STDP ratio, which was interpreted to be tLTD (timing-
dependent LTD) whereas DA1 receptor agonist had the opposite effect and led to tLTP. Furthermore,
DA1 receptor activation when presynaptic neurons were stimulated 30 ms prior to postsynaptic
neurons, the STDP ratio was above baseline, thus indicative of LTP. Yet, DA1 receptor inactivation for
the same conditions causes tLTP but to a lesser extent. Furthermore, it is the only condition in which
DA1 receptor inactivation can cause tLTP, otherwise tLTD is always observed. Moreover, when DA1
receptors are activated, tLTP can occur over a larger time interval—regardless of which neuron fires first,
pre or postsynaptic. The marked difference in DA1 receptor activation vs. inactivation occurs within
10ms of either neuron firing first; inactivation resulting in lowest STDP ratio (greatest extent of tLTD).
Furthermore, when the same procedure was conducted on 9 DA1 knockout mice and 9 DA5 knockout
mice, seven of the nine in the former experienced tLTD whereas all nine experienced tLTD in the latter.
Since DA1 and DA5 receptors cannot be accurately distinguished, it can only be concluded that both
these receptors are important in tLTP, and that DA5 is more important. The importance of DA1 and DA5
on downstream effectors was tested using Kv4.2 knockout mice (lack IA potassium channel current) and
it was observed that lack of this subunit and DA1 inactivation resulted in tLTP but to a lesser degree than
solely DA1 receptor activation. Thus, DA1 probably has some role in turning off IA potassium channels,
which facilitates tLTP. They showed the inactivation of the IA potassium channel might be linked to the
MAPK-MEK cascade.
Conclusions:
One of the major conclusions drawn in this paper is that dopamine is an important facilitator
of timing-dependent LTP. The DA1 and DA5 receptors in the granule cells of the hippocampus are
receptive and activated by dopamine, a neurotransmitter important in stimulus salience and rewards.
The hippocampus gets input from the entorhinal cortex providing spatial information; thus, there can
be a link between drug tolerances learned to be associated with the environment. Furthermore, LTP
is a mechanism important in learning and memory, thus dopamine facilitates spatial learning and
memory in the hippocampus, and increases the time frame for the potentiation to occur. A clinical
implication this study has is the role of DA1 and DA5 receptors in memory-related neurodegenerative
disorders, such as in Parkinson’s disease. Lastly, this paper provides insight to possible mechanisms
of dopamine modulted tLTP in the hippocampus. Previously it was known that it is possible dopamine
influences synaptic strength at the hippocampus, but now there is a better understand of the
receptors involved and the possible mechanisms (blocking of potassium A-currents).
35
Yang, K., & Dani, J.A. (2014). Dopamine D1 and D5 Receptors Modulate Spike Timing-Dependent
Plasticity at Medial Perforant Path to Dentate Granule Cell Synapses. J Neurosci, 34(48), 15888-
15897. doi:10.1523/JNEUROSCI.2400-14.2014
Summary by: Pranay Siriya

36
Summary of:
Conditioned same-sex partner preference in male rats is
facilitated by oxytocin and dopamine: Effect on sexually
dimorphic brain nuclei
Authors: Rodrigo Triana-Del Rio, Miriam B. Tecamachaltzi-Silvaran, Victor X. Diaz-Estrada, Deissy
Herrera-Covarrubias, Aleph A. Corona-Morales, James G. Pfaus, Genaro A. Coria-Avila
This research focused on development of same-sex social and sexual preference in
male rats. Researchers hypothesized that male cohabitation with rats injected with
oxytocin, quinpirole (D2 agonist) or oxytocin and quinpirole could result in same-sex
partner preference and that neither drugs nor cohabitation alone could yield equivalent
preference. Particular importance was placed on dopamine receptor and oxytocin activity
due to past studied enhancement effects on social attachment. Knowledge of social and
sexual preference in relation to reduced sizes in the sexually dimorphic nucleus of the
medial preoptic area (SDN-POA) as well as the supraoptic nucleus of the hypothalamus
(SON) was also explored.
Male rats were injected with saline, quinpirole, oxytocin, both oxytocin and quinpirole
or nothing at all during either cohabitation with another male rat or alone. Injected and
non-injected rats experienced three 24-hour trials of cohabitation with an almond-scented
male (conditioned stimulus). Social and sexual preference was measured after the last trial,
drug-free (to ensure outcomes were based solely on learning). Subjects later chose between
their familiar scented male and an unscented, sexually receptive female. Preference was
measured in terms of mounts, contacts, genital investigations, intromissions, ejaculations,
non-contact erections and female-like solicitations. After the first experiment, subject
brains were processed for Nissl dye (stained with cresyl violet) to aid in measuring SDN-
POA and SON sizes. Digital photographs enabled software to calculate nuclei areas.
Major Results:
Male rats that received quinpirole, oxytocin or no injection without cohabitation showed
preference for females (higher visit incidence, more body contact, mounting, non-contact
erections and olfactory investigations). Saline injections paired with male cohabitation also
resulted in opposite-sex female partner preference. Rats who received quinpirole, oxytocin
and quinpirole and oxytocin together, all with cohabitation, displayed same-sex preference
for their male partner in terms of increased visit frequency and duration, shorter contact
latency, as well as more body contact, olfactory investigations, female-like solicitations,
and non-contact erections with the male partners. No significant findings emerged from
SDN-POA and SON measurements, as same-sex preference was not seen to correspond
with the sizes of these nuclei. Males who received quinpirole and oxytocin together with
cohabitation, as well as those who received only oxytocin with and without cohabitation
had the smallest SDN-POA areas. Rats who received quinpirole with cohabitation and both
quinpirole and oxytocin with cohabitation had the largest SON areas. In essence, the most
significant findings suggest that with increased dopamine receptor and oxytocin activity,
conditioned same-sex social/sexual partner preference can develop when accompanied by
cohabitation, but this did not correlate with decreases in SDN-POA and SON areas.
Conclusions:
This research indicates that conditioned same-sex social and sexual partner preference
in supposed formerly heterosexual male rats can develop when male cohabitation occurs
along with injections of quinpirole, oxytocin, or both, showing that varying neurotransmitter
dynamics can have significant consequences on the effects of conditioning. With cohabitation
and enhanced oxytocin, quinpirole and both oxytocin and quinpirole, learning was maintained
and expressed three days after training, without drugs, showing that stimulus-response
training paired with specific heightened neurotransmitter activity can result in enhanced
learning. This study also demonstrates the complexity of the interaction between context and
neurotransmitters in sexual preference development.
37
Triana-Del Rio, R., Tecamachaltzi-Silvaran, M. B., Diaz-Estrada, V. X., Herrera-Covarrubias, D.,

Corona-Morales, A. A., Pfaus, J. G., & Coria Avila, G. A. (2015). Conditioned same-sex partner
preference in male rats is facilitated by oxytocin and dopamine: Effect on sexually dimorphic brain
nuclei, Behavioural Brain Research, 283.
Summary by: Alana Brown

38
Summary of:
Emotional learning selectively and retroactively strengthens
memories for related events
Authors: Joesph E Dunsmoor, Vishnu P Murty, Lila Davachi & Elizabeth A. Phelps
Previous research suggest that after a memory has been encoded, it can be further
strengthened at a future time by a novel event such as an increase in arousal or stress.
It has been postulated that unstable memories are tagged for consolidation at a later
time by long-term potentiation (LTP) via a synaptic tag and capture mechanism in
the hippocampus. However, the specificity in the strengthening of previously encoded
memories has not been clearly elucidated. Dunsmoor et al.’s study employs human
participants to investigate the possibility of specifically enhancing a previously encoded
weak episodic memory by presenting information related in context to the previously
encoded memory in an amygdala dependent manner.
In the pre-conditioning phase of the experiment, participants were shown 60
photographs using a stimulus presentation software and asked to classify them into the
basic categories of tools or animals. Then participants were put through a fear conditioning
trial where an uncomfortable shock is paired with certain photograph presentations (either
tools or animals) that the participants were not previously aware of. Following that, in a
post-conditioning phase, participants were again shown 60 photographs and asked to
classify them similarly to the pre-conditioning phase. In a second part of the experiment,
subjects were given a recognition task using the originally presented photographs either
immediately after the post-conditioning phase or after a 6 or 24 hr delay.
Major Results:
A significant result was found in the 24 hour delay condition. Specifically, memories
that were conceptually related to the conditioned stimulus from the pre-conditioning
photographs were enhanced but not other memories encoded at the same time. This
suggests that in the pre-conditioning phase, weak memories formed of the photographs
presented, later, if emotionally relevant information is presented, it will retroactively
strengthens memories of previously encoded photographs that are related to the
emotional conditioning. This retroactive enhancement of memory did not occur in the 6
hr delay period condition or the immediately after post-conditioning phase, suggesting
that this enhancement of previously encoded memories via fear conditioning requires
some time for consolidation. Dunsmoor et al. suggests that during the preconditioning
task, encoding occurred while leaving a tag in the hippocampus, fear conditioning via the
amygdala modulates the tag in the hippocampus and can enhance past memories related
in context to the conditioning stimulus.
Conclusions:
This study suggests that previously encoded weak memories can be strengthened by a
related future experience. The strengthened past memory is conceptually relevant to the
future stimulus and other memories coded at the same time are not enhanced. These
findings may contribute to the field of neuroscience globally: if emotional events can
selectively enhance memories of experiences that we’ve had in the past, this mechanism
may be related to intrusive memories and overgeneralizations of fear memories that may
in turn lead to stress related neurological disorders. This is a field that requires future
empirical research.
39
Joesph E Dunsmoor, Vishnu P Murty, Lila Davachi & Elizabeth A. Phelps. “Emotional learning
selectively and retroactively strengthens memories for related events” Nature (2015) doi: 10.1038/
nn.14106 Published online 21 January 2015.
Summary by: Chuqi Sandy Wang

40
Summary of:
Effects of Resveratrol on Memory Performance, Hippocampal
Functional Connectivity, and Glucose Metabolism in Healthy
Older Adults
Authors: A. Veronica Witte, Lucia Kerti, Daniel S. Margulies, and Agnes Floel
Resveratrol is a plant-based polyphenol often used as a calorie restricted mimetic
which are thought to slow the process of neurodegeneration. The compound is found
in foods such as red grapes therefore found in wine, as well as peanuts and Japanese
knotweed. The effects of resveratrol have been tested on many animal models with the
following conclusions: helps reduce oxidative damage, reduce proinflammatory molecules,
reduce blood pressure (by a means of improved vascularity) and potentially alters gene
expression. In mouse with AD, resveratrol has been noted to deter the learning and
cognitive deficits that is associated with the disorder. However, aside from short-term
studies on inflammation and glucose digestion, the effects of resveratrol supplementation
have not been investigated with regards to long term effects on memory and learning.
Initial screening of individuals via telephone interviews. Overweight (but not obese)
participants were targeted. Baseline visits consisted of psychological and medical
examinations using standardized tests such as the Mini Mental State Examination and
Beck’s Depression Inventory. There were 23 subjects in both the control and treatment
group that were randomly chosen—the control subjects were matched with treatment
subjects according to age, sex, and body mass index. Treatment group was given two
13-week stocks of resveratrol capsules, amounting to 26 weeks of supplementing
with resveratrol 4 times a day. Control group was given two 13-weeks supply of
indistinguishable placebo capsules. Memory assessments (via the Auditory Learning Verbal
Test), neuroimaging (using MRI and diffusion tensor imaging) anthropogenic data and
blood content were evaluated before and after the intervention trial.
Major Results:
The group with resveratrol supplementation was able to significantly improve their
memory retention scores from baseline testing. Increases in functional connectivity
within the hippocampus to various brain regions were observed. Improvements in
memory retention coincided with increases in functional connectivity in the medial pre
frontal cortex which also happened to negatively correlate with decreases in HbA1c.
Leptin levels increased for the resveratrol treatment group whilst they decreased for the
placebo group.
Conclusions:
Resveratrol has the ability to enhance functional connectivity in the hippocampus
demonstrating it’s beneficial effects on memory and learning as well as it’s ability to
lower glucose markers in the blood. It has been known that elevated glucose levels have
harmful effects on the brain thus further research could indicate whether it was the
more efficient glucose metabolism that contributed to the cognitive improvements. This
study suggest resveratrol as a potential use to alleviate the effects of age-related brain
deterioration.
41
Witte, V., Kerti, L., Margulies, D., & Floel, A. (2014). Effects of Resveratrol on Memory Performance,
Hippocampal Functional Connectivity, and Glucose Metabolism in Healthy Older Adults. The Journal
of Neuroscience, 34(23), 7862-7870.
Summary by: Vanessa Bracaglia

42
Summary of:
Deletion of a-neurexin II results in autism-related behaviours
in mice.
Authors: J Dachtler, J Glasper, RN Cohen, JL Ivorra, DJ Swiffen, AJ Jackson, MK Harte, RJ Rodgers

and SJ Clapcote
Autism is a widely known cognitive disorder that is characterized by the lack of social
engagement, communication and language progression, possibly due to various biological
causal factors. Recently, it was found that two unrelated autism individuals carried mutations
on exon 1 of the NRXN2 gene that synthesizes the synaptic adhesion protein a-neurexin II
(Nrxn2a). Neurexins are responsible for connecting neurons, constituting various effects. They
can bind molecules for pre-synaptic release or bind neuroligins of the post-synaptic neuron to
alter NMDA, AMPA or GABAergic receptors, depicting inhibitory or excitatory properties of the
cell. It was hypothesized that Nrxn2a knockout (Nrxn2a KO) mice would result in autism-
associated behaviour, suggesting synaptic dysfunction as a possible cause for this disorder. For
experimental purposes, only Nrxn2a expression was eliminated by mutation on the first exon of
the NRXN2 gene, and the B-neurexin II was still allowed expression.
Three different types of mice strains (Nrxn 1 heterozygous KO, Nrxn2 homozygous KO and
Nrxn3 wild-type) were continuously outbred to the C57BL/6NCrl strain to achieve Nrxn2a
KO heterozygotes that are wild-type (WT) at Nrxn1 and Nrxn3. This F1 generation was then
intercrossed to achieve WT or Nrxn2a KO progeny. Mice were allowed to develop past 8 weeks of
age before being used for experimental behavioural testing. Such tests included the open field
test, emergence test, social interaction testing and novel conspecific exploration. Quantitative
RT- PCR analysis and western blot analysis were done afterwards to quantify noticeable
differences from various genes expressed in the frontal cortex and hippocampus that interact with
a-neurexin either at the pre-synaptic/ post-synaptic level.
Major Results:
Nrxn2a KO mice were placed in a three-chambered assay to test for sociability, with a choice
of interacting with a novel mouse or an empty wire cage. The Nrxn2a KO mice showed much
less interest in terms of engagement with the unfamiliar mouse, suggesting social deficits, which
is a symptom of autism. Moreover, upon introduction of a novel mouse in addition to the first
stranger mouse, the Nrxn2a KO had failed to preference to either. The WT mice realized they have
interacted with the old stranger mice and preferred the new one. This suggests that Nrxn2a KO
mice may have reduced social memory of what they have observed. To determine anxiety levels
in mice, the open field test allowed mice to explore a luminous open arena. Graphs showed that
Nrxn2a KO mice displayed more thigmotaxis (contact with the wall) than wild-type mice, and
spent elongated periods in the peripheral zone. In the emergence test, Nrxn2A KO mice needed a
lengthier amount of time to emerge from the small enclosure to luminous open arena, suggesting
higher aversion to a new stimulus. These last two tests measured state anxiety in mice, which
is a temporary emotional response as a reflex to a danger signal. The Nrxn2a KO mice viewed
the open bright space as more of a threat than the WT companions did, feeling more anxious
to approach the different environment. Levels of aversion can be correlated with anxiety, but
the causality has not yet been determined. Western blotting showed that Munc18-1, a protein
engaging with syntaxin-1 during presynaptic vesicular release, was drastically reduced in the
Nrxn2a KO hippocampus. This altered pathway is one of many, and may have led to autistic-
related behaviours.
Conclusions:
Only some core symptoms of autism such as decreased sociability with conspecifics and
avoidance or latency to explore were shown, while other symptoms were not displayed/tested
for. The procedures during this experiment were able to measure social novelty interactions and
brief anxiety levels. However other symptoms such as cognitive deficiency, repetitive behaviours
or language impairments were not observed/ could not be measured. Such an experiment done
with Nrxn2a KO mice gives insight into further exploration for autism, a rather complex genetic
neurodevelopmental disorder that may be linked to various genes. Deciphering the biological
basis of autism by its genetic and perhaps, non-genetic factors would be of great contribution
towards those who have it, especially in school settings.
43
Dachtler, J. et al. (2014). Deletion of a-neurexin II results in autism-related behaviours in mice.

Translational Psychiatry, 4(484), 1-8. Retrieved from http://dx. doi:10.1038/tp.2014.123
Summary by: Vivian Liu

44
Summary of:
Alcohol consumption, drinking patterns, and cognitive function
in older Eastern European adults
Authors: Pia Horvat, Marcus Richards, Ruzena Kubinova, Andrzej Pajak, Sofia Malyutina, Sergey
Shishkin, Hynek Pikhart, Anne Peasey, M.G. Marmot, Archana Singh-Manoux, Martin Bobak
Individuals with dementia show decreased cognitive function, and have been observed
to show predictors in their cognition prior to actually having dementia. Observational
studies have shown that people who drink moderately not only display increased
cognitive test scores, but also decrease the risk of having dementia when older. Although
some would argue that alcohol decreases overall cognitive function, a decrease is only
observed when individuals engage in binge drinking. No studies have been conducted to
show if moderate alcohol consumption actually causes increases in cognitive function,
and decreases in risk of dementia.
Participants, aged 45 – 69, from multiple countries where randomly chosen to take part
in this study after taking part in the Health, Alcohol and Psychosocial Factors in Easter
Europe (HAPIEE) study, where they had to self-report their alcohol consumption (amount
and frequency), health, and take part in a physical examination (2002-2005). They later
had to take cognitive tests. Nurses were trained in administering the test while scores were
later assessed by scientists. In alcohol consumption a scale was developed and participants
were placed on a discrete spectrum of non-drinkers to problem drinkers. The test scores
were compared with drinking habits. The same individuals were later re-examined and
tested for the same variables as originally tested (2006-2008). Males and females where
studied separately.
Major Results:
Males tend to compose a larger proportion of the binge and problem drinking
populations. Of the individuals studied 58% remained in the same categorization
for alcohol consumption amounts, and 44% were in the same category for alcohol
consumption frequency. In men alcohol consumption did not significantly correlate
with cognitive scores when confounders were considered, but lower cognitive scores in
non-drinkers were observed in comparison to baseline scores (moderate- continuous
drinkers). For women non-drinkers had lower cognitive test scores. Moderate drinking
scores were better than those who drank less. For changes in alcohol consumption men
who stopped drinking scored significantly lower than those who continued.
Conclusions:
Quantity and frequency of drinking in men did not show any significant data, but
women who were moderate drinkers showed increases in cognition. No significant data
was observed to show an overall decrease in heavy drinkers. In the scope of this study
better cognition is observed in those who continue to drink in comparison to those who
either stop or didn’t drink in the first place.
45
This paper claims that those who drink moderately and continue to drink alcohol steadily have increased cognitive
function. Each graph displays a different cognitive test for each of the specified drinking conditions. These results are the
standardized cognitive scores found in 6,608 men. Those who quit drinking and those who do not drink at all have the
lowest scores. Stable drinkers are the baseline Reversed scores are used for all graphs.
Horvat P., Richards M., Kubinova R., et al. “Alcohol consumption, drinking patterns, and cognitive
function in older Eastern European adults” 2014. Neurology, 84, 287-295
Summary by: Bernie Longange
46
Summary of:
The artist emerges: Visual art learning alters neural structure
and function
Authors: Schlegel, A., Alexander, P., Fogelson, S. V, Li, X., Lu, Z., Kohler, P. J., Riley, E., Tse, P. U.,
Meng, M.
To disambiguate ambiguous stimuli, the visual modality performs Bayesian inferences
from previous subjective incidences, allowing for optical illusions and subjective
experiences. However, representational artists must overcome these processes to produce
works that are true to the external image, and translate their thematic perspectives to
a medium, be it a painting or drawing. Once perceived, an artist has improved skills in
honing the dorsal stream more associated with spatial information and motor abilities,
enabling for motor actions to capture perceived scenarios in painting/drawing. In this
work, the neural correlates to these processes, discounting of Bayesian inferences,
original cognition, and higher activation of the dorsal processing stream were examined
to investigate processes within cultivating representational drawing/painting skills.
17 undergraduates enrolled in an 11-week introductory course about observational
drawing/painting (experimental) and 18 undergraduates in an intensive program requiring
problem-solving for fixed solutions, as opposed to open ones required of creativity, (control)
were randomly selected. Both groups did not discernibly differ in gender, handedness, age
(18-22 years), and vision, but these parameters were not tightly controlled due to the nature
of the selection process. To measure progress in artistic abilities, 30-minute Torrence Tests
of Creative Thinking Figural Form A (TTCT) were administered before and after the course.
Furthermore, 4 monthly fMRI and DTI sessions coupled to 2 behavioral tasks, one of which
required perceptual abilities and another artistic creativity, were administered to measure
changes in brain activity and changes in abilities between the two groups.
Major Results:
TTCT indicated significant improvement of divergent thought process, system/process
modeling, and depiction of intricate, rich, salient imagery within individuals of the
experimental group compared to control. Of these, skills associated with modeling themes
through different paradigms, such as storytelling, correlated significantly with decreased
fractional anisotropy of white matter in prefrontal regions from DTI scans. Interestingly,
perceptual acuity neither improved nor diminished in the experimental group.
From the monthly DTI and fMRI sessions, the experimental group exhibited
improvement in creative cognition and motor skills for gesture drawing. To expound,
statistical analyses indicated no correlation between increased creative cognition with
increased skill in fine motor movements.
Lastly, throughout the duration of the study, the initially absent differences in brain
activity related to the monthly artistic tasks indicated increasing neural activity in the
right anterior lobe of the cerebellum in the experimental group, whilst overall neural
activity levels did not change significantly compared to control. Upon analyses, this
differential neural activity in the right cerebellum was positively correlated with increased
technical skills in complex, motor control of the upper limbs for drawing/painting.
Conclusions:
Neural circuitry involved in executing a creative action has been shown to change
with gaining creative skills of representational art. The right anterior cerebellum is
correlated to proprioceptive feedback and is found to project to hand and arm areas of
the left primary motor cortex and eye and hand movements. Increased activation of this
area is intuitive with increased technical skills in fine motor movements associated with
observational drawing/painting. However, the decreased activation in white matter of
frontal lobes correlated to increased creative skills is not well understood.
47
Schlegel, A., Alexander, P., Fogelson, S. V, Li, X., Lu, Z., Kohler, P. J., … Meng, M. (2015). The artist
emerges: Visual art learning alters neural structure and function. NeuroImage, 105, 440–451.
Summary by: Dong-Eun (Raquel) Lee

48
Summary of:
Chronic coffee and caffeine ingestion effects on the cognitive
function and antioxidant system of rat brains
Authors: Renata Viana Abreu, Eliane Moretto Silva-Oliveria, Marcio Flavio Dutra Moraes, Grace
Schenatto Pereira and Tasso Moraes-Santos
Despite the fact that the brain intakes approximately a fifth of the body’s total oxygen
supply, it receives relatively low levels of endogenous antioxidants as compared to
other tissues. These two factors in junction allow for increasing numbers of reactive
oxygen species (ROS) to take up residence among neurons. This ultimately leads to the
gradual accumulation of oxidative damage with age, making the brain highly susceptible
to deterioration of cells and therefore decreases in cognitive performance. Coffee
contains numerous substances and many of their biological effects have been examined
independently. However, little is known about coffee’s overall effects on the body as
interactions between components can cause fundamentally different outcomes. As a
result, this study seeks to understand the consequences of chronic coffee and caffeine
consumption on the endogenous antioxidant system of the brain and in turn, their effects
on cognitive performance. On the basis of previous studies, the authors hypothesized that
coffee and caffeine would act as a protective food for the brain and thereby slow cognitive
decline.
For the purpose of this study, weaned newborn rats were randomly selected and divided
into five groups, each subjected to different diets: a control diet, a 3% brewed coffee diet,
a 6% brewed coffee diet, a 0.04% caffeine diet and a 0.08% caffeine diet. When the rats
were 90 days of age, they partook in two behavior tasks: open field task (to observe their
exploratory behavior) and novel object preference task (to observe their short-term and long-
term memory). At 100 days of life, the rats were decapitated and their brains were tested for
indicators of oxidative damage.
Major Results:
It was found that coffee and caffeine supplemented diets had no effect on how much
the rats ate, their overall weight gain and their exploratory behavior (it did not increase
nor decrease the number of crossings and rearings in the open field test). Additionally,
rats in all conditions displayed habituation (indicating normal non-associative memory
processes) as exploration was decreased on the second day of testing. Additionally,
neither coffee nor caffeine had an effect during the novel performance task administered
90 minutes after, but coffee/caffeine conditions did have better discrimination during
the test given 24 hours after, indicating an enrichment in long-term memory. Analysis of
brain matter revealed enhancement changes to the antioxidant system, such as increased
concentration of potent endogenous antioxidants (mainly glutathione) and increased
activity of antioxidant enzymes (glutathione reductase and superoxide dismutase). These
alterations are believed to be the fundamental basis for reductions in cognitive decline as
brain matter is protected from oxidation.
Conclusions:
The most essential finding to be noted from this study is that moderate doses of
chronic coffee or caffeine consumption has beneficial effects in reference to cognitive
functioning through the pathways of antioxidants, without causing changes in sensory
and motor functioning. This study has major implications for the field of neuroscience as
caffeine has been shown to act on the central nervous system by blocking certain types
of adenosine receptors to negatively impact the production of free radicals in the brain,
ultimately acting as a safeguard. Perhaps these findings will lead to discoveries of other
preventative measures for neurodegenerative diseases.
49
Renata Viana Abreu, Eliane Moretto Silva-Oliveria, Marcio Flavio Dutra Moraes, Grace Schenatto
Pereira and Tasso Moraes-Santos. “Chronic coffee and caffeine ingestion effects on the cognitive
function and antioxidant system of rat brains” Elsvier (2011) doi:10.1016/j.pbb.2011.06.010 Published
online 15 June 2011
Summary by: Vonny Pui Ying Wong
50
Summary of:
LTP requires a reserve pool of glutamate receptors
independent of subunit type
Authors: Adam J. Granger, Yun Shi, Wei Lu, Manuel Cerpas, and Roger A. Nicoll
Long – term potentiation only occurs when there is an increase in AMPA receptors
(AMPAR), which strengthens the synapses between neurons when forming new memories
in the hippocampus. In the CA1 pyramidal neurons of the hippocampus, they contain
mostly GluA1/A2, but it also contains GluA2/A3 receptors. In a research finding they
found that LTP will not be generated if GluA1/A2 receptor are not trafficked to the
synapse by the C-tail of GluA1, nor if GluA1 is knocked out. In this article they wanted to
see if the C-tail of GluA1 has any effect on LTP formation
In this article several known methods were used to do this experiment. One of them is
Electrophysiology, where they did voltage – clamp recording of the CA1 pyramidal neurons
in either acute hippocampal slice or organotypic slice culture. The second method that was
used is the whole-cell synaptic recording, in this method they were recording the response of
the whole cell when they induced LTP at 2 Hz for 90 sec. Lastly, they used the Outside-out
patches method, where they measured the current of glutamate receptor or Kainate receptor,
when the induced HEPES-aCSF (contains many different molecules such as NaCl)
Major Results:
The researchers wanted to see what role the GluA1 C-tail has on the trafficking of
AMPAR. They did that by looking first at the surface expression of GluA subtype, what
they found was, when the C-tail was truncated up to the amino acid 824 (GluA1∆824)
or when removed membrane proximal region (GluA∆MPR), there was still surface
expression of AMPAR. However, when truncated all of the C-tail there was less surface
expression. Later they looked at the basal synaptic transmission and they found that
even though GluA1 C-tail was truncated the AMPAR was able to be transmitted to the
synapse. Even though the researchers found that the truncated C-tail has no effect on
the AMPAR trafficking, but they still wondered if it has an affect on LTP. What they found
was that no matter how much of the C-tail is truncated whether small pierces or the
whole C-tail LTP was still expressed, but not to the extent as the control. The researchers
then wondered what will happen to LTP if the synapse expressed another family type of
glutamate receptor called KAR (GluK1) instead of the AMPAR, and they found that LTP
was generated with the GluK1 receptor.
Conclusions:
Therefore two major findings were concluded, first of all being that whether the C-tail
is present or not in the GluA1subunit had no affect on LTP production. It was also found
that even if GluA1 subunit is not present, there are other glutamate receptors such as
GluK1 that can undergo normal levels of LTP. So regardless of the glutamate subtype,
LTP will be generated as long as there is a large amount of receptors on the membrane
surface.
51
Granger.A.J, Shi.Y, Lu.W, Cerpas.M, Nicoll. R.A. (2013). LTP requires a reserve pool of glutamate
receptors independent of subunit type. Nature, 493(7433), 495-500
Summary by: Ola Taji

52
Summary of:
Oxytocin improves mentalizing - Pronounced effects for
individuals with attenuated ability to empathize.
Authors: Melanie Feeser, Yan Fan, Anne Weigand, Adam Hahn, Matti Gärtner, Heinz Böker, Simone
Grimm, Malek Bajbouj
Individuals with high empathy are better equipped for inferring mental and emotional states
of other individuals, also known as “mentalizing”. Empathy and mentalizing activities contribute
to an understanding of interpersonal interactions, social norms, different beliefs and different
perspectives. Past literature displays that the neuromodulator Oxytocin (OXT) is vital in the
modulation of social-cognitive functions, promoting social memory, decreasing fear and anxiety,
and stimulating social trust and approach.
While empathy and mentalizing activities rely on different neural areas and have different
ontogenetic trajectories, both are shown to be privy to OXT stimulation. The neuropeptide has
shown to enhance empathic accuracy in those who are less socially proficient, by enhancing
attentional selectivity towards relevant social stimuli. It is also able to elevate mentalizing abilities
as shown by increased accuracy on the Reading the Mind in the Eye Test (RMET).
Hypothesis: OXT-induced results would be more distinct for difficult items compared to
easy items in mentalizing and that OXT administration would enhance mentalizing abilities in
individuals with low empathy as opposed to high empathy.
71 male subjects were subjected to a double-blind, 2 (difficult vs easy items) x 2 (assigned
randomly to either an oxytocin (OXT) or the placebo condition) experimental design.
Control variables: to ensure group matching, the Mehrfach Wortschatz Intelligenztest, NEO
Five-Factor Inventory were completed. The Multidimensional Mood State Questionnaire was
completed before OXT administration and after the task to asses mood, wakefulness and
calmness.
Participants self-administered a dose of 24 international units (IU) nasally 45 minutes prior to
the Reading the Mind in the Eye Test (RMET). This test sequentially presents 36 photographs of
complex mental states after a fixation cross (that lasts for 1000 ms). Participants are required to
infer internal states in others from a selection of four labels presented as quickly and accurately
as possible by selecting a correspondingly labeled key on a standard computer keyboard. Correct
answers were computed.
Empathy, measured using the Empathy Quotient (EQ) which is a 60-item self-report
questionnaire with a 4-point Likert scale, was later administered to estimate empathy’s possible
moderating effects of OXT.
Major Results:
Results showed that there were higher rates of accuracy associated with the OXT group when
compared to the placebo group in difficult items on the RMET. In contrast, there was a lack of
difference between these two groups on the easy items of the task.
Regression analysis confirmed the hypothesis that empathy moderates the results of
mentalizing accuracy; participants characterized to be low in empathy (with an EQ one
standard deviation below the mean) showed an increase in accuracy with OXT administration
as compared to receiving a placebo. On the other hand, there were no differences among the
OXT administration and the placebo administration for individuals with an EQ of one standard
deviation above the mean (high empathy participants).
Conclusions:
Empathy has a moderating impact on the processing of relevant social information, and
individuals who are less receptive to these cues benefit from oxytocin. As oxytocin receptors are
found in the amygdala, striatum, hippocampus, nucleus accumbens and midbrain, the presence
of this neuropeptide will enhance activity in these regions, which have been long implicated with
social bonding in neuroscience. Specifically to the study, oxytocin can incur a variety of prosocial
benefits that include enhancing activation in areas associated with empathy (limbic areas) and
mentalizing (by establishing connections between the amyglada and the prefrontal cortex).
53
Feeser, M., Fan, Y., Weigand, A., Hahn, A., Gärtner, M., Böker, H., ... & Bajbouj, M. (2015). Oxytocin
improves mentalizing–Pronounced effects for individuals with attenuated ability to empathize.
Psychoneuroendocrinology. 53, 223- 232.
Summary by: Ashima Agarwal
54
Summary of:
The Involvement of ERK/CREB/Bcl-2 in depression-like
behavior in prenatally stressed offspring rats
Authors: Lixia Guan, Ning Jia, Xiaoyan Zhao, Xiaohua Zhang, Guokui Tang, Li Yang, Hongli Sun,
Dan Wang, Qian Su, Qian Song, Dongge Cai, Qing Cai, Hui Li, Zhongliang Zhu
This article studies the expression levels of CREB/ERK/Bcl-2 in rat brains and their
immobility time through a swimming test after experiencing prenatal stress (PS). These
levels were measured in the hippocampus, prefrontal cortex and striatum. The prenatal
stress that was given was social isolation. The motive of the article is to understand the
role of the ERK-CREB pathway and its changes that occur after PS exposure and how
that reflects in a swimming test. These proteins were studied due to their important
functions. CREB is involved in neuronal plasticity and regulating transcription of
genes that are associated with stress response. ERK responds to extracellular stimuli
by regulating gene expression, cellular growth, synthesis of new proteins in order to
protect cells. Bcl-2 is regulated by CREB and is an anti-apoptotic factor. It is involved
in regulating cell death, cell plasticity and growth of new neurons. ERK is activated
by NMDA receptor excitation. MK-801 is a drug used in the study as it is been
demonstrated to be affiliated with antidepressant properties. It is a non-competitive
antagonist of NMDA receptor therefore blocks glutamate from binding to this receptor.
Saline was used alongside to MK-801. The results showed PS rats showed an increased
immobility time. There was lower expression of ERK2 mRNA, CREB mRNA, Bcl-2 mRNA
in the hippocampus, prefrontal cortex of PS rats with saline compared to control and
MK-801 (modified the expression). The CREB levels were fixed by MK-801 as the levels of
CREB were similar to that of the control even after experiencing stress prenatally. There
was no significant difference seen in expression of mRNA expression among the three
proteins in the striatum. These changes were all reflected in the increased immobility
timing correlated to depressive behaviour.
Method/Experiment:
The method that was utilized consisted of mating sexually active male rats to females
over night within a room temperature of 22-26 degrees, humidity 60% and with a 12
hour day/night cycle (control group). Each pregnant rat was than separated into a
control group, PS-Saline group, and PS-MK-801 group. The control group was not given
any stress, but the other two groups were socially isolated 3 times a day for 45 minutes.
The rats were given either saline or MK-801 on days 14-21 of pregnancy. The researchers
than did a forced swimming test (FST) on the offspring to see the effects of PS on
them. Also, RNA was extracted from the three brain areas (hippocampus, striatum and
prefrontal cortex) and went through an RT-PCR to examine the intensity of ERK, CREB,
and Bcl-2 mRNA expression in each.
55
Guan L., Jia X., Zhao X., Zhang X., et al. (2013). The involvement of ERK/CREB/Bcl-2 in depression-
like behaviour in prenatally stressed offspring rats. Journal of Brain Research Bulletin, 99, 1-8.
Summary by: Ariba Alam

56
Summary of:
Aerobic exercise is the crititical variable in an enriched
environment that increases hippocampal neurogenesis and
water maze learning in male C57BL/6J mice
Authors: Martina L. Mustroph, Shi Chen, Shalin C. Desai, Edward B. Cay, Erin K. DeYoung, and
Justin S. Rhodes
The role of sensory and motor enrichment on adult hippocampal neurogenesis has been
the target of many studies. Previous research on mice has shown that environmental
enrichment increases the level of BDNF gene expression in the dentate gyrus; the
increased neurotrophic levels are correlated to the enhanced adult hippocampal
neurogenesis and cognitive benefits seen in these animals. Separation of the sensory and
motor component of environmental enrichment by later studies showed that presence
of motor stimuli alone is responsible and sufficient for neurogenic and pro-cognitive
benefits in mice. With the hypothesis that novel and broad sensory stimuli can increase
neurogenesis, this study aims to test the effects of different sensory modalities including
tactile, visual, dietary, auditory, and vestibular in an environment enriched group and
compare the results to the effects of motor stimuli on adult hippocampal neurogenesis
and cognitive abilities in mice.
32 male C57BL/67 mice of 5 weeks age were housed singly in either of the 4 housing
conditions: Running wheel present (RUN), Novel toys and diet enrichment present (EE),
Running wheel and Enrichment present (RUN+EE), and Standard caging (Control).
Mice were videotaped and the time spent on the running wheel versus engaged with
sensory stimuli was recorded. Mice were injected with BrdU (bromodeoxyuridine) during
the first 10 days of the experiment to label the dividing cells. Spatial learning and
memory was tested on a water maze during the last 5 days of the experiment following
which the animal was euthanized. Coronal hippocampal slices were collected and
immunohistochemistry protocols were followed to co-label new neurons with BrdU and
NeuN (neuronal nuclear marker). Cells count and imaging were done using a Leica SP2
laser scanning confocal microscope.
Major Results:
From the video recordings, it was shown that mice in the RUN group ran a greater
distance than mice in RUN+EE, EE, and Control respectively. Performance on water maze
was assessed by measuring the path length to find the hidden platform; at the end of
the 5 days learning period animals within all groups showed significant decrease in path
length, however, mice in the RUN group the path length decreased by 75% in the second
day of trial. There was an increase in the volume of granule layer in RUN and EE group,
the effect was additive and the largest granule layer was seen in mice of RUN+EE group.
Mice in RUN group had the greatest number of BrdU and NeuN co-labeled cells per
granule layer volume which was followed by mice in the RUN+EE, EE, and Control group
respectively.
Conclusions:
Through segregating and modulating the novelty and modality of different sensory
and motor stimuli, this study aimed to find distinct neurogenic and cognitive benefits
that could be implemented in treatments for different neurodegenerative and cognitive
deficiency disorders. With no significant difference in the levels of neurogenesis between
RUN and RUN+EE and the insignificant increase in neurogenesis in EE group compared
to the Control, it was shown that sensory stimulations with toys and treats do not have
neurogenic benefits. Moreover, lack of enhanced spatial learning in mice in EE group
compared to RUN group showed that sensory enrichments of different modalities do
not confer cognitive benefits. It was concluded that exercise can enhance the survival of
new neurons in the dentate gyrus of mice which is the main drive for pro-cognition and
neurogenic benefits.
57
Mustroph, M. L., Chen, S., Desai, S. C., Cay, E. B., DeYoung, E. K., & Rhodes, j. S. (2012, September 06). Aerobic
exercise is the crititical variable in an enriched environment that increases hippocampal neurogenesis and water maze
learning in male C57BL/6J mice. Neuroscience, 219, 62-71.
Mustroph, M. L., Chen, S., Desai, S. C., Cay, E. B., DeYoung, E. K., & Rhodes, j. S. (2012, September
06). Aerobic exercise is the crititical variable in an enriched environment that increases hippocampal
neurogenesis and water maze learning in male C57BL/6J mice. Neuroscience, 219, 62-71.
Summary by: Samin Alikhanzadeh
58
Summary of:
KIBRA Polymorphism Is Associated with Individual
Differences in Hippocampal Subregions: Evidence From
Anatomical Segmentation Using High-Resoultion MRI
Authors: Palombo, D. J., Amaral, R. S., Olsen, R. K., Müller, D. J., Todd, R. M., Anderson, A. K., &
Levine, B.
The KIBRA gene is found throughout the brain and kidney and exists in higher
concentrations in the Cornu Ammonis and Dentate Gyrus of the Hippocampus. The gene
has been shown to be associated to episodic memory performance. A single nucleotide
polymorphism in this gene from cytosine to thymine has been linked to increased
performance on episodic memory tasks, especially those involving consolidation and
delayed retention. Since the Hippocampus has a strong role in episodic memory, the
study theorizes that people who are carriers of the T-allele will have volumetric differences
compared to non-carriers. Along with a larger global volume of the hippocampus, regional
volumetric enlargements in the Cornu Ammonis and Dentate Gyrus are expected.
32 participants were recruited from a larger study involving genetics and memory. A
saliva genotype was preformed for all participants testing for SNP in genes previously
implicated in episodic memory (BDNF, KIBRA, APoE, COMT). These results were then
used to match participants for all genes and create 2 groups consisting of 18 T-allele
carriers and 14 non-carriers. High resolution T2 weighted images taken perpendicular to
the long axis of the hippocampus were analyzed and compared using ROI segmentation
of the Cornu Ammonis (CA), Dentate Gyrus(DG)/CA, subiculum, medial temporal lobe
(further divided into perirhinal cortex. Entorhinal cortex, parahippocampal cortex) and
head of tail of hippocampus by single rater blind to group status.
Major Results:
Three-mixed design ANCOVAs were used to test for significant differences in whole
hippocampus, segmented hippocampus and segmented MTL cortices of carriers and non-
carriers of the t-allele SNP. In line with the prediction of the hypothesis, T-carriers were
found to have larger overall hippocampal volume than those of non-carriers. T-carriers
were also found to have significantly larger segmented hippocampi than no carriers.
Using post-hoc analysis the CA and DG/CA were found to be significantly larger in
T-carriers and no significant enlargement was found in the subiculum; in this region
non-carriers were found to have relatively larger volumes. There were no significant group
interactions and KIBRA was found to have no significant effect on MTL structures. Using
pot hoc analysis T-carriers were found to have a small but significant increase in volume
in the parahippocampal cortex indicating some effect of KIBRA here.
Conclusions:
The KIBRA T-allele SNP was found to be associated with increased volume of the
hippocampus, specifically in the CA and DG. If we can identify KIBRA’s effects on memory
we may be able to apply this knowledge to develop clinical treatments to help populations
in which these areas and functions are targeted like those with Alzheimer’s Disease.
59
References:
1) http://www.integragen.com/32-the-genetics-of-
autism.htm
2) http://www.thomaskoenig.ch/Lester/Files/
SPAMs_Hippocampus.jpg
3) http://www.jneurosci.org.myaccess.library
Palombo, D. J., Amaral, R. S., Olsen, R. K., Müller, D. J., Todd, R. M., Anderson, A. K., &
Levine, B. (2013). KIBRA polymorphism is associated with individual differences in hippocampal
subregions: evidence from anatomical segmentation using high-resolution MRI.The Journal of
neuroscience : the official journal of the Society for Neuroscience, 33(32), 13088–93. doi:10.1523/
JNEUROSCI.1406-13.2013
Summary by: Megan Cabral
60
Summary of:
Memory Deficits Induced by Inflammation Are Regulated by
α5-Subunit-Containing GABAA Receptors
Authors: Dian-Shi Wang, Agnieszka A. Zurek, Irene Lecker, Jieying Yu, Armen M. Abramian,
Sinziana Avramescu, Paul A. Davies, Stephen J. Moss, Wei-Yang Lu, Beverley A. Orser
Acute systemic inflammation caused by infection, autoimmune diseases, and traumatic
brain injury can lead to memory loss. Some neurodegenerative diseases, such as
Parkinson’s and Alzheimer’s disease, are known to occur following inflammation. The
release of various cytokines during inflammation, primarily interleukin-1β (IL-1β), is
correlated with cognitive deficits. It is impractical to inhibit membrane-bound type 1
IL-1 receptors as that would delay wound healing and interfere with normal memory
processes. Therefore, it is necessary to identify a downstream mediator to effectively
treat inflammation-induced memory deficits. Current studies show that activation of
the α5GABAA receptor blocks memory and that reduction of α5GABAA activity improves
certain memory-tasks. It is hypothesized that α5GABAA receptors are also involved in
inflammationinduced memory deficits.
The experiments were performed on wild-type (WT) and α5GABAA knockout (Gabra5-/-)
mice that were 3- to 4-months of age. Experiments began three hours after injection of
IL-1β (1 μg kg-1) or bacterial endotoxin lipopolysaccharide (LPS) (125 μg kg-1) to ensure
peak plasma levels of cytokines. Pavlovian fear conditioning using a tone (3,600 Hz tone,
20 seconds) with an electric foot shock (2 seconds, 0.5 mA) was used to study memory
performance. Hippocampal slices, cell cultures, and neuron-microglia co-cultures were
used for whole-cell voltage clamp recordings. LTP was induced via theta burst stimulation
(10 stimulus train at 5 Hz, each train had four pulses at 100 Hz). Tonic GABAergic
currents were recorded at -60 mV, using 0.5 μM or 5 μM GABA for cultured or sliced
neurons respectively. Cell surface biotinylation assay was used to determine expression
of α1, α2, or α5 subunits from the GABAA receptor.
Major Results:
Inflammation via IL-1β or LPS resulted in impaired contextual fear memory in WT
mice, as indicated by lower freezing scores. Gabra5-/- mice were not affected. This
suggests that the α5GABAA receptors are necessary for impaired contextual fear memory.
It was found that inhibition of α5GABAA receptors using L-655,708 could reverse the
effects induced by IL-1β in WT mice. Using hippocampal slices, it was determined
that LPSmediated inflammation resulted in a smaller increase in LTP in WT mice.
This decrease was not seen in Gabra5-/- mice. The reduction in LTP was eliminated
after application of L-655,708. In addition, it was found that mice treated with IL-1β
had a 2-fold increase in tonic inhibitory current density in CA1 pyramidal neurons. In
cultured neurons, it was determined that the amplitude of the tonic current produced
by α5GABAA receptors was dependent on the concentration of the IL-1β treatment.
Application of other cytokines, such as TNF-α and IL-6, did not produce a current.
Introduction of L-655,708 into the IL-1β-treated WT neuron inhibited the tonic current.
WT hippocampal slices treated with IL-1β showed greater expression of α5GABAA
receptors. It was determined that inhibition of p38 mitogen-activated protein kinase
via SB203,580 blocked the IL-1β-induced tonic current in WT neurons by reducing
α5GABAA receptor expression on the membrane surface.
Conclusions:
The results from this experiment show that inflammation can cause memory deficits via
an increase in tonic currents produced by α5GABAA receptors. Although no treatments
currently exist, the use of α5GABAA receptor inverse agonists, rather than antagonists,
for can be used in future experiments to determine possible treatments for inflammation-
induced memory loss.
61
Wang, D.S., Zurek, A.A., Lecker, I., Yu, J., Abramian, A.M., Avramescu, S., Davies, P.A., Moss, S.J., Lu,
W.Y., Orser, B.A. Memory deficits induced by inflammation are regulated by α5-subunit-containing
GABAA receptors. Cell Reports, 2, 488-496.
Summary by: Sammy Cai

62
Summary of:
Reduced anxiety-like behaviour and central neurochemical

change in germ-free mice
Authors: Neufeld, K.M., Kang, N., Bienenstock, J., and Foster, J.A
Previous studies have shown and established the importance of intestinal microbiota,
which is formed in the first few days after birth, on the development and function of gut,
immune, and endocrine systems. There has also been observed that bowel diseases tend
to be accompanied by anxiety and mood disorders. And, diet, which changes intestinal
microbiota, also alters learning and memory. The interaction between microbiota and
the brain/behaviour is, however, poorly understood. This study demonstrates the effect
of intestinal microbiota on behaviour and the central nervous. Neufeld et al. shows that
germ free mice with no intestinal microbiota have lower anxiety and higher exploratory
behaviours.
Eight-week-old germ free (GF) and specific pathogen free (SPF) female Swiss Webster
mice were used. Fifty-one hours after the mice arrived, their behaviours were tested using
elevated plus maze, and their number of arm entries and duration in arms were recorded.
Blood and brain samples were also collected from a separate group of mice to test for
corticosterone, brain-derived neurotrophic factor (BDNF), 5HT1A serotonin receptor,
and N-methyl-D-aspartate (NMDA) subunit levels. A standard radioimmunoassay kit
was used to measure the corticosterone levels. And, in situ hybridization was used to
identify and measure the mRNA expression levels of BDNF, 5HT1A receptor and NMDA
subunit. Then, statistical programs were used to compare and determine the statistical
significance of the data.
Major Results:
In the elevated plus maze, GF mice spent more time in the open arms, less time in the
closed arms, and entered open arms more frequently compared to SPF mice. GF mice’s
plasma corticosterone level, however, was higher than SPF mice’s. GF mice also increased
in BDNF mRNA expression, specifically in the dentate gyrus of the hippocampus, while
the expressions in other regions, CA1 and CA3, did not differ compared to SPF mice.
On the other hand, compared to SPF mice, GF mice’s 5HT1A receptor and NMDA mRNA
expression decreased in the dentate gyrus and central amygdala, respectively. The
expression of 5HT1A mRNA expression did not differ between GF mice and SPF mice
in the CA1 region. The NMDA subunit that showed significant decrease was the NR2B
subunit.
Conclusions:
The presence or the absence of intestinal microbiota influences the development
of behavior and central nervous system in mice. GF mice, which have no microbiota,
decreased in anxiety-like behaviour and increased in exploratory behaviour. Alterations
in the gene expression in BDNF, 5HT1A, NMDA subunit NR2B are consistent with the
behavioural findings and contribute to the exploratory behaviour observed. Previous
studies have shown that low BDNF levels increase in anxiety-like behaviours; the
decrease in serotonin level from 5HT1A receptor increases exploratory behaviour; and
NR2B antagonist blocks amygdala synaptic plasticity and fear learning. Thus, higher
BDNF levels and lower 5HT1A and NR2B levels in GF mice are related to reduced anxiety-
like behaviour observed.
63
Neufeld, K.M., Kang, N., Bienenstock, J., and Foster, J.A “Reduced anxiety-like behaviour and
central neurochemical change in germ-free mice” Neurogastroenterology & Motility (2011) doi:
10.1111/j.1365-2982.2010.01620.x. Published online 05 November 2010.
Summary by: Chun-Chi Chu

64
Summary of:
The Neural Correlates of Cognitive Control: Successful

Remembering and Intentional Forgetting
Authors: Avery A. Rizio and Nancy A. Dennis
This study explores neural activity for forgetting and remembering. The neural
differences between incidental and intentional forgetting are under investigation. The
hypothesis is that if incidental and intentional forgetting are separate, there should
be different neural activity for both. Incidental forgetting would be related to encoding
activity. Therefore certain parts of the brain related to the ability and inability to encode
information(prefrontal cortex and the medial temporal lobe) should be associated with
incidental forgetting. Alternatively, intentional forgetting should be associated with
activity in areas of the brain involved in control and inhibition(prefrontal cortex and
parietal lobe)
A directed forgetting paradigm was used to induce forgetting and remembering. In the
first phase, participants were presented with words and were directed to remember or
forget them. Different cognitive processes were executed for the direction to remember
or forget. The second stage involved a task that served as a distraction. In the third
stage(retrieval stage), participants were shown the words again( including new words) and
participants were asked if they did or did not recognize them. Words that were directed
to be forgotten and were indeed forgotten during the retrieval stage were represented
as intentionally forgotten. Words that were directed to be remembered but were in turn
forgotten during the retrieval stage were represented as incidentally forgotten. An MRI
and psychophyioslogical interaction analysis were used to detect brain areas that were
active during stages.
Major Results:
Intentional forgetting in participants is associated with right parietal cortex activity. On
the other hand, incidental forgetting is connected to a greater extent with activity in the
left inferior frontal gyrus, left superior frontal gyrus, early visual cortex, and left superior
parietal lobe. In addition, intentional forgetting was associated with prefrontal cortex
activity inhibiting medial temporal lobe activity. The medial temporal lobe is involved
with encoding, and there is an inhibition of its activity during intentional forgetting.
In contrast, there is no sign of inhibition for incidental forgetting. Therefore there is a
difference in incidental forgetting and intentional forgetting like hypothesized. Also, it has
been hypothesized that the right parietal cortex is associated with controlled processes
including intentional motivations like intentional forgetting and it has been shown that
intentional forgetting has activity in the right parietal cortex.
Conclusions:
This study has shown that memory suppression is controlled by separate processes
depending on which type of memory loss. Specifically, there is a difference between
incidental and intentional forgetting as shown by the different brain region activity. This
is relevant to neuroscience because it provided additional information regarding the
cognitive control of memory and neural activity associated with it.
65
Dennis, N. A., Rizio, A. A. (2013). The Neural Correlates of Cognitive Control: Successful
Remembering and Intentional Forgetting. Journal of Cognitive Neuroscience, 25(2), pp. 297-312.
Summary by: Chantel George
66
Summary of:
Variation in the oxytocin receptor gene is associated with
increased risk for anxiety, stress and depression in individuals
with a history of exposure to early life stress
Authors: Amanda J. Myers, Leanne Williams, Justine M. Gatt, Erica Z. McAuley-Clark, Carol Dobson-
Stone, Peter R. Schofield, Charles B. Nemeroff
The neuropeptide Oxytocin (OXT) is a mammalian hormone that is synthesized both in the
paraventricular and supraoptic nuclei of the hypothalamus but also in other brain regions. It
targets oxytocin receptors (OXTR) that are located similarly. Once produced, the hormone is
transported to the posterior pituitary and consecutively released into the blood circulation. OXT
is commonly associated with maternal behaviour as well as lactation and parturition, however,
the findings of several studies suggest that the hormone may also be involved in altered mood,
anxiety and depression phenotypes. Moreover, alterations in OXT levels were also shown to
correlate with early life stress (ELS). Combining these two aspects, this study investigated
whether ELS could influence the susceptibility of certain OXTR haplotypes to develop depression.
Out of the initial amount of 1226 participants, 653 were qualified to take part in the study.
Criteria for inclusion were availability of Depression Anxiety Stress Scale (DASS) and Early Life
Stress Questionnaire (ELSQ) scores. DNA had to be available previously and its genotyping
must have been successful. The genotyping revealed 7 SNPs that had the desired quality
characteristics. In order to detect further genetic variance on the OXTR gene, MaCH-Admix
was run. Of the found SNPs, 51 were analyzed. To investigate the downstream effects of all
those OXTR SNPs, brain tissue was gained from brain tissue storing institutions. Only brains
of individuals that were classified as cognitively normal at the time of death were included. For
analysis purpose, four different tests where then conducted to investigate the following
1. The differences in DASS scores between individuals with and without ELS
2. Covariates contributing to the relationship between DASS and ELS
3. The effects of SNPs on symptoms and the influence of ELS on symptom-genotype
interaction by using certain models
4. Whether SNPs had downstream effects especially on OXTR expression levels by
performing the analysis in human brain
Major Results:
For test 1, significant differences between DASS scores of people experiencing no
traumatic events in their early life and people that were exposed to at least one event
classified as ELS could be shown. The results were consistent for all parameters in the
DASS score (depression, anxiety, stress). Test 2 did not reveal significant covariates
in demographic variables. Also, those variables did not contribute to the relationship
between DASS and ELS. Moving forward to test 3, stress and depression symptoms were
significantly affected by the SNP genotype in contrast to anxiety, where this was not the
case. Furthermore, in the context of ELS, the researchers were able to find SNPs significant
for each symptom. One of the found SNPs was rs139832701, which is located very close
to OXTR. It not only showed significant results in the ELS including model of DASS
depression and stress, but also had main effects on depression and stress scores. However,
for DASS anxiety, these correlations could not be detected. In test 4, the previously
associated SNPs did not show any significant effects on OXTR levels in the human brains,
concluding that their mechanism of action does not include a change in OXTR levels. In
contrast, another SNP (rs3831817) was shown to significantly affect OXTR levels.
Conclusions:
It was found that certain variants on the OXTR gene as well as early life stress seem
to have an influence on depression, anxiety and stress in later life. The strongest signs
of association were made with the rs139832701 SNP. However, it could not be shown
in which downstream mechanism rs139832701 acts upon OXTR, which could be the
subject of a consecutive study.
67
Sources
http://www.phantasiereisen.de/stressmanagement-mit-zehn-punkte-skala.html
http://www.phantasiereisen.de/stressmanagement-mit-zehn-punkte-skala.html
http://ghr.nlm.nih.gov/chromosome/X
http://de.fotolia.com/id/9423787http://www.rdnattural.es/plantas-y-nutrientes-para-el-organismo/diccionario-medico/gen/
Amanda J. Myers, Leanne Williams, Justine M. Gatt, Erica Z. McAuley-Clark, Carol Dobson-Stone,
Peter R. Schofield, Charles B. Nemeroff “Variation in the oxytocin receptor gene is associated with
increased risk for anxiety, stress and depression in individuals with a history of exposure to early life
stress” Elsevier – Journal of Psychiatric Research
Summary by: Patrick Hornlimann
68
Summary of:
Exposure to kynurenic acid during adolescence increases sign-
tracking and impairs long-term potentiation in adulthood
Authors: Nicole E. DeAngeli, Travis P. Todd, Stephen E. Chang, Hermes H. Yeh, Pamela W. Yeh,
David J. Bucci
This experiment was conducted to determine the long-term effects of high exposure to
kynurenic acid (KYNA) during youth on adult long-term potentiation (LTP) and sensitivity
to cues related to reward. KYNA has been shown in past studies to be an antagonist
to NMDA and alpha7 nicotinic acetylcholine receptors that play a key role in LTP and
therefore may impair cognitive functions. KYNA also impacts reward behaviours by
modulating dopamine release into the nucleus accumbens. Past experiments have shown
that the increases in KYNA in experimental models mimicked the KYNA increases found
in schizophrenic individuals. Therefore this experiment postulated that increased levels
of KYNA in adolescents would increase reward-seeking behaviours and would decrease
the ability for learning and memory at the adult stage.
The experiment was conducted on 16 male rats and began on post-natal day (PND) 27. The
animals were injected with L-KYN, a KYNA precursor, from days 27-29, and then allowed to rest
for 3 days; this interval was repeated until 15 injections had been administered. The injections
were administered in this method so that the animal would not have metabolic adaptation. The
control group followed the same process, but were injected with a vehicle. To assess changes
in reward seeking behaviours on PND 100 the animals were placed in a cage where they were
active for 60-minute sessions per day for 7 days. During the sessions they were exposed to
25 conditioned stimuli (CS+) responses –pressing lever lead to food, and 25 stimuli free (CS-)
responses – no outcome for pressing the lever. In the second experiment, to assess changes in
LTP, on PND 70 the brains of the animals were removed and electrophysiological recordings were
taken. Excitatory post-synaptic field potentials (fEPSP) were monitored for 10 minutes before
stimulation of the Schaffer collateral and then every minute for 42 minutes post LTP induction.
Recordings were made by the use of an electrode in the CA1.
Major Results:
From the reward seeking experiment it was determined that the control group and the
experimental group had no differences when pressing the lever in the CS- condition, however,
there was a significant difference in lever pressing between groups in the CS+ condition. The
experiment also showed that while the experimental group initially had a greater response to
the stimulus, over the course of the experiment the two groups developed a similar response
rate. The overall result showed that the groups acted similarly in both the CS- condition and
the late CS+ condition and acted differently in the early CS+ condition. The final result of the
first experiment showed that the L-KYN group had a greater response to the food cup in the
CS- than the CS+ condition but the control group showed no difference.
The LTP experiment showed that the control group had a significant increase of field
excitatory post-synaptic potential (fEPSP) from baseline, showing that LTP has occurred.
Conversely, the L-KYA treated group had no statistically significant increase.
Conclusions:
This study showed that when L-KYA was present in higher levels early in life there was
an increase in sensitivity to rewards due to the increase in dopamine levels at the nucleus
accumbens. This increase in sensitivity to reward can play a role in the development
of addiction later in life. It was also demonstrated that early high levels of L-KYA will
result in diminished ability for LTP and deficits in social behaviour, both of which are
hippocampal related. This is relevant to understand and to treat the cognitive symptoms of
schizophrenia. Individuals with schizophrenia tend to have high levels of KYNA when young
and will exhibit behavioural changes when they are adults. This may be linked to the effect
of KYNA on the hippocampus and further examination can lead to potential therapies.
69
Images from:http://images.clipartof.com/small/1212555-Cartoon-Of-An-Outlined-Chinese-Zodiac-Rat-Royalty-
Free-Vector-Clipart.jpg, http://i46.photobucket.com/albums/f119/ttorek/syringe.jpg, http://www.nature.com/
ncomms/2013/130827/ncomms3258/images/ncomms3258-f4.jpg,
http://www.indmedica.com/journals/images/curr_neuro/01_02_14_fig01.jpg and http://journal.frontiersin.org/
Journal/10.3389/fnbeh.2014.00451/abstract
Bucci, D. J., Chang, S. E., DeAngeli, N. E., Todd, T. P., Yeh, H. H., & Yeh, P. W. (2015). Exposure
to kynurenic acid during adolescence increases sign-tracking and impairs long-term potentiation in
adulthood. Frontiers in Behavioral Neuroscience, 8, 1-9. doi: 10.3389/fnbeh.2014.00451
Summary by: Shikha Kuthiala
70
Summary of:
A Potential Spatial Working Memory Training Task to

Improve Both Episodic Memory and Fluid Intelligence
Authors: Rudebeck, S., Bor, D., Ormond, A., O’Reilly, J., Lee, A., & Chao, L.
Previous studies suggest that training working memory activates the medial temporal lobe,
which can contribute to better episodic memory by stimulating interacting brain areas. Most
studies do not examine the small effects of training on episodic memory processes, such as
familiarity in the perirhinal cortex and recollection in the hippocampus. Rudebeck et al. follow
up on their recent finding that a high demand of executive function to process complex spatial
information increases prefrontal cortex activity too. Development of a new spatial task targeting
both episodic memory processes necessitates participants to adjust their viewpoint accordingly.
Thus, multiple training tasks are not required to improve cognition, as their spatial working
memory task led to stronger long-term memory and fluid intelligence for abstract reasoning.
Participants are split into a control group and a training group, which follows a daily
behavioural procedure for 20 minutes over 20 weekdays. The training task requires monitoring a
3D room with 8 picture frames of real world scenes that are presented in 12 blocks sequentially.
The program contains unfamiliar indoor and outdoor scenes without color, people, objects or
words, to avoid verbal encoding. Subjects identify repetition of a picture frame location with
one response, and a scene image with another. Participants are assessed similarly pre and post
training with the BOMAT to measure problem solving skills and two computer-based recognition
tasks. Participants complete a matrix of patterns in order to fill an empty field during the BOMAT.
The object and scene recognition memory tasks present a distinct set of 120 items during the
encoding phase, in which the participant either states if each scene is indoor or outdoor, or if an
everyday object would fit in a shoebox. Filler tasks take 20 minutes before moving onto the test
phase, in which 120 new items are randomly added to distract the participant, who provides a
recognition judgment on a 6-point confidence scale.
Major Results:
No significant differences in pre-training scores account for the improvements in the training group,
which is split at the median into a high gain and low gain group for recollection and familiarity.
Both groups achieve greater scores with time, but there are significant differences between them,
as well as the high gain compared to the control, and the low gain versus the control. The training
group performs significantly better on the BOMAT, in comparison with the control group. However,
low pre-training scores lead to higher BOMAT scores, irrespective of training task gain. In addition,
the gain scores positively correlate with the recognition tasks for both episodic memory processes.
There is a significant difference between the high gain group compared with the control, or compared
with the low gain group. Even if the object and scene tasks are considered separately, there is still
no significant difference between the scores for the low gain and control groups. Therefore, training
score improvement links with increased recognition seen through familiarity scores, whereas poor
recollection pre-training predicted a marked improvement only in recollection scores, regardless of
training scores.
Conclusions:
For optimal encoding and retrieval of episodic memory, the ability to maintain information in
working memory is crucial. Also, neural mechanisms overlap as medial temporal lobe lesions
affect working memory if/when the stimuli are difficult to verbalize or relational processing is
complicated. Moreover, BOMAT improvements are due to the task-induced activation of a common
network from the lateral prefrontal cortex to the parietal cortex, leading to better episodic memory.
Hence, the more working memory is improved, the larger transfer affects episodic memory, and so
the prefrontal cortex and medial temporal lobe structures are involved in non-specific gains. As a
result, depending on the cognitive skills required, appropriate training tasks must be created based
on existing ability and training task gains pursued. Furthermore, the hippocampus is important
for both recollection and familiarity as well as object and scene recognition, implying that further
research would allow generalization to all forms of episodic memory in various populations by using
different kinds of stimuli and targeting certain neural processes.
71
Benit, N., & Soellner, R. (2014). Misst gut, ist gut? Vergleich eines abstrakten und eines berufsbezogenen Matrizentests.
Journal of Business and Media Psychology, (1). Retrieved from http://journal-bmp.de/2012/05/1068/
http://cdn.iphonephotographyschool.com/wp-content/uploads/Black-White-iPhone-Photos-21.jpg
https://ellenandjim.files.wordpress.com/2012/03/1963houseforjacksonsnovel.jpg
Rudebeck, S., Bor, D., Ormond, A., O’Reilly, J., Lee, A., & Chao, L. “A Potential Spatial Working
Memory Training Task to Improve Both Episodic Memory and Fluid Intelligence” (2012). PLoS
ONE, E50431-E50431. Retrieved February 6, 2015, from http://journals.plos.org/plosone/
article?id=10.1371/journal.pone.0050431
Summary by: Shonali Rajesh Lakhani
72
Summary of:
Social deficits in IRSp53 mutant mice improved by NMDAR

and mGluR5 suppression
Authors: Woosuk Chung, Su Yeon Choi, Eunee Lee, Haram Park, Jaeseung Kang, Hanwool Park, Yeonsoo Choi,
Dongsoo Lee, Sae-Geun Park, Ryunhee Kim, Yi Sul Cho, Jeonghoon Choi, Myoung-Hwan Kim, Jong
Won Lee, Seungjoon Lee, Issac Rhim, Min Whan Jung, Daesoo Kim, Yong Chul Bae & Eunjoon Kim
Social deficits are observed in many neuropsychiatric disorders such as autism
spectrum disorder, schizophrenia, and attention deficit hyperactivity disorder. IRSp53
is an excitatory synaptic signalling scaffold protein that has been implicated with the
control of the actin cytoskeleton. Its deficiency has been shown to reduce AMPA/NMDA
ratios. IRSp53 knockout mice demonstrate augmented NMDAR function, augmented
long-term potentiation dependent on NMDA receptors, and diminished hippocampus-
dependent memory and learning. Certain drugs can be used to normalize NMDA function.
MPEP is a metabotropic glutamate receptor 5 (mGluR) antagonist and memantine is a
NMDA receptor antagonist that is used to treat Alzheimer’s disease.
Behavioural experiments such as the three chambered test or counting the number of
ultrasonic vocalizations was done to quantify social activity were done with in both wild
type and IRSp53 knockout male mice. In vivo experiments involved injections of the drugs
and saline followed by electrophysiological recording. LTD experiments were done with
sagital and coronal slices acquired with a vibratome from 21-28 day old mice. The slices
were placed in artificial cerebrospinal fluid that was infused with the drugs memantine
or MPEP. Layer II/III pyrimidal neurons from the prelimbic medial prefrontal cortex were
recorded for excitatory post synaptic currents (EPSC). Whole-cell patch clamp recordings
and field potential recordings were used.
Major Results:
IRSp53 knockout mice displayed many social deficits. Compared to wild-type mice,
they spent less time with the stranger mice in the three chambered setup, sniffing,
and following stranger mice. The IRSp53 knockout mice also exhibited fewer ultrasonic
vocalizations, more time spent on emitting the first vocalization, greater locomotion in
an open field and home cage, and more movement in a 48 hour period. Injecting the
mice with memantine or MPEP rescued social interaction in the IRSp53 knockout mice.
IRSp53 knockout mice had impaired LTD of NMDA receptor EPSCs but normal LTD
of AMPA receptor EPSCs and mGluR-dependent LTD in the medial prefrontal cortex.
Furthermore, the neurons had a lower apical dendrite complexity, less miniature EPSC
amplitude and frequency, and excitatory synapses. Memantine increased firing rates in
the medial prefrontal cortex slices for both the wild type and IRSp53 knockout mice but
induced a even greater increase in IRSp53 knockout mice.
Conclusions:
This paper demonstrated that a deficiency in a single protein, IRSp53, could cause
social deficits and unravelled part of the mechanism by which it might do so, which is
the hyperactivity of NMDA receptors. It also demonstrated two drugs that can rescue the
social deficit. Describing biological mechanisms for disorders and diseases furthers the
study of neuroscience by adding to the collection of knowledge which may help to find
better and more effective treatments in the future.
73
Woosuk Chung, Su Yeon Choi, Eunee Lee, Haram Park, Jaeseung Kang, Hanwool Park, Yeonsoo
Choi, Dongsoo Lee, Sae-Geun Park, Ryunhee Kim, Yi Sul Cho, Jeonghoon Choi, Myoung-Hwan Kim,
Jong Won Lee, Seungjoon Lee, Issac Rhim, Min Whan Jung, Daesoo Kim, Yong Chul Bae & Eunjoon
Kim “Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression” Nature
Neuroscience (2015). doi:10.1038/nn.3927 Published online 26 January 2015
Summary by: Victor Lee
74
Summary of:
Effects of defeat stress on behavioural flexibility in males and

females: modulation by the mu-opioid receptor
Authors: Sarah A. Laredo, Michael Q. Steinman, Cindee F. Robles, Benjamin J. Ragen and Brain C. Trainor
Behavioural flexibility is a method to adjust and respond to changing environments.
Stress can negatively affect behavioural flexibility. This is demonstrated in studies
with anxiety and depression patients performing worse on behavioural flexibility tasks
when compared to controls. Animal models have also shown that defeat stress such as
aggression from peers can reduce behavioural flexibility. Mu-opioid receptors (MORs) in
the orbitofrontal cortex (OFC) are known to mediate behavioural flexibility. Noteworthy is
that sex differences exist in the cortical areas controlling behavioural flexibility indicating
that stress may sexes differently. This study looks at how stress affects MOR control
impacting behavioural flexibility between the sexes. While stress in males has shown to
enhance behavioural flexibility with MOR activation, females’ response to stress has not.
Thus, the authors hypothesize that defeat social stress will down-regulate MOR function
and decrease behavioural flexibility in males while stressed females will have a null
response.
Male and female California mice were subjected to 3 days of either a social defeat
condition where they were caged with an aggressive mouse or in a control condition
in an empty cage. Four weeks after conditioning, the mice were tested on a Barnes
maze and taught to find the same exit hole for 5 days then in a reversal period the
mice must adapt to find a new exit hole. After the trails, some rats were sacrificed for
MOR autoradiography to analyse MOR binding in OFC. The Barnes maze test was also
conducted with MOR antagonists, (ß-FNA) and MOR agonist, morphine injections once
before acquisition period and once before reversal period.
Major Results:
Number of errors and travel distance were measured from the Barnes maze test. The
reversal period had a new exit hole testing the mice for behavioural flexibility. Stressed
males made more errors in finding the new exit hole compared to control males and
stressed females. Stressed males also entered the former target hole more frequently than
stressed females indicating inflexibility. In the MOR autoradiography, stressed males had
a reduction in MOR binding to OFC compared to control while there were no differences
in stressed and control female mice. Antagonising MOR with ß-FNA increased the number
of errors stressed males made compared to saline-injected males or females. In contrast,
females receiving ß-FNA made significantly fewer errors than saline-injected females.
MOR agonist, morphine increased stressed male performance in the reversal period and
travelled less distance to find the exit hole. These results indicate that upregulating MOR
for greater activation can improve behavioural flexibility in stressed males resulting in
less erroneous steps and faster learning curves while females have differing responses.
Conclusions:
Behavioural flexibility in males but not females is impaired when exposed to social
stress. The process is mediated by MOR binding with inhibitions leading to poorer
performance in reversal trials for stressed males than females whereas MOR agonists
have a reverse effect on males. These results suggest that future neuroscience research
needs to consider the differences between the sexes and study certain processes
independently. Understanding the effect of MOR with stress on behavioural flexibility and
sex differences can result in more targeted and effective psychiatric treatments for males
versus females.
75
Laredo, S.A., Steinman, M.Q., Robles, C.F., Ragen, B.J., & Trainor, B.C. (2015). Effects of defeat
stress on behavioural flexibility in males and females: modulation by the mu-opioid receptor. European
Journal of Neuroscience, 1-8. doi:10.1111/ejn.12824
Summary by: Ella Lew

76
Summary of:
Hippocampal Memory Traces Are Differentially Modulated by

Experience, Time, and Adult Neurogenesis
Authors: Denny, C., (2014). Kheirbek, M., Alba, E., Tanaka, K., Brachman, R., Laughman, K., Tomm, N., Turi, G.,
Losonczy, A., Hen, R.
Memory traces are theorized to be ensembles of cells activated during retrieval of a memory.
This study aims to visualize the memory traces of fearful episodic memories in the dental gyrus
(DG) and CA3 regions of the hippocampus (HPC), regions currently theorized to be important
in episodic and contextual memories. Expression pattern of the Arc gene in DG and CA3 are
closely associated with synaptic plasticity and HPC dependent memory, and its presence
is useful as a marker for such processes. Cells that expressed Arc both during encoding of
fearful memory and during later re-exposure to the same context were hypothesized to form
the memory trace. The effects of optogenetic inhibition of encoding cells, and X-ray ablation of
adult-born neurons from subgranular region of DG on memory trace were also tested.
In the ArcCreERT2 x R26R-stop-floxed-EYFP line, when Arc is expressed, so is EYFP and the
cells will fluoresce red temporarily (Arc+). Addition of tamoxifen (TAM) activates cre-lox mediated
deletion of a regulatory element causing the cells to permanently fluoresce green (EYFP+). Mice
were injected with TAM then subjected to context dependent fear conditioning (CFC) in the form
of foot shock in Context A. Mice were later returned to either unchanged Context A or novel
Context B, their stress behavior recorded and hippocampal slice used for immunohistochemistry
analysis. Yellow fluorescence indicates Arc expression during both encoding and retrieval
(EYFP+/Arc+). C-fos was used as a marker for CA3 instead of Arc, because Arc expression
was mostly dendritic. For optoinhibition test fibre optics were installed above DG and CA3 on
ArcCreERT2xArch-GFP line of mice to allow toggle on and off of photostimulation.
Major Results:
Mice were returned either 5 days (recent) or 30 days (remote) to Context A or B. In
recent re-exposure, mice froze more in context A. EYFP+ and Arc+ levels were similar, but
significantly higher EYFP+/Arc+ (c-fos+) for Context A in both DG and CA3, suggesting better
retrieval of encoded memory in Context A. In remote re-exposure, high degrees of freezing
were observed in both Context A and B, and number of all labeled cells were similar, which
may indicate memory generalization. CA3 levels of EYFP+/c-fos+ was significantly lower in
remote compared to recent. The same was not observed for DG.
For the optoinhibition test mice were placed into Context A 2 weeks later, the first 3 minutes with
light ON and following 3 minutes with lights OFF. 2 days later the same mice were placed in Context
B with same light epochs. Less freezing was observed during lights on in both Context A and B in
ArcCreERT2- mice than ArcCreERT2+, but freezing levels became similar when lights were turned
back on. This suggests that neurons marked during encoding are necessary for memory retrieval.
X-ray ablated mice and control were subjected to either 1 or 3 foot shocks and returned
to Context A 6 weeks later. In 1 shock CFC, x-ray mice showed less context elicited freezing
than control. Interestingly, only the numbers of EYFP+/c-fos+ were significantly different in
x-ray mice and not EYFP+/Arc+, showing that the memory trace was affected in CA3 rather
than DG, the site of neurogenesis. In 3 shocks CFC, no significant difference in freezing or
number of all labeled cells was observed, suggesting that intense conditioning could rescue
the effect of neurogenesis deficit.
Conclusions:
The authors propose cells in DG and CA3 re-activated during memory retrieval were
component of memory trace for the CFC. They were surprised that many cells activated
during encoding were not the same as those activated during retrieval, and that may due
to retrieval cells correspond to multiple related memories. Decrease in CA3 reactivation in
remote re-exposure may suggest that the component of memory trace has moved away to
other parts of the brain. Decreased reactivation in CA3 rather than DG in response to adult-
born neuron ablation was surprising, but the same result has been observed in other studies.
The newly recruited neurons may function in transmission of information from DG to CA3.
77
Denny, C., (2014). Kheirbek, M., Alba, E., Tanaka, K., Brachman, R., Laughman, K., Tomm, N., Turi,
G., Losonczy, A., Hen, R. Hippocampal Memory Traces Are Differentially Modulated by Experience,
Time, and Adult Neurogenesis. Neuron, 83(1), 189-201.
Summary by: Yi Xuan Li

78
Summary of:
VTA CRF neurons mediate the aversive effects of nicotine
withdrawal and promote intake escalation
Authors: Taryn E Greider, Melissa A Herman, Candice Contet, Laura A Tan, Hector Vargas-Perez, Ami Cohen,
Michal Chwalek, Geith Maal-Bared, John Freilling, Joel E Schlosburg, Laura Clarke, Elena Crawford,
Pascale Koebel, Vez Repunte-Canonigo, Pietro P Sanna, Andrew R Tapper, Marisa Roberto, Brigitte L
Kieffer, Paul E Sawchenko, George F Koob, Derek van der Kooy, Olivier George.
It is hypothesized that neuroadaptations, in which dopamine (DA) activity in the ventral
tegmental area (VTA) is decreased and corticotropin-releasing factor (CRF) activation is
increased, is responsible for drug addiction. Although past studies on nicotine addiction
and abstinence in nondependent animals suggested that forebrain-originated axons
release CRF into the VTA, the precise mechanism on how DA interacts with CRF in the
VTA is unknown. In this paper, the authors showed that chronic nicotine results in DA
neurons to express CRF and recruit local CRF neurons to the VTA, mediating withdrawal
aversion in rodents.
The authors used Crh mRNA in situ hybridization to identify CRF neurons in the
pVTA. To examine chronic nicotine effects on CRF neuron recruitment to the pVTA, they
used CRF immunohistochemistry. Downregulation of Crh mRNA in drug naïve, nicotine-
dependent and nicotine-withdrawn mice allowed them to examine CRF’s GABAgeric
effects on DA neurons, aversive behaviours and escalating nicotine-intakes. They
measured spontaneous inhibitory postsynaptic currents (sIPSCs), used place conditioning
and self-administration of nicotine respectively. CRF1 receptors in pVTA were then
blocked with MPZP antagonists to test if they were involved in withdrawal aversion.
Major Results:
Compared to the saline-control condition, CRF peptide density was decreased in mice
under both nicotine-dependent and withdrawal conditions, indicating there is local
release of pVTA CRF in chronic nicotinic exposure. Downregulation of Crh mRNA in
pVTA of nicotine dependence mice showed increased sIPSC frequencies compared to
control nicotinic-dependent mice without Crh downregulated. This indicates that Crh
downregulation can reverse the GABAergic regulation of DA neurons due to long-term
nicotine exposure. Nicotine-withdrawn mice did not respond aversively to withdrawal,
and self-administration of nicotine-intake was reduced significantly in rats that had
longer access to nicotine in mice with downregulated Crh compared to controls. By
blocking CRF1 receptors, withdrawal aversion was not observed in mice treated with
MPZP under nicotine-withdrawn conditions. This indicates that CRF1 receptor activation
in nicotine-withdrawal is required for producing the aversive withdrawal behaviour and
blocking these receptors would prevent this response.
Conclusions:
In conclusion, the authors showed how CRF neurons expressed in VTA DA neurons
could be one interacting pathway responsible for nicotine addiction through withdrawal
averse and inducing drug intake responses. This paper provides greater understandings
to the mechanisms of drug addiction and further work is needed to elucidate whether
this pathway also occur in humans, which may aid in therapeutic approaches for drug
addiction in humans.
79
Picture idea from: Fields, H.L., Margolis, E.B. (2015). Understanding opioid reward. Trends in Neurosciences,
doi:10.1016/j.tins.2015.01.002
Grieder, T.E., Herman, M.A., Contet, C., Tan, L.A., Vargas-Perez, H., Cohen, A.,…George, O. (2014).
VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation.
Nature Neuroscience, 17(12), 1751-1758.
Summary by: Rose Ly
80
Summary of:
Reduction of p75 neurotrophin receptor ameliorates the

cognitive deficits in a model of Alzheimer’s disease
Authors: Mark Murphy, Yvette M. Wilson, Ernesto Vargas, Kathryn M. Munro, Belinda Smith, Amy
Huang, Qiao-Xin Li, Junhua Xiao, Colin L. Masters, Christopher A. Reid, Graham L. Barrett
The common signs of the Alzheimer’s disease are the amyloid plaques formation and
the degeneration of the cholinergic neurons in brain. Previous studies have shown that
the binding of amyloid-beta protein to the p75 neurotrophin receptors could promote cell
death and neurodegeneration. The p75 has a negative effect on the synaptic transmission
and the release of neurotransmitter. Previous studies suggested that p75 plays a role
in the neurodegeneration in AD patients. Murphy et al. bred mutant AD transgenic
mice Tg2576 (contain the human APP gene) with reduce level of p75 to perform in
multiple cognitive tasks. They were able to show that the down-regulation of the p75 can
ameliorate the memory deficit in the AD transgenic mice.
The AD transgenic mice Tg2576 were crossed with p75-/- mice to produce the Tg2576/
p75+/- mice with lower p75 expression. Four types of mice with different genotypes
were used in the experiment: wild type p75, mutant p75, Tg2576, and Tg2576/p75+/-
. Mice were between 4 to 8 months old in the tests, except for the Barnes maze test
which used 2 age groups (4-8 months and 12-14 months). PCR was used to determine
the genotypes of the mice. Western blot analysis was used to show the different level
of p75 expression across genotypes. Several memory experiments were performed: fear
conditioning testing for fear memory; Y maze testing for short term memory; and Barnes
maze testing for spatial memory. Field excitatory postsynaptic potentials (fEPSC) and the
LTP level (using tetanic stimulation) of the hippocampal CA1 neurons from the mice brain
slices were measured. The amyloid-beta levels were determined using the enzyme-linked
immunosorbent assay.
Major Results:
Reducing the level of p75 receptors in the Tg2576 mice showed significant improvement
in performance in all of the cognitive tests. The Tg2576 mice exhibited less shock
response in the fear conditioning test compare to the other three groups. The Tg2576/
p75+/- mice preferred to use more spatial search strategy in the Barnes Maze and
have longer memory retention about the familiar arms in the Y maze. The synaptic
transmission of the hippocampal CA1 neurons was enhanced after the reduction of p75.
The LTP of the Tg2576/p75+/- and wild type exhibited similar magnitudes whereas the
Tg2576 had a reduction in LTP. There was an increase in human Ab expression in the
Tg2576 mice with reduction of p75.
Conclusions:
The down-regulation of p75 rescued the memory deficit, synaptic transmission,
neuronal death in the AD transgenic mice Tg2576. The reduction of p75 in Tg2576 not
only attenuated the symptoms, the performances of the Tg2576/p75+/- were somewhat
comparable to the wild type mice. If future research seek out techniques/medications
that could target the p75 in human AD patients, they might be feasible to rescue some of
the deficits of the disease.
81
Mark Murphy, Yvette M. Wilson, Ernesto Vargas, Kathryn M. Munro, Belinda Smith, Amy Huang,
Qiao-Xin Li, Junhua Xiao, Colin L. Masters, Christopher A. Reid, Graham L. Barrett “Reduction
of p75 neurotrophin receptor ameliorates the cognitive deficits in a model of Alzheimer’s disease”
Neurobiology of Aging (2014) 1-13 DOI: http://dx.doi.org/10.1016/j.neurobiolaging.2014.09.014
Published online 25 September 2014
Summary by: Tong Mai
82
Summary of:
Correlation of Brain Biomarker Neuron Specific Enolase

(NSE) with Degree of Disability and Neurological Worsening
in Cerebrovascular Stroke
Authors: Anuradha Bharosay, Vivek Vikram Bharosay, Meena Varma, Kiran Saxena, Ajoy Sodani,
Ravi Saxena
Ischemic stroke is one of the world’s leading causes of death. In countries where MRI or
CT scans are not widely available, being able to find biomarkers in the blood to diagnose
stroke would be very beneficial. This study aims to find a biomarker that can be found
within 72 hours of the stroke occurrence. Neuron specific enolase (NSE) is an enzyme
released from the neurons upon apoptosis and crosses the blood brain barrier. This
can be measured in the bloodstream. Also, the severity of stroke, degree of disability,
and neurological worsening can be determined by using the National Institute of Health
Stroke Scale (NIHSS). Hypothesis: Higher levels of NSE will correspond to higher degree of
disability and neurological worsening in cerebrovascular stroke patients.
Normal levels of cerebrospinal fluid NSE are 17.3 ng/ml and this was used to
distinguish between control group and the study group. Adults who were over 21 years
of age and had a stroke less than 72 hours ago were chosen for the study group. For the
control group, adults who had no clinical signs and symptoms of cerebrovascular disease
were chosen. Blood samples were drawn and immunoassay was done using monoclonal
antibody against gamma, gamma-NSE isoform. NIHSS was used to assess the severity of
stroke and neurological worsening was assessed with the same scale by adding at least
two points extra to the NIHSS score if conditions worsened between admission day and
day five.
Major Results:
In the study group, approximately 47% of the adults had NSE levels >25ng/ml and
about 9% had >35ng/ml. The study group generally had higher NSE levels, as mean
for study group was 22.68 ng/ml and for control group was 7.48 ng/ml. In the control
group, all adults had NSE levels below 25ng/ml. As the NSE levels in the blood increased,
the severity of stroke also increases, providing a high positive correlation of 92%.
Similarly, there was also a positive correlation between the NIH scores, plus addition of
two points, and the worsening of disability in stroke patients. NSE found in the blood is
a result of apoptosis of endothelial cells, after which the NSE found in the cytosol is able
to spill out and cause the blood brain barrier (BBB) and into the bloodstream. Adults
who had higher levels of NSE also were the ones who tended to have worse neurological
outcome.
Conclusions:
Biomarkers such as NSE allow to gain more understanding of the neural and vascular
pathways of brain related injuries. As there was a high positive correlation between
NSE levels and neurological worsening, biomarker NSE can be used to determine future
consequences after the onset of stroke. This is why it is so important to find a biomarker
relating to stroke to have rapid treatment within the onset of stroke, instead of waiting for
CT or MRI scan, the diagnosis and treatment can be made within 48 hours.
83
http://www.futuremedicineonline.com/detail_news.php?id=143
http://www.nlm.nih.gov/medlineplus/ency/imagepages/9076.htm
https://lookfordiagnosis.com/mesh_info.php?term=immunoassay&lang=1
http://sigmadiagnosticsinc.com/neuron-specific-enolase-nse-elisa/
Bharosay, A., Bharosay, V., Varma, M., Saxena, K., Sodani, A., & Saxena, R. (2011). Correlation
of Brain Biomarker Neuron Specific Enolase (NSE) with Degree of Disability and Neurological
Worsening in Cerebrovascular Stroke. Indian Journal of Clinical Biochemistry, 27(2), 186-190.
Retrieved February 1, 2014.
Summary by: Fazila Malek
84
Summary of:
Neuroprotective effects of collagen matrix in rats after

traumatic brain injury
Authors: Samuel S. Shin, Ramesh Grandhi, Jeremy Henchir, Hong Q. Yan, Stephen F. Badylak & C.
Edward Dixon
Traumatic brain injury (TBI) is a problem that plagues all human populations, yet
very little treatment options are available. TBI is often characterized by neuronal loss,
inflammation, and neurological deficits both acutely and long-term. Here, the authors’
implant bovine collagen matrices into controlled cortical impact (CCI) injured rats in
order to test their efficacy in preventing the symptoms associated with TBI. Collagen has
intrinsic abilities to aid in neuronal survival, and cellular migration, making it a good
candidate for the graft. No exogenous growth factors are used to promote regeneration in
this study.
Four groups of rats were used; TBI rats+collagen matrix graft (IC), sham rats+collagen
matrix graft (SC), TBI rats+no graft (IN), sham rats+no graft (SN). TBI was induced under
anaesthesia using craniectomy CCI procedure (for IC and IN), CCI exposes brain tissue
by disrupting the meninges; thus facilitating collagen matrix graft implantation(for IC).
Crossing a balance beam was used as a test of motor abilities of rats on d1-5, this was
normalized by recording latency versus a pre-treatment cross-time in the same animal.
A hidden platform Morris water maze (MWM) was used for training of spatial learning.
Removal of the platform and time spent in the correct quadrant post-training was used to
measure spatial memory. After sacrifice, brain tissue was fixed, sliced and measured for
volume and cell counts were made of specific CA1 and CA3 hippocampal sections. GFAP
staining was used to visualize astrocytes at injury & graft site. Trichrome staining was
used to visualize brain slices and detect remaining collagen from graft at the injury site.
Major Results:
IC and IN rats exhibited statistically equally depressed performance on both beam
balance and beam walking tests versus SC an SN rats, demonstrating no difference in
motor ability. IC rats outperformed IN rats in the MWM latency spatial memory task,
meaning they learned to find the submerged platform faster, IC rats also demonstrated
a more uniform, progressive form of learning from trial to trial. IC and IN rats exhibited
equal reduction in time spent in the correct quadrant of the MWM after removal of
the platform versus SC and SN rats. Collagen matrix graft implantation resulted in
decreased lesion volume accompanied by lesser-reduced CA1 and CA3 neurons in
hippocampal slices in IC rats versus IN rats. GFAP staining of astrocytes in the CCI
region is equal in IC and IN, meaning there is no excess glial scar associated with the
collagen matrix graft versus IN. Finally, tricolour staining of brain slices reveals no
matrix-collagen remains bordering the CCI site.
Conclusions:
The use of a collagen matrix graft following CCI induced TBI in rats led to decreased
injury size, increased neuronal survival, and equivalent astroglial scarring versus non-
treated TBI rats. Collagen matrix grafting also allowed ameliorated spatial learning
versus non-treated TBI rats. Since no bovine collagen remained exposed at the injury
site following sacrifice of the rats, the authors propose its benefits remain as a transient
scaffolding to facilitate repair post-injury. More tests to elucidate the mechanisms the
graft uses to ameliorate prognosis following rat TBI are required for more definitive
conclusions.
85
http://www.nap.edu/openbook.php?record_id=13121&page=33
http://www.hindawi.com/journals/bmri/2014/672409/fig1/
entitled paper
Image sources (top left to bottom right):
clipart
Shin, S.C., Grandhi, R., Henchir, J., Yan, H.Q., Badylak, S.F. & Dixon, C.E. (2015). Neuroprotective
effects of collagen matrix in rats after traumatic brain injury. Restorative Neurology and Neuroscience.
[Epub ahead of print] doi: 10.3233/RNN-140430
Summary by: Catherine Matolcsy
86
Summary of:
Differentially Methylated Plasticity Genes in the Amygdala of
Young Primates are Linked to Anxious Temperament, an at
Risk Phenoytpe for Anxiety and Depressive Disorders.
Authors: Ried S. Alisch, Pankaj Chopra, Andrew S. Fox, Kailei Chen, Andrew T. J. White, Patrick
H. Roseboom, Sunduz Keles, and Ned H, Kalin.
Rhesus monkeys are an ideal animal model for human childhood anxious temperament
(a risk factor for future anxiety and depression) due to their brain and social structure.
Young rhesus monkeys also show anxious temperament (AT) symptoms very similar
to those seen in humans. PET scans suggest that there is higher brain activity in the
amygdala and anterior hippocampus in individuals with AT, but that these two areas
are not affected by genetic and environmental factors in the same way. This study
hypothesizes that high AT individuals will have different expression and methylation of
genes that may lead to anxiety.
Whole brains of young AT rhesus monkeys had sections of their amygdala biopsied,
and these sections were homogenized before RNA and DNA extraction. Reduced
representation bisulphite sequencing gave information on dinucleotide methylation.
Sequences were mapped to a human genome reference and filtered. Methylation was log
transformed and correlated as a percentage with AT severity (graphed as a continuous
variable). Fixed effect regression models were used to find 1) the level of methylation
which could most predict gene expression and 2) the gene expression that correlated best
with AT. All methylation data was assigned to a gene element, such as upstream, exon,
gene body etc.
Major Results:
Regions within the gene body and farther away from the transcription start site tended
to be more methylated. CpG islands were much less methylated than the areas around
them, which is consistent with other studies. 3’USR and intergenic regions were most
statistically overmethylated or unmethylated. This suggests that AT associated DNA
methylation is not random. 5489 CpG sites were found to be correlated with AT, some
negatively and some positively. Most of these areas are under 10% methylated, but those
genes that were over 60% methylated were more likely to be related to AT. Chromosome
1 has more AT related methylation, and chromose 19 has less, than would be expected
by chance. The AT associated genes were found to be related to such functions as
neuron generation and synaptic transmission, and many of them have been implicated
in psychiatric disorders before. Statistically differential gene transcription was found in
the same monkeys, in 22 genes that were also found have AT associated methylation
changes. These genes include two glutamate receptors which have been shown to have
roles in fear and anxiety behaviour, and genes with roles in brain plasticity
Conclusions:
Important genes which were found to have differential methylation and reduced gene
expression predicting AT phenotype include BCL11A and JAG1. BCL11A is a downstream
glutamate receptor effector involved in neurite branching, and JAG1 is a NOTCH receptor
with a role in spatial memory formation and plasticity. Although both of these genes
show the most methylation inside CpG islands, overmethylation of CpGs outside of CpG
islands probably contribute to the majority of AT changes. The observed methylation
changes most likely impact factor binding sites or noncoding RNA regulatory sites.
87
Alisch R. S. et al. (2014). Differentially Methylated Plasticity Genes in the Amygdala of Young Primates
are Linked to Anxious Temperament, an at Risk Phenotype for Anxiety and Depressive Disorders. The
Journal of Neuroscience, 34(47), 15548-15556.
Summary by: Lucy McPhee

88
Summary of:
Musical Experience and the Aging Auditory System:
Implications for Cognitive Abilities and Hearing Speech in
Noise
Authors: Alexandra Parbery-Clark, Dana L. Strait, Samira Anderson, Emily Hittner, Nina Kraus
The purpose of this study was to investigate if adults from ages 45-65 that have had previous musical
experience can comprehend speech in background noise more effectively than adults who have had
no musical experience. This does not only mean understanding speech at the basic level, but also
determining if underlying cognitive abilities have not been compromised. There are a complexity of
reasons as to why hearing becomes difficult, some include hearing loss due to age, as well as attention
and memory are factors in this issue. There have been studies suggesting that hearing becomes
integrated with attention, which is the ability to focus on a specific sound, and other cognitive functions.
Therefore, better memory calls for an increase in understanding speech and targeted sounds. One of the
tests used in this study is known as Backward Masking, which is a way to measure one’s perception
of sound as it is being played with another sound at the same time in order to make it difficult to
understand. There have already been studies showing that having previous musical experience does
in fact have a positive effect on perception of speech to the point where areas of the brain that process
auditory sounds have been improved compared to non-musicians (tested on only younger populations),
consequently, this study focused on an the older musical and non-musical population.
Out of 37 participants, 18 were considered musicians, which indicated that they played
instruments for over 30 years. The rest that were not musicians either had absolutely no previous
musical training or had 3 or less years of experience. Prior to beginning the tests, all participants
were asked to rate their musical skills, how many hours they participated in physical activity, all
were tested for normal cognition and hearing, and were also tested for IQ levels. This was a way
of controlling confounding variables within the study in order to be able to manipulate only the
variable of musical experience while all others remain constant. The study also took into account
that physical activity could be a possible factor that can affect cognition and even hearing, therefore,
the participants were categorized based on the amount of hours each spent on physical activity.
Results showed no significant differences between the categories. Then, the participants partook in a
series of tests to assess understanding speech in background noise, any auditory and visual memory
improvements, and included the backward masking test for cognitive hearing ability. After all tests
were completed, the researchers used statistical analyses to find any relationships in the data.
Major Results:
Throughout all the tests, excluding the visual component of memory, the results for musically
experienced participants showed a significant improvement to non-musicians. That being said, the
musicians were able to understand speech and had lower scores, suggesting better results than
non-musicians as the tests progressively became more challenging. Being able to understand speech
in background noise correlated with memory relating to the auditory path, such that a positive
relationship demonstrated improved results for both variables. In addition to having lower scores,
musicians demonstrated lower signal-to-noise-ratio (SNR), meaning the ability to perceive a target
signal playing simultaneously with background noise at different volumes. A lower result indicates
that the participant was able to distinguish both sounds even though they were relatively the same
volume. Correlations among the tests that measured for the same variable of speech perception were
calculated and found that no significant relationship could be determined even though participants
had similar results for each test. Other statistical analyses that were calculated also suggest no
significant relationships between number of musical training years and its effect on cognition.
Conclusions:
Activities such as playing an instrument can have some serious implications on enhancing the
brain as we age. It can improve our memory, speech perception and cognitive performance. It is
important to begin developing these skills at an earlier age as it is easier to take up new interests
and learn quickly and practice should be continued even until adulthood in order to attain the
aforementioned result. These results can be implemented in the present population such that, as life
expectancy increases, there will be an increase of older adults who will have difficulty hearing, thus
having musical experience may provide some reinforcement to overcome daily auditory obstacles.
89
Parbery-Clark A, Strait DL, Anderson S, Hittner E, Kraus N (2011) Musical Experience and the Aging
Auditory System: Implications for Cognitive Abilities and Hearing Speech in Noise. PLoS ONE 6(5):
e18082. doi:10.1371/journal.pone.0018082
Summary by: Arinda Muntean

90
Summary of:
Fast BDNF serum level increase and diurnal BDNF
oscillations are associated with therapeutic response after
partial sleep deprivation
Authors: Maria Giese, Johannes Beck, Serge Brand, Flavio Muheim, Ulrich Hemmeter, Martin
Hatzinger, Edith Holsboer-Trachsler, Anne Eckert
Brain-derived neurotrophic factors (BDNFs) affect neuroplasticity, and serum BDNF levels
exhibit circadian patterns in which mornings have the highest and midnights the lowest levels
of BDNFs. Because patients with major depressive disorder (MDD) have decreased hippocampal
BDNF levels, BDNF has been proposed as a potential target for antidepressant treatments and
as a biomarker for therapy efficacy because of BDNF’s ability to readily cross the blood-brain
barrier. In this study, researchers studied the effectiveness of increased BDNF levels after partial
sleep deprivation (PSD) therapy as a potential antidepressant treatment. They further tested
whether pre-existing BDNF circadian patterns are an early predictor of antidepressant therapy
responsiveness. They hypothesized that if patients had stable BDNF diurnal patterns and higher
levels of BDNF before PSD treatment, then PSD treatment will garner better antidepressive
results than those patients who began treatment with lower baseline BDNF levels.
28 major depression patients (15 female, 13 male) around the ages of 19-65 were studied.
All participants were evaluated using the Hamilton Depression Rating Scale (HDRS)
before partial sleep deprivation (PSD) treatment, in which they were woken up at 1:30 AM.
Participants were randomly assigned either modafinil (drug to reduce daytime sleepiness) or
placebo after PSD. Blood was drawn from each patient at seven different time points:
Day 1 (Before PSD for baseline BDNF assessment)
• 8am
• 2pm
• 8pm
Day 2 (After PSD)
• 1.30 am (right after being awoken)
• 8am
• 2pm
• 8pm
ELISA kits were used to assess serum BDNF levels, and two weeks after PSD treatment, all
patient were evaluated again using the HDRS scale. All statistical analysis was done using
Two-way ANOVA.
Major Results:
All participants’ BDNF oscillation patterns on day 1 before PSD treatment showed highest BDNF
levels in the morning (8am) and lowest at midnight (day 2—1:30AM), as was expected. After PSD
(day 2), mean BDNF levels increased 10.4% (8am), 16.2% (2pm), and 20.7% (8pm) when compared
to pre-treatment levels, showing that PSD results in rapid BDNF level increases. However, modafinil
and placebo treatments showed no significant differences in HDRS ratings or BDNF levels, showing
that managing sleep patterns after PSD treatment has no significant effect on treatment efficacy.
Two weeks after PSD, however, participants took the HDRS questionnaire and those who scored
lower on it, and therefore had better antidepressant results from the PSD, were classified as “long-
term responders” (n=10), whereas those who did not show lasting treatment effects and scored
higher HDRS scores were classified as “non-responders” (n=18). Long-term responders not only
had higher post-PSD (Day 2) BDNF levels than their counterparts, but also had higher serum
BDNF levels pre-PSD treatment (Day 1).
Conclusions:
Partial sleep deprivation (PSD) is effective in inducing rapid increase in BDNF levels and
garnering relief from depressive episodes, yet both of these outcomes are short-lived. More
importantly, however, patient predisposition to stable BDNF circadian rhythms and higher
BDNF levels prior to therapy are good predictors of antidepressant treatment efficacy and
response in a patient. In short, BDNF’s role in neurogenesis and long-term potentiation are
critical to mood disorders like depression and targeted studies into BDNF activity can prove
worthwhile in Neuroscience and Psychiatry.
91
Maria Giese, Johannes Beck, Serge Brand, Flavio Muheim, Ulrich Hemmeter, Martin Hatzinger, Edith
Holsboer-Trachsler, Anne Eckert “Fast BDNF serum level increase and diurnal BDNF oscillations are
associated with therapeutic response after partial sleep deprivation” Journal of Psychiatric Research,
59(2014) 1-7.
Summary by: Yuki Nishimura
92
Summary of:
Changes in White Matter Integrity before Conversion from
Cognitive Impairment to Alzheimer’s disease
Authors: Defrancesco, M., Egger, K., Marksteiner, J., Esterhammer, R., Hinterhuber, H.,
Deisenhammer, E. A., & Schocke, M.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that causes the loss
of memory and cognitive decline over time. Since it is a progressive disease, individuals
whom display a “mild cognitive impairment (MCI)” may have a higher probability of
developing AD, but not always since it is an onset for other neurodegenerative diseases
as well. Those individuals with MCI that develops AD are called converters, and those
that do not develop AD are called non-converters. Previous studies have identified that
patients that exhibit pre-clinical AD has atrophy of gray matter (GM) in many cortical and
subcortical structures as well as a loss of white matter (WM) integrity in the brain.
Data from fifty five German speaking patients older than 62 years of age were collected;
13 MCI converters, 14 MCI non-converters, and 28 healthy individuals. All subjects were
given a clinical interview and neuropsychological assessment which include, the MMSE
and CERAD battery to test for cognitive functions. Diffusion weighted imaging and T1-
weighted structural MRI scans were obtained for each subject and were compared using
voxel-based morphometry (VBM) analysis and apparent diffusion coefficient (ADC) maps
constructed which reflected the mean diffusivity values (MD). VBM is a technique that
allows for difference in brain volume to be compared. MD values reflected on the ADC
maps, are a measure of diffusivity of water protons in the brain structure.
Major Results:
Based on the multiple regression analysis in MCI converters through T1 MRI scans, it
was seen that they scored lower on the MMSE and verbal memory test, this had a positive
correlation with increased GM atrophy in the left putamen and the left inferior frontal
gyrus which are structures that are involved in speech functions. Using VBM analysis of
the T1 MRI scans to compare MCI converters and non-converters, results showed that
there is more GM atrophy in converters in the left parietal, left putamen, left insula, right
parahippocampal gyrus, left and right frontal lobe, as well as a very consistent decrease
in GM density in the left temporal lobe. However, no significant difference was seen in
the brain volume of MCI non-converters and healthy individuals. From ADC maps, when
comparing MCI converters and healthy individuals, there shows a widespread increase
of MD values are seen in GM of the left limbic lobe, right middle temporal lobe, and
the basal ganglia. Increased MD values of white matter is in the parietal, frontal, and
temporal lobe. An increase of MD value is due to neuronal loss in those areas resulting in
a disruption of the brain structure, thus having a larger extracellular space to allow for
more diffusion of water protons. Once again, the difference in non-converters and healthy
individuals is not significant.
Conclusions:
From this correlation study, changes in MD values can be detected throughout the
brain for GM and WM atrophy and lesions. Also, the difference between MCI converters
and MCI non-converters can be distinguished since data shows that there is not much
difference between non-converters and healthy individuals. Changes in MD values detect
areas of neurodegeneration and neuronal loss. This suggests that MD can be a potential
biomarker to more accurately identify the early onset of AD from MCI conversion, to allow
an earlier treatment of the disease.
93
Defrancesco, M., Egger, K., Marksteiner, J., Esterhammer, R., Hinterhuber, H., Deisenhammer, E.
A., & Schocke, M. (2014). Changes in White Matter Integrity before Conversion from Mild Cognitive
Impairment to Alzheimer’s Disease. PLoS ONE, 9(8), e106062.
Summary by: Miranda Nong

94
Summary of:
Extended Wakefulness: Compromised Metabolics in and
Degeneration of Locus Ceruleus Neurons
Authors: Jing Zhang, Yan Zhu, Guanxia Zhan, Polina Fenik, Lori Panossian, Maxime M. Wang,
Shayla Reid, David Lai, James G, Davis, Joseph Baur, & Sigrid Veasey
Previous studies have shown that extended wakefulness can reduce antioxidant
activity and ATP production in the brain, but few studies have shown the metabolic
responses to sleep deprivation in wake-active neurons. Zhang et al. showed that the
neurons in the locus ceruleus (wake active) fail to maintain SirT3 pathways in extended
sleep loss, resulting in neuronal degeneration. The SirT3 pathway is an essential
metabolic homeostatic pathway for short-term wakefulness, located in the mitochondrial
membrane. It is a NAD+ dependent enzyme that coordinates ATP production and
antioxidant production. Low levels of NAD+ and increased oxidative stress (high
concentrations of superoxide) can impair SirT3.
SirT3wt (wild type) and SirT3-/- (loss of SirT3 function) mice were introduced to
3 treatment groups: rest, short-term wakefulness (3 hours in light), and long term
wakefulness (8 hours in light). All mice underwent surgery to implant EEG and EMG
recording wires to observe sleep homeostasis given different genotypes, SirT3wt and
SirT3-/-. To visualize the locus ceruleus neurons, they were tagged with anti-tyrosine
hydroxylate (red fluorescence) to view under confocal microscopes. To observe the
level of SirT3 activity, dihydroethidine (green fluorescence), a superoxide indicator was
used. Dihydroethidine freely passes the blood brain barrier and converts to fluorescent
dihydroethidine in the presence of superoxide in neurons.
Major Results:
mRNA and protein concentrations increased for short term wakefulness than rest and
extended wakefulness. This allowed for the maintenance of redox homeostasis in the
locus ceruleus neurons. When wake duration was observed given superoxide availability,
extended wakefulness showed the highest superoxide level whereas rest and short term
wakefulness declined. In addition, SirT3 acetylation in the mitochondria had a significant
increase for extended wakefulness when compared to rest and short term wakefulness.
SirT3 acetylation in the cytosol had no significant differences within the 3 groups. This
suggests that the SirT3 pathway is more responsive to extended wakefulness in the
mitochondria. When the dendrites of locus ceruleus neurons were observed, SirT3wt
in extended wakefulness showed a reduction of dendritic segments when compared to
rest. The neuron cell estimate shows a reduction in neurons by 25%. In SirT3-/-, the
difference in neuron cell estimate was not significant. When the dendritic segments
were observed, there was no loss but changed in morphology, increase beading and
vacuolization.
Conclusions:
Short term wakefulness was found to upregulate SirT3 levels in the mitochondria and
increase antioxidant enzyme production, ultimately promoting metabolic homeostasis.
In the case of extended wakefulness, SirT3 activity dropped. This was supported by the
increase in mitochondrial acetylation of proteins as well as an increase in superoxide
production. The next step in research could be on overexpression of SirT3 in neurons. If
this could protect cells, it could lead to a promising therapeutic method for sleep deprived
individuals.
95
Zhang J., Zhu Y., Zhan G., Fenik P., Panossian L., Wang M.M., …Veasey S. (2014). Extended
Wakefulness: Compromised Metabolics in and Degeneration of Locus Ceruleus Neurons. Journal of
Neuroscience, 34(12), 4418-31. doi: 10.1523/JNEUROSCI.5025-12.2014.
Summary by: Hyun Park

96
Summary of:
Traces of Experience in the Lateral Entorhinal Cortex
Authors: Albert Tsao, May-Britt Moser, and Edvard I. Moser
The entorhinal cortex is a structure that shares reciprocal connections with the
hippocampus and neocortical structures and so it can be viewed as a hub for cortical
information processing and long-term memory formation. The lateral part of the
entorhinal cortex (LEC) is believed to play a role in encoding information about objects
within the environment. The goal of the Tsao et al.’s study was to explore whether
neurons in the LEC respond simply to physical features of an object within a spatial
location or whether the LEC encodes a higher order representation of an object, such as a
previous experience with it.
To address this question, the authors implanted rats with tetrodes for single unit
recording and trained the animals to run in the enclosed environment, a 1x1 m box with
black walls, containing both proximal and distal cues. After habituation, the animals were
given three consecutive 10 min trials: “object-free” trial (to determine baseline activity),
“object” trial with an object placed at a specific location, followed by the “object-free trial”
again. The initial task was then modified such that the object trials included novel objects
in a different location, a familiar object in the novel environment (the same box but with
brown walls and different spatial cues), a familiar object in a familiar environment but
different locations, and also an object was substituted with the rewarding microstimulation
of the medial forebrain bundle (MFB) when a rat entered a specific location. While the rats
were performing the task, single call activity was recorded from the LEC.
Major Results:
Activity of the single units was quantified as the mean frequency of cell firing. The firing
rate of a neuron when a rat was in the location of the object was compared to firing rate
outside of the object area. The researchers identified one group of cells that increased the
firing rate when the animal entered the location of the object during the “object” trials and
a second group of neurons that responded to the location of the object on the following
“object-free” trials, i.e., the cells were representing a trace of the familiar object. When tested
with the novel object, the activity of the new “object” and the “object-trace” cells could be
identified. When the authors moved the familiar object to different locations within the
box, the activity of the “trace” cell increased at every location where the familiar object was
encountered during the previous trial. However, when a familiar object was placed in the
novel environment, the “trace” cell activity did not follow it, suggesting that the trace cells
code for experience in a unique environment. Finally, when the rats were tested with the
MFB microstimulation delivered at a specific location instead of an object, one set of the LEC
neurons responded to the experience of stimulation itself and a distinct set of “trace” cells
increased the firing rate when the animal entered the location where during the previous
trial, but not the current trial, the stimulation was delivered. Tsao et al. demonstrated that
the differential neuronal activity was not due to animal’s movement behaviour.
Conclusions:
In conclusion, the authors emphasize that the LEC “object-trace” cells represent a
unique group of neurons, activity of which is distinct from the place cells or “misplace”
cells found in the hippocampus, or any pair-association cells in the temporal lobe. It is
still not clear whether the LEC processes the information about the location of an object
present in the past, or this information is being coded for in the hippocampus and then
sent back to the LEC. Finally, Tsao et al. compare their findings of the “trace” cells with
the report about similar cells coding for past experience in the anterior cingulate (ACC). It
is possible that the LEC serves as an interface between the hippocampus and the ACC in
the distributed network of the long-term memory formation.
97
Tsao, A., Moser, M. B., & Moser, E. I. (2013). Traces of experience in the lateral entorhinal cortex.
Current Biology, 23(5), 399-405.
Summary by: Maryna Pilkiw

98
Summary of:
The effects of social defeat on behavior and dopaminergic
markers in mice
Authors: H.-M. Jin, S. Shrestha Muna, T.R. Bagalkot, Y. Cui, B.K. Yadav, Y.C. Chung
The impacts of motivation and reward on an organism’s body are regulated mainly
through the neurotransmitter dopamine. DARPP is a phosphoprotein that has been
proven to play an important role in normal functioning of dopaminoceptive neurons by
acting as a mediator between dopamine and several other neurotransmitters and the
dopaminoceptive neurons.
The experiment conducted in the discussed article tests the effects that social defeat
has on mice behaviour and their dopamine levels. Social defeat is the phenomenon where
an organism is defeated by others of its kind in a confrontation. This defeat results in the
activation of the stress axis leading to a stress response in the body. Since dopamine is
the neurotransmitter than is know to be associated with reward and motivation it would
most likely be impacted as result of social defeat.
Hypothesis
Mice subjected to the social defeat procedure will show a decrease performance levels
in locomotion light preference, novel object recognition, social integration, Morris water
maze and forced swimming test for the defeated mice as compared to the control mice.
The experiment used mice aged between seven and 14 weeks and weighing 22–25g and 40–44 g.
The researchers executed a social defeat procedure that inflicted social defeat stress on
selected mice and lasted 10 days. This form of stress is directed at making the organism
feel beneath its social compatriots and feeling defeated. They also kept a set of control
mice that weren’t subjected to any artificially induced stress as a control condition. A
locomotion test, light/dark preference test, novel object recognition test, social integration
test, Morris water maze test and the forced swimming test were conducted on both the
control and the mice subject to the social defeat procedure.
Finally, western blotting procedure was used on mice brains after conducting the
experiment to test dopamine levels in the prefrontal cortex (PFC), amygdala (AMY) and
hippocampus (HIP) of both the defeated and control mice.
Major Results:
A significant reduction was observed in the total movement of defeated mice as compared
to the control mice. Defeated mice were also found to prefer spending much longer time
in dark and congested areas as compared to the control mice. Additionally, Defeated mice
performed worse on novel recognition test as compared to control mice. Similarly, in the
social interaction test defeated mice spent a decreased amount of time, social sniffing as
compared to the control mice.
As for the difference in dopamine 1 and 2 receptor, no significant differences were seen
between the control and defeated mice. The phosphor- Thr34 and Thr75 DARPP beta-actin
levels showed a significant difference between the defeated and control mice, as the defeated
mice were observed to have much higher levels of DARPP in their prefrontal cortex (PFC) and
amygdala (AMY) as compared to the control.
Conclusions:
Social defeat can result in an organism activating symptoms that involve defense
mechanisms that one would usually see when an organism is under stress. The
experiment conducted in the article discussed above showed that a defeated organism
shows symptoms similar to a depressed or anxious organism with signs of cognitive
impairment. These symptoms can be attributed to the changes in dopamine levels in
the prefrontal cortex (PFC), amygdala (AMY) and hippocampus (HIP) of defeated mice as
compared to control mice, which were tested, and shown to be different from each other.
99
Diagrams taken form: Jin, H. M., Muna, S. S., Bagalkot, T. R., Cui, Y., Yadav, B. K., & Chung, Y. C. (2015). The
Effects of Social Defeat on Behavior and Dopaminergic Markers in Mice. Neuroscience. 228, 167-177
Jin, H. M., Muna, S. S., Bagalkot, T. R., Cui, Y., Yadav, B. K., & Chung, Y. C. (2015). The Effects of
Social Defeat on Behavior and Dopaminergic Markers in Mice. Neuroscience. 228, 167-177
Summary by: Joravir Singh Riar
100
Summary of:
Exercise and time-dependant benefits to learning and memory
Authors: N.C. Berchtold, N. Castello and C.W. Cotman
Much research has been done to investigate the role of exercise on cognitive functions,
often describing facilitation in rodent memory acquisition on cognitive tasks like the
radial-arm water maze (RWM). During these trials, it has been demonstrated that BDNF
is a molecular mechanism that is up-regulated in response to exercise. Furthermore,
blocking BDNF’s binding to TrkB by antibodies has been shown to attenuate the
acquisition of spatial learning tasks. This paper hereby investigates the influence of
exercise on acquisition in RWM, the effects of introducing a delay period after exercise on
cognitive performance, and the persistence of exercise-induced BDNF protein levels after
exercise has ended.
Two groups were created to distinguish between sedentary and exercising mice. The
latter had access to running wheels for 3 weeks. At this point wheels were removed and
cognitive training began. One exercising group (EX) started the training immediately
whilst other groups had a one-week delay (EX/delay 1) or two-week delay (EX/delay 2)
before proceeding. The training was a RWM task that took place for four days. Spatial
cues on walls were provided in order for mice to recognize the correct arm that leads to
the escape platform. If the mouse did not find the platform within one minute, it was
guided there. After training, mice brains were extracted to determine average BDNF
protein levels. Furthermore, average errors and latency to the escape platform by all
mice were determined. A probe trial was done on 4th day of training to assess strength of
memory of escape route.
Major Results:
The fastest acquisition of the cognitive task in RWM was by EX1 mice, followed closely
by EX2 mice. All exercising mice had fewer errors in the RWM than sedentary mice, and
also showed better retention of memory during the probe trial. Interestingly, EX mice
performed better than EX1 and EX2 in the probe trial, perhaps due to the recency of
training, as this group experienced no waiting period. Average BDNF protein levels across
all exercising mice were observed to increase for 3-4 weeks after exercise before declining
to baseline. BDNF protein levels were highest in the EX group, followed by EX-delay
groups and Sedentary groups respectively. Performance scores showed a steep increase
in response to small BDNF increments but reached a plateau with more BDNF levels,
suggesting a saturation limit to the effect of BDNF on cognitive performance.
Conclusions:
Authors Berchtold et. al have been instrumental in providing further evidence for the
facilitative effect of exercise on memory acquisition and retention. This relates greatly to
the field of neuroscience as it serves to expand our currently limited understanding of the
important effects of exercise on cognitive functions. In addition, this article provides new
findings by investigating the effect of exercise delay periods on cognitive performance:
enabling future research inquiries in this area by neuroscientists. The authors of this
paper also demonstrate another new finding: the temporal dependence effect of exercise
on molecular mechanisms of the synapse like BDNF, which is relevant to neuroscience by
providing another potential area to investigate in future research.
101
Berchtold, N.C. Castello, N. and Cotman C.W. (2010). Exercise and time-dependant benefits to learning
and memory. Neuroscience 167 (2010) 588–597.
Summary by:Ashkan Salehi

102
Summary of:
Cognitive impairment following high fat diet consumption is
associated with brain inflammation
Authors: Pistell, P. J., Morrison, C. D., Gupta, S., Knight, A. G., Keller, J. N., Ingram, D. K., &
Bruce-Keller, A. J.
Obesity has been linked to chronic inflammation and irregular cytokine production.
Clinical research has also shown that obese patients, on average, have deficits in learning
and memory when compared to non-obese individuals. However, the mechanism by
which obesity affects the brain is unclear. Studies have indicated that brain inflammation
is detrimental to cognitive function. Pro-inflammatory cytokines have been found to
impair memory. This study examined the relationship between obesity and impaired
cognitive ability, and proposed a role for inflammation as the link between the two.
Twelve-month-old C57Bl/6 male mice were used. For 21 weeks, a cohort of mice was
administered a Western Diet (WD) consisting of 41% fat, while at the same time a control
diet (cWD) was administered to a separate cohort of mice. A third cohort was placed on a
high fat lard diet (HL) consisting of 60% fat for 16 weeks, while simultaneously another
group was given a control diet (cHL). Mice were then tested for cognitive ability using
a stone T-maze. Mice were required to correctly navigate 13 consecutive left and right
turns. The number of errors each mouse committed was used as a measure of cognitive
ability. Brain tissue slices were then taken from the cerebral cortices of the mice and
tested for IL-6, TNF-alpha, MCP-1, and BDNF with an ELISA. As well, western blots for
GFAP and Iba-1 were used to measure astrocyte and microglia reactivity, respectively.
Major Results:
There was no significant difference found in the number of errors in the Stone T-maze
between the WD and cWD groups; therefore the WD diet did not cause a reduction in
cognitive ability. Interestingly there also was not a significant difference in the levels of
inflammatory cytokines or BDNF growth factor between mice given the WD diet and those
given the control cWD diet. Astrocytes were more reactive in WD mice, which was seen by
an increase in GFAP expression in the tissue. There were no significant differences in the
Iba-1 microglia marker between the two cohorts. Between HL and cHL mice, a significant
difference was found in cognitive ability, illustrated by the larger number of errors
committed by HL mice. As well, HL mice were found to have higher levels of inflammatory
cytokines in brain tissue, and lower levels of BDNF. Astrocytes and microglia were
significantly more reactive in HL mice compared to cHL mice.
Conclusions:
Mice given the WD diet were not characterized with either brain inflammation or
cognitive impairment. By increasing the fat content to an HL diet, mice were then found
to have both brain inflammation and reduced cognitive ability. When taken together
this data suggests that obesity may be associated with a reduction in cognitive function,
through the inflammation of the brain.
103
References For Pictures:

http://media.peaceasw.com/2014/02/black-mouse.jpg
http://marginalrevolution.com/wp-content/uploads/2013/08/fat-mouse.png
http://what.h8r.net/fatmouse/fatmouse.jpg
http://blogs-images.forbes.com/joshwolfe/files/2014/06/brain_on_fire.jpg
http://cdn.shopify.com/s/files/1/0080/8372/products/tattly_christoph_niemann_low_battery_web_design_01_grande.
jpg?v=1336586731
Pistell, P. J., Morrison, C. D., Gupta, S., Knight, A. G., Keller, J. N., Ingram, D. K., & Bruce-Keller, A.
J. “Cognitive impairment following high fat diet consumption is associated with brain inflammation “
Journal of Neuroimmunology
Summary by:Husain Shakil
104
Summary of:
Transiently Increasing cAMP Levels Selectively in
Hippocampal Excitatory Neurons during Sleep Deprivation
Prevents Memory Deficits Caused by Sleep Loss
Authors: Robbert Havekes, Vibeke M. Bruinenberg, Jennifer C. Tudor, Sarah L. Ferri, Arnd
Baumann, Peter Meerlo, and Ted Abel
The article begins by introducing the reader to the negative effects of sleep deprivation on
hippocampal-dependent forms of memory. Multiple behavioural experiments are cited, each
observing the negative effect of sleep deprivation on spatial memory in animal models. This
is followed by a summary of the known molecular mechanisms behind this phenomenon.
Work done by Vecsey et al. (2009) demonstrated that the cAMP degrading enzyme PDE4
phosphodiesterase increased in activity during periods of sleep deprivation. This group also
observed that injections of a PDE4 inhibitor (Rolipram) into the hippocampus made memories
resistant to sleep deprivation. From these findings, the authors hypothesized that decreases in
hippocampal cAMP signalling that occur during sleep deprivation underlie associated memory
deficits. To test their hypothesis, the authors aimed to transiently increase cAMP levels in mice
during periods of sleep deprivation and observe the effects on spatial memory.
In order to increase cAMP levels solely in the hippocampus, the authors created a viral
vector containing the octopamine receptor gene DmOctβ1R. The octopamine receptor is
a GPCR natively found in Drosophila. Binding of the octopamine ligand to the receptor
results in adenylyl cyclase activation, leading to increased intracellular cAMP levels. The
addition of this receptor allowed the authors to increase hippocampal cAMP levels by
systemically injecting mice with octopamine. The viral vector also contained a CAMKIIa
promoter to ensure the octopamine receptor would only be expressed in excitatory
hippocampal neurons, as CAMKIIa is only expressed in such cells. Control mice were
given a vector with the DmOctβ1R gene swapped for a GFP gene. Spatial memory was
tested in an object-place recognition paradigm. The mice were placed in a chamber
with 3 objects and were allowed to explore for 6 minutes. The mice were removed from
the chamber and put back in their cages. Some mice were kept awake for 5 hours
by experimenters disturbing their cage, while others were allowed to sleep. The mice
were placed in the same chamber, with one of the objects in a different location. Task
performance was measured based on the preference for the displaced object.
Major Results:
The viral delivery of the DmOctβ1R was successful, as expression of the receptor was
detected in hippocampal excitatory neurons in the CA1, CA2, CA3, dentate gyrus, and granule
cell layer areas. Moreover, IP injections of octopamine resulted in significant cAMP increases
in the aforementioned areas. Other brain areas like the prefrontal cortex did not show the
same increase, strongly suggesting that the receptor was only present in the hippocampus.
The brains of some mice were harvested upon IP injection of octopamine to yield these results.
cAMP levels during the trials themselves were not measured. The time mice spent exploring
during their 6 minute training trial was not affected by DmOctβ1R presence. Sleep-deprived
mice expressing DmOctβ1R performed almost identically to all non-sleep deprived groups.
Furthermore, sleep-deprived mice expressing DmOctβ1R significantly outperformed control
sleep deprived mice in terms of preference for the displaced object.
Conclusions:
The authors demonstrated that transiently increasing cAMP levels in excitatory
hippocampal neurons via octopamine injections protected spatial memories from the
negative effects of sleep deprivation. Cognitive deficits associated with sleep deprivation
may be mediated by changes in cAMP signalling. Understanding the role cAMP plays in
humans and elucidating its downstream effectors could yield insight into the molecular
mechanisms of memory consolidation. The clinical applications for sleep-deprived
university students are obviously of immense interest as well.
105
Havekes, R., Bruinenberg, V., Tudor, J., Ferri, S., Baumann, A., Meerlo, P., & Abel, T. (2014).
Transiently Increasing cAMP Levels Selectively in Hippocampal Excitatory Neurons during Sleep
Deprivation Prevents Memory Deficits Caused by Sleep Loss. The Journal of Neuroscience, 34(47),
15715-15721.
Summary by:Arman Shekari

106
Summary of:
Alzheimer Disease in a Mouse Model: MR Imaging–guided
Focused Ultrasound Targeted to the Hippocampus Opens the
Blood-Brain Barrier and Improves Pathologic Abnormalities
and Behavior
Authors: Alison Burgess, Sonam Dubey, Sharon Yeung, Olivia Hough, Naomi Eterman, Isabelle
Aubert, Kullervo Hynynen
Magnetic resonance (MR) imaging-guided focused ultrasound has been discovered as a
technique for locally opening the blood-brain barrier non-invasively to improve the delivery of
drugs to the brain. When this method was applied in one hemisphere of the TgCRND8 mouse
model of Alzheimer’s disease (AD), plaque load significantly declined even without the delivery
of therapeutic agents. The study looked at whether MR imaging-guided focused ultrasound
treatments targeting the hippocampus could lead to improvements in behaviour and a
reduction in pathological abnormalities associated with AD.
The TgCRND8 mouse model of AD was used in this experiment. The focused ultrasound
beam was targeted onto the bilateral dorsal hippocampus for sonication. The seven-
month-old mice were treated with MR imaging-guided focused ultrasound to open the
blood-brain barrier once per week for three weeks. Next, Y-maze analysis was performed.
The mice were kept in two of the arms of the maze for 10 minutes, and then were put
in the maze again with access to all three arms. The time the mice spent exploring
the novel arm was used to test the improvement in spatial memory post-treatment.
Immunohistochemical analysis and plaque analysis were also performed.
Major Results:
MR imaging-guided focused ultrasound showed that levels of BBB opening were the same
in both the TgCRND8 mice and the non-TgCRND8 mice. Without treatment, Tg mice spent
61% less time than the non-Tg mice in the novel arm of the Y-maze. After MR imaging-guided
focused ultrasound, Tg mice spent about 99% more time in the novel arm of the Y-maze. The
TgCRND8 mice spent 48 seconds in the novel arm after treatment, while without treatment,
they spent only about 24 seconds exploring the novel arm. The mice behaviour in the Y-maze
was reflected by the significant reduction in the number and size of amyloid plaques in the
ultrasound-treated mice. There was a plaque size reduction in the treated TgCRND8 mice by
about 20%, and a 19% decrease in plaque load in the hippocampus. In addition, there was an
increase in the number of newborn neurons in the hippocampus in the treated mice group,
and a 227% increase in dendrite length in both treated non-Tg and TgCRND8 mice.
Conclusions:
The results in the Y-maze suggest that after treatment, the mice had an increase in
spatial memory and cognition, which are commonly diminished as AD progresses. This
shows that MR imaging-guided focused ultrasound may ameliorate memory deficits in
AD, decrease amyloid plaques in the AD brain, and increase the number of neurons and
synapses in the hippocampus.
107
Source: Burgess, A., Dubey, S., Yeung, S., Hough, O., Eterman, N., Aubert, I., Hynynen, K. (1994). Alzheimer
Disease in a Mouse Model: MR Imaging–guided Focused Ultrasound Targeted to the Hippocampus Opens the
Blood-Brain Barrier and Improves Pathologic Abnormalities and Behavior. Radiology, 273 (3), 736-745.
Burgess, A., Dubey, S., Yeung, S., Hough, O., Eterman, N., Aubert, I., Hynynen, K. (1994). Alzheimer
Disease in a Mouse Model: MR Imaging–guided Focused Ultrasound Targeted to the Hippocampus
Opens the Blood-Brain Barrier and Improves Pathologic Abnormalities and Behavior. Radiology, 273
(3), 736-745. Summary by:Jaclin Simonetta
108
Summary of:
Metabotropic NMDA receptor function is required for
β-amyloid-induced synaptic depression
Authors: Kessels HW, Nabavi S, Malinow R.
Alzheimer’s disease (AD) is characterized by an increase in extracellular plaques containing
β-amyloid (Aβ) peptide and intracellular tau tangles. In AD models, Aβ has been shown to
cause synaptic depression, loss of spines and reduced synaptic plasticity. This article seeks to
elucidate the mechanism behind Aβ’s contribution to synaptic deficits in AD. Previous studies
have shown that blocking NMDA receptors (NMDARs) can lessen the effects of Aβ on synapses.
Composed of two glycine binding GluN1 and two glutamate binding GluN2 subunits, NMDARs
are ionotropic receptors that are controlled by a voltage-dependent Mg2+ block. The GluN2
subunit can occur in two isoforms- GluN2A and GluN2B in hippocampal neurons. Upon
glutamate binding, its primary function allows Ca2+ ion flow through the receptor however
a previous study has proposed a secondary function where there is receptor endocytosis and
an NMDAR subunit switch. Based on this background information, the authors of this study
focus on the function of NMDARs in the hippocampus in the presence of Aβ oligomers.
Using the Sindbis virus, the authors infected CA1 neurons in hippocampal rat slices
with constructs of AP-CT100 (product of β-secretase cleavage of APP, precursor of Aβ)
and AP-CT84 (product of α-secretase cleavage of APP). The slices were incubated for
20-30h to allow for expression of the virus. During the incubation period, the authors
performed experiments with a variety of drugs including Aβ inhibitors, NMDA antagonists
specific for the GluN2 subunit or GluN2B isoform, and ion-channel blockers. Then,
neighbouring control and CA1 pyramidal neurons were stimulated with two separate
electrodes and the AMPAR-mediated excitatory postsynaptic current (EPSC) and the
NMDAR-mediated currents were measured. The EPSC amplitudes were created from an
average of 50 sweeps.
Major Results:
First, the authors confirmed that there is synaptic AMPAR depression in the increased
presence of Aβ produced by APP-CT100 expressing neurons and not with expression of APP-
CT84 or with expression of APP-CT100 and inhibitors of Aβ production such as a γ-secretase
inhibitor or scyllo-inositol. In the next series of experiments, the authors confirmed that the
Aβ-driven synaptic depression needs GluN2B activation. During APP-CT100 expression, the
slices were incubated with d-APV or R-CPP (NMDAR antagonists), Ro or ifenprodil (antagonists
that lock GluN2B in a closed conformation), and PEAQX (competitive GluN2 antagonist).
Now that the authors established that Aβ works on the GluN2B subunit of the NMDAR, they
wanted to further investigate the NMDAR’s function. During APP-CT100 expression, slices
were incubated with MK-801 or ketamine (ion-channel blockers) and CK-7 (blocks NMDAR at
glycine binding site). From this set of experiments, the authors were able to conclude that the
Aβ driven synaptic depression is not due to ion flux through the NMDAR but rather suggests
that there is a change in the GluN2B conformation. Finally, the authors compared NMDAR
transmission in infected versus non-infected cells before and after the addition of Ro to find
that the ratio of GluN2A:GluN2B increased, suggesting switching of the subunits.
Conclusions:
The authors were able to show that Aβ incudes AMPAR synaptic depression by activating
the GluN2B subunit of the NMDAR and not through ion flux of the NMDAR. They also
showed that the Aβ oligomers were able to increase the GluN2A:GluN2B ratio by removing
the GluN2B NMDARs from synapses. This study provides a preliminary mechanism
for Aβ function on synapses. If components of this pathway are identified upon further
investigation, they may serve as potential drug targets in AD patients to reduce synaptic
depression and thereby learning and memory problems in this population.
109
Kessels HW, Nabavi S, Malinow R. (2013). Metabotropic NMDA receptor function is required for
β-amyloid–induced synaptic depression. PNAS, 110(10):4033–4038. doi:10.1073/pnas.1219605110
Summary by: Olivia Singh

110
Summary of:
Default Mode Network Mechanisms of Transcranial Magnetic
Stimulation in Depression
Authors: Liston, C., Chen, A. C., Zebley, B. D., Drysdale, A. L., Gordon, R., Leuchter, B., Voss, H.
U., Casey, B. J., Etkin, A., & Dubin, M. J.
Depression has been one of the most common psychiatric conditions affect individuals
worldwide. However, many of the current antidepressant medications have been shown
to be limited in efficacy in terms of treatment and remission prevention. Transcranial
magnetic stimulation (TMS) appears to be a safer and more tolerable treatment
alternative that is effective in depressed individuals, including those resistant or averse to
medication. This study investigates the effects of TMS as a treatment of depression and
the mechanisms in which it modulates resting state functional networks in the human
brain.
17 depressed individuals and 35 healthy controls were given resting state fMRI scans
to establish their resting state functional networks in the brain. Healthy controls were
scanned once; whereas depressed individuals were scanned pre- and post-treatment.
The treatment consisted of 25 sessions of 10Hz excitatory TMS delivered at the left
dorsolateral prefrontal cortex (DLPFC) over 5 weeks. Functional connectivity maps of the
Central Executive Network (CEN) and Default Mode Network (DMN) were generated to
compare the difference in brain activity between depressed and healthy individuals as
well as the difference in brain activity in depressed individuals pre- and post-treatment.
The symptom of depressed individuals was assessed using the Hamilton Rating Scale for
Depression (HAM-D) pre- and post-treatment.
Major Results:
Comparison between pre-treatment depressed and healthy individuals shows
hypoconnectivity between the DLPFC and CEN and, contrastly, hyperconnectivity
between the subgenual anterior cingulate cortex (sgACC) and DMN in the depressed
brain. 25 sessions of TMS treatment at left DLPFC over a 5 weeks period result in mostly
normalized connectivity between the DLPFC and DMN but no difference in connectivity
between the sgACC and CEN, which remains abnormally elevated. Overall, the symptoms
of depressed individuals improved as assessed using the HAM-D by over 9 points.
Conclusions:
Results suggest that TMS treatment modulates functional connectivity in the brain,
and provides treatment effect in reducing depressive symptoms. This study has clinical
importance in the understanding of depression and further development of more effective
treatments.
111
Liston, C., Chen, A. C., Zebley, B. D., Drysdale, A. T., Gordon, R., Leuchter, B., … & Dubin, M. J.
(2014). Default mode network network mechanisms of transcranial magnetic stimulation in depression.
Biological psychiatry, 76(7), 517-526
Summary by: Eugene Tang

112
Summary of:
Dopamine neurons derived from human ES cells efficiently
engraft in animal models of Parkinson’s disease.
Authors: S. Kriks, J.W. Shim, J. Piao, Y.M. Ganat, D.R. Wakeman, Z. Xie, L. Carrillo-Reid, G.
Auyeung, C. Antonacci, A. Buch, et al.
Kriks, et al. investigated the significance of human pluripotent stem cells (PSCs) in
regenerative cell therapy by examining its performance in animal models of Parkinson’s
disease.
In this study, a floor-plate protocol (in comparison to the rosette method) was used
to derive dopaminergic (DA) neurons from human PSCs cells. The expression of floor-
plate precursors was especially important to stem cell specialization/differentiation. It
is known that CHIR activates canonical Wnt signalling and induces the expression of
LMX1A (roof plate marker), which promotes the specialization of PSCs into DA neurons
in vivo. Specific precursors such as LMX1A and FOXA2 were expressed after eleven days
of exposure to Wnt signalling and sonic hedgehog (SHH) factors. After differentiation
these specialized midbrain DA neurons were then obtained and engrafted into three host
animal populations, each of which was a model for Parkinson’s. The researchers also
looked at ongoing concerns associated with engraftment. One major problem associated
with stem cell engraftment would be overgrowth or non-neuronal differentiation in host
organisms.
Major Results:
The first group of animals used was composed of a control group with non-lesioned
mature mice. The stem cell derived DA neurons showed high survival rate even six
weeks after engraftment, no overgrowth was observed in the control population. The
second group of rodents used was composed of 6-hydroxy-dopamine (6-OHDA) lesioned
parkinsonian rats. The development of PSC-derived DA neurons showed high survival
rates even after four months. Further analysis illustrated a rescue of amphetamine-
induced rotation behaviour, which is usually impaired in rats that are affected by
Parkinson’s. In addition, these rats also showed improvements in tests that required
movement and motor functions (i.e. stepping test and the cylinder test). Lastly, the final
group of animals used was adult MPTP lesioned rhesus monkeys. The stem cells were
injected along with the DA precursors in the caudate and putamen (basal ganglia region)
within both sides of the brain. In addition, one side of the brain was also injected with
green fluorescent protein (GFP) to track the development of the DA neurons. After one
month, the results illustrated high DA neuron survival rates and no overgrowth.
Conclusions:
In conclusion, all three animal models showed high efficacy of engrafted PSC-
derived DA neurons. Thus with future research, we can explore many other
biomedical applications of human pluripotent stem cell therapies for treating other
neurodegenerative disorders (such as dementia) in addition to Parkinson’s disease.
113
S. Kriks, J.W. Shim, J. Piao, Y.M. Ganat, D.R. Wakeman, Z. Xie, L. Carrillo-Reid, G. Auyeung, C.
Antonacci, A. Buch, et al. Dopamine neurons derived from human ES cells efficiently engraft in animal
models of Parkinson’s disease.
Nature, 480 (2011), pp. 547–551. Retrieved from: http://www.nature.com/nature/journal/v480/n7378/
full/nature10648.html
Summary by: Jiawei Zhang
Huntington’s disease (HD) is a neurodegenerative disease that severely affects motor,
cognitive and psychological functions. HD patients are observed with striatum atrophy
from the loss of medium-sized spiny neuron. Despite mechanisms regarding how the
huntingtin gene causes the degeneration of striatal neurons is unclear, many researchers
began to focus on the effects of increased BDNF levels in the striatum and its effect on
HD patients. It has been shown the there is a reduction in striatal BDNF protein levels in
patients. BDNF deficiency in the striatum causes neuronal alterations such as neuronal
loss and dendritic abnormalities that affects HD pathogenesis.
Xie et al., tested the effects of increased BDNF expression in the forebrain on a double
transgenic mice (of BDNF overexpression gene and YAC gene to induce HD) to observe
striatal changes which may influence HD. They used various methods such as Rotarod,
Beam walk, footprint, and muscle strength test to examine phenotypic characteristic
changes between HD mice (YAC128 mice), BDNF transgenic mice (BTg mice), widetype
between YAC128 and BTg, and double transgenic mice (YAC;BTg mice). Xie et al., also
performed in situ hybridization, immunoblotting, immunohistochemistry to compare
molecular changes within the brain between the four mice strains. They ran a Western
Blot to verify that BDNF protein level has increased in the striatum.
Xie et al., observed that BDNF overexpression in the forebrain of the YAC128 mice
increased BDNF in the striatum. Moreover, BDNF was able to activate TrkB receptor
which signals various pathways that mediates neuronal differentiation, neuronal
survival, synaptic plasticity and soma size in both YAC128 and BTg mice. BDNF
overexpression was able to improve motor related performance of YAC; BTg mice. BDNF
overexpression can reverse cognitive deficiencies in YAC128 mice, as seen through
improvements in procedural learning of swim tests. As well, BDNF was able to prevent
and normalize striatal atrophy (and therefore, brain weight overall) and loss in striatal
neurons. In general, amplifying BDNF protein expression increased receptor levels related
to neurotransmitters important for striatal function such as dopamine receptor D2.
Most importantly, it reversed striatal medium-sized spiny neuronal spine and dendritic
morphology that were previously altered in the YAC128 mice.
BDNF overexpression was able to prevent and normalize many functions that are
affected by HD, such as motor and cognitive deficiencies. On a molecular level, it was also
able to reverse atrophy in the striatum and neuronal loss and alterations. Furthermore,
it was shown BDNF overexpression can also stimulate signaling pathways that promotes
neuronal differentiation and survival in a YAC128 mice. These evidence suggests BDNF
overexpression in the striatum is a potential therapeutic treatment for HD. The study
did observing activities of seizure in some BTg and YAC; BTg mice and advises to not
overstimulate BDNF in epileptic regions in brain regions such as hippocampal and
entorhinal cortex.
115
Summary by: Yidong Zhan

116
Summary of:
Pharmacological Rescue of Mitochondrial Deficits in iPSC-
Derived Neural Cells from Patients with Familial Parkinson’s
Disease
Authors: Graziotto J, Marder K, Andrabi S, Perez-Torres E, Klein C, McLean JR, Clark L, Isacson O, Sundberg M, Feng J, Trojanowski JQ, Guardia-Laguarta C,
Dawson VL, Opala G, Chen L, Moskowitz C, Krainc D, Volpicelli-Daley L, Dawson TM, Scarffe LA, Xie Z, Surmeier DJ, Jiang H, Romero N, Wszolek ZK,
Przedborski S, Cooper O, Huang Z, Mazzulli J, Osborn T, Bogetofte H, Lee VM-Y, Carrillo-Reid L, Ross OA, Uitti RJ, Seo H, Lawson T, Deleidi M, Hargus G
Parkinson’s disease is the result of ongoing degeneration of dopamine-generating neurons and
synapses of the nigrostriatal pathway which can be induced by both environmental and genetic
factors. This paper looks at the mutations in genes that impact the activity of kinases LRRK2
(leucine-rich repeat kinase 2) and PINK1 (PTEN-induced putative kinase 1) that seem to increase
the risk of developing Parkinson’s disease. By using iPSCs (induced pluripotent stem cells)
derived from fibroblasts of familial Parkinson’s disease patients as well as healthy patients and
patients with the mutations who have not yet shown signs of PD, to form neural cells, researchers
from several labs were able to combine assay results to compare the cell phenotypes from each.
This paper pays attention to deficits in mitochondrial function in particular.
First, the researchers generated iPSCs from fibroblasts of patients with familial PD, patients carrying
the mutations but pre-symptomatic and from healthy subjects used as a control. Next, they observed
levels of vulnerability of the derived neural cells to chemical stressors that affect specifically the function
of mitochondria or the degradation of proteins using an LDH (lactate dehydrogenase) assay (measuring
its release), and used immunocytochemistry to quantify levels of dopamine neurons. They then focused
further on the PINK1 mutation by measuring mROS levels in response to cellular stressors (and later
GSH levels) by fluorescently labeling the cells with an indicator of mROS and recording the amount of
fluorescent cellular events that occurred. Next, oligomycin, followed by FCCP and finally rotenone, all
compounds which inhibit proteins or complexes that deal with oxygen consumption, were administered
and the oxygen consumption rate was measured using an XF24-3 Extracellular Flux Analyzer during
injection of the compounds. To measure rates of mitochondrial mobility, live-cell imaging was used
on all three classes of subjects. In the final step the researchers used antioxidants Coenzyme Q10,
rapamycin or GW5074 to see if they could pharmacologically rescue the increased vulnerability of PD
neural cells to chemical stressors, again measuring the amount of LDH released.
Major Results:
1) Patients with familial PD and pre-symptomatic patients who carry the mutations as well,
both show higher vulnerability when exposed to low concentrations of chemical stressors such as
valinomycin, which causes the depolarization of mitochondria with an influx of K+ ions. However
they do not show vulnerability to CCCP, a chemical stressor that does the same function, except
using protons. This may show that the mutations in the derived neural cells cause the inability to
respond to mitochondria that has been damaged by K+ ions.
2) Those carrying the PINK1 mutation again demonstrated the inability to handle oxidative
stress as seen by a significant increase of mROS (mitochondrial reactive oxygen species), a major
cause of cellular stress, and a decrease in GSH, an antioxidant that should be present to prevent
damage done by high levels of mROS.
3) The basal oxygen consumption rate of patients with PD with the PINK1 mutation was higher than
those who did not carry the mutation, and injection of oligomycin, an inhibitor of ATP-synthase, did
not reduce this suggesting that the electron transport chain is impaired in this situation. However in
the LKKR2 mutated neural cells, the OCR is less than that of healthy subjects which suggests that
the electron transport chain is fine, but that increased kinase activity reduces the OCR.
4) The LKKR2 mutations show more mitochondrial mobility as well as in a more bidirectional
manner, and shorter mitochondrial length than in healthy individuals and the PINK1 mutation.
This mutation is then further implicated in mitochondrial impairment.
5) Pharmalogical rescue only occurred by coenzyme Q10 rescuing the PINK1 vulnerability to low
concentrations of concanamycin A and valinomycin.
Conclusions:
The continuous degeneration of dopamine-generating neurons in the nigrostriatal pathway is the key feature
of Parkinson’s disease. The iPSCs generated in this study were efficient in responding to low concentrations
of cellular stressors that can be thought to mimic the gradual amassing of dysfunctional mitochondria (as
you would see in aging PD patients) and so they provide an opportunity to delve into how these significant
mutations affect the degenerative aspects of this disease. Individual treatment is possible by using iPSCs, and
can be done by using cellular reprogramming technology as seen from the data collected of which mutations
respond to which antioxidants for pharmacological rescuing. In short, these neural cells derived from iPSCs
allow for major advances in understanding the foundation of PD and possible treatments.
117
Graziotto J, Marder K, Andrabi S, Perez-Torres E, Klein C, McLean JR, Clark L, Isacson O, Sundberg M, Feng J,
Trojanowski JQ, Guardia-Laguarta C, Dawson VL, Opala G, Chen L, Moskowitz C, Krainc D, Volpicelli-Daley L,
Dawson TM, Scarffe LA, Xie Z, Surmeier DJ, Jiang H, Romero N, Wszolek ZK, Przedborski S, Cooper O, Huang Z,
Mazzulli J, Osborn T, Bogetofte H, Lee VM-Y, Carrillo-Reid L, Ross OA, Uitti RJ, Seo H, Lawson T, Deleidi M, Hargus
G “Pharmacological Rescue of Mitochondrial Deficits in iPSC-Derived Neural Cells from Patients with Familial
Parkinson’s Disease” Sci Transl Med (2012) doi: 10.1126/scitranslmed.3003985 Published online 04 July 2012.
Summary by: Nimara Dias-Karunaratne
118
Summary of:
Social Interaction Rescues Memory Deficit in an Animal
Model of Alzheimer’s Disease by Increasing BDNF- Dependent
Hippocampal Neurogenesis
Authors: Ya-Hsin Hsiao, Hui-Chi Hung, Shun-Hua Chen, and Po-Wu Gean
Strong social connections have been found to decrease the risk of cognitive decline
and Alzheimer’s but the underlying mechanisms are unknown. BDNF has been found
to play an important role in the differentiation and survival of certain neurons involved
in LTP, learning and memory. Previous research has revealed that increased BDNF will
enhance neurogenesis. Hsiao et al. provided first evidence that when APP/PS1 mutant
mice with impaired contextual fear memory are cohoused with wild type mice, there will
be increased levels of BdnfmRNA and protein production which will result in increased
neurogenesis and ultimately rescue memory in mutant mice.
Male APP/PSI mutant mice were obtained from the Jackson Labertory. At 6 months
old an APP/PS1 randomly housed with WT mice for 3 months. 2 APP/PS1 mice where
cohoused to serve as control. Sociability of APP/PS1 and WT mice was measured by
measuring total duration of contact for 10 minutes. Fear conditioning, morris water maze
and object-place recognition was used to test for memory. BdnfmRNA and protein were
measured by dissection of hippocampal tissue from the mutant mice. BrdU and NeuN
were injected into mice to detect neurogenesis. Methylazoxymethanol acetate, diphtheria
toxin and a retrovirus vector encoding DT receptor was injected into post-cohousing
mutant mice to block/ablate cell proliferation and test the relationship between
neurogenesis and memory improvement. Loss of function by shRNA transfection and
overexpression of BDNF was conducted to test for the role of BDNF in rescuing memory.
Statistical analysis was conducted to determine significance of the data.
Major Results:
After cohousing with WT mice, APP/PS1 mice showcased reversal of contextual memory
impairments and performed better in the memory tests. Social interaction with wild type
mice increased BDNF mRNA and protein in the hippocampus. Elevated BrdU+/NeuN+
cells in the dentate gyrus after cohousing indicates increased neurogenesis in mutant
mice. Chemically blocking cell proliferation using methylazoxymethanol acetate abolished
the positive effects of social interaction in APP/PS1 mutants. Ablation of specific mitotic
neurons using diphtheria toxin and a retrovirus vector encoding DT receptor also
had the same effect. Lastly it was also shown that overexpression of BDNF mimicked
memory improving effect while genetic knockdown blocked memory improvement. Which
indicates that the rescue of contextual memory by social interaction is mediated by BDNF
hippocampal neurogenesis.
Conclusions:
It was found that social interactions in effect reversed memory deficits in APP/PS1
mice. The results provided evidence social housing improves memory and cognition in the
mouse model of Alzheimer’s disease via BNDF expression and associated neurogenesis
in the hippocampus. The proposed mechanism provided a basis in the prevention,
treatment and management of cognitive decline such as Alzheimer’s disease associated
dementia .
119
Citation: Hsiao YH, Hung HC, Chen SH, Gean PW. (2014) Social Interaction Rescues Memory Deficit in an
Animal Model of Alzheimer’s Disease by Increasing BDNF- Dependent Hippocampal Neurogenesis. The Journal
of Neuroscience, 34(49), 16207-16219
Hsiao YH, Hung HC, Chen SH, Gean PW. (2014) Social Interaction Rescues Memory Deficit in an
Animal Model of Alzheimer’s Disease by Increasing BDNF- Dependent Hippocampal Neurogenesis.
The Journal of Neuroscience, 34(49), 16207-16219 Summary by: ZiTeng Li
120
Summary of:
Intra-amygdala microinjection of TNF-α impairs the auditory
fear conditioning of rats via glutamate toxicity
Authors: He Jing, Yongxin Hao, Qiang Bi, Jiaozhen Zhang, Pingting Yang
The production of pro-inflammatory cytokines during systemic infection is known to
contribute to cognitive impairment via various mechanisms. This study examines, in
particular, the cytokine TNF-α and its effects on cognitive functions by directly injecting
TNF-α into the brain. Past research have shown that TNF-α can interfere with proper
learning and memory functions. In addition, high levels of TNF-α have also been found
in patients with Alzheimer’s disease, a neurodegenerative disorder. Thus, the study
further investigates excitotoxicity as a possible mechanism for TNF-α-induced cognitive
impairment since TNF-α is known to enhance glutaminergic transmission in vitro.
Cannula implantation surgery was performed on rats to facilitate Intra-amygdala
microinjection of TNF-α. Auditory fear conditioning was employed to assess rodent
learning and memory function by scoring the freezing responses exhibited in rats. The
rats were allowed to habituate to the conditioning chamber on Day 0. On Day 1, the
rats were injected with TNF-α (experimental) or ACSF (control). The conditioning session
began on Day 2, where the rats first habituated to a tone (CS) and is later subjected to
a footshock (US) paired with a tone. The rats then underwent 15 extinction sessions.
Foot shock sensitivity was also tested. In order to determine whether the glutaminergic
pathway is involved in TNF-α induced cognitive impairment, 1) HPLC was used to
measure glutamate (experimental) and GABA (control) levels in the amygdala and 2) Rats
were administrated PBS+TNF-α, MK-801 (an NMDAR antagonist), or MK-801+TNF-α
before they were subjected to fear conditioning in a second experiment.
Major Results:
Rodents treated with TNF-α displayed a lower percentage increase in freezing
behaviour during conditioning compared to the rapid increase in rats treated with the
vehicle (ACSF). During the extinction phase, the percentage of freezing behaviour in the
vehicle group decreased significantly while freezing percentage decreased much less in
the TNF-α groups. There were no differences in foot shock sensitivity between the two
groups; therefore, the possibility that TNF-α affected fear conditioning is eliminated.
TNF-α-treated rats were also found to have higher levels of glutamate in the amygdala
than vehicle-treated rats, however, GABA levels remained unchanged. Results of the 2nd
fear conditioning experiment showed that rats in the MK-801 groups displayed proper
acquisition and extinction of the freezing response whereas it is impaired in TNF-α+PBS-
treated rats. Moreover, the application of MK-801 with TNF-α is seen to be able to rescue
proper fear learning.
Conclusions:
Glutamate levels can be increased in vivo by TNF-α; thus, TNF-α can cause learning
and memory deficits via neurotoxicity induced by excessive stimulation of NMDAR
by glutamate. Pharmacological blockade of glutaminergic pathway using an NMDAR
antagonist such as MK-801 can prevent cognitive dysfunction. The study is relevant to
neuroscience because it furthers our understanding of how the immune response and
consequent cytokines affect the brain and cognitive function.
121
Picture Sources:
http://imgs.tuts.dragoart.com/how-to-draw-yuki-sohma-as-rat_1_000000002561_5.png
http://images.clipartpanda.com/consternation-clipart-hypodermic-needle.gif
http://comparative-cognition-and-behavior -reviews.org/wp/wp-content/uploads/2013/10/kesner_figure1.png
http://www.nature.com/nm/journal/v16/n4/images/nm0410-369-F1.jpg
He Jing, Yongxin Hao, Qiang Bi, Jiaozhen Zhang, Pingting Yang “Intra-amygdala microinjection of
TNF-α impairs the auditory fear conditioning of rats via glutamate toxicity” Neuroscience Research.
(2014). http://dx.doi.org/10.1016/j.neures.2014.10.015 Summary by: Man Lai Ho
122
Summary of:
An fMRI study on the influence of sommeliers’ expertise on the
integration of flavor
Authors: Pazart L, Comte A, Magnin E, Millot J-L and Moulin T
Flavour integration is a complex neurological process. It involves emotions, gustatory
and olfactory sensing, and semantic, episodic and flavour memory. Flavour integration is
important to study because of its effects on eating behaviour. In this study the authors
examine the differences in brain activation during wine sampling between experts and
novices via fMRI. By blinding the participants to the types of wine, the authors can show
the importance of memory and sensing capabilities in flavour integration. Temporally,
the authors hypothesize that wine experts (the better flavour integrators) will be able to
integrate flavours before swallowing, contrary to the previous study on this topic.
Ten wine experts were matched with a wine novice of similar age, sex and locality. All
20 subjects did a water pre-test to practice drinking in the controlled way: 7 seconds
of swishing the liquid, 13 seconds of after-taste. For the actual task, wine and water
were randomized and each was tried twice in a row then rinsed with water. No visual
information was possible, as the wine/water was delivered in a custom contraption, and
the participants were asked to close their eyes. During the task the participants were
measured with an fMRI machine. The water rinse was used as a control.
Major Results:
The results highlight the differences between experts and controls during the wine
testing trials. The authors analyzed both taste and after-taste activation by all subjects,
by group: experts vs contols, and by contrast: expert-controls and controls-experts. For
all subjects there was activation in the insula and frontal lobe during taste and after-
taste, and in the pallidum, left parahippocampal gyrus and left thalamus during taste.
Analyzing by group revealed significant differences in activation between experts and
controls. During taste, experts showed activation in more brain areas, particularly the
brainstem, subcortical areas, the amygdala/hippocampus complex, and temporal and
occipital lobes. Controls showed greater activation in the parietal lobes. During after-
taste, experts showed much less activation overall. They showed more activation in the
right temporal lobe and the left hippocampus than controls, but the controls showed
more activation in the caudate nucleus, anterior insula, and frontal, parietal, and
temporal lobes.
Conclusions:
The main conclusions to be drawn from the study are that expertise promotes faster
and more efficient flavour processing. Further, the brain areas involved appear to be
memory-related, implying a deeper understanding of the flavour (associated origins,
familiar characteristics). Expertise implies faster processing at the appropriate levels of
the brain to integrate flavour from various modalities.
123
Images from Pazart et. al. (2014)
Pazart L, Comte A, Magnin E, Millot J-L and Moulin T (2014) An fMRI study on the influence of
sommeliers’ expertise on the integration of flavor. Front. Behav. Neurosci. 8:358.
Summary by: Sylvia Jennings
124
Summary of:
BDNF mediates improvements in executive function following
a 1-year exercise intervention
Authors: Leckie, R. L., Oberlin, L. E., Voss, M. W., Prakash, R. S., Szabo-Reed, A., Chaddock-
Heyman, L., …Erickson, K. I.
Ample research in the field of cognitive and behavioral neuroscience has demonstrated
a link between age-related neurodegeneration and progressive loss of executive function.
Age-related neurodegeneration is the process by which the elderly brain, heaped with
knowledge of ones past, undergoes neuronal dwindling and synaptic pruning due
to programmed cell death (apoptosis) of brain cells. As neurons are lost, executive
function - a higher cognitive ability involved in managing working memory, reasoning,
rationalizing and planning forthcoming behaviors - becomes impaired. To decrease the
rate of neurodegeneration - particularly in the prefrontal cortex where executive function
is regulated - researchers have begun to investigate weather an elevation in brain derived
neurotrophic factor (BDNF) can improve neurite outgrowth and cell survival well into old
age. A depletion of this growth factor in the prefrontal cortex has been tied to increased
neurodegeneration, as demonstrated by reduced grey and white matter volumes and thus
compromised executive control. Researchers have considered natural elevation in BDNF
serum levels via aerobic exercise. In the following study, Leckie et al. (2014) sought to
demonstrate that a 1-year daily exercise intervention, specially that of the aerobic kind,
increases BDNF serum levels and improves performance on a test of executive function in
elderly subjects.
A sample of 92 elderly adults (mean age = 67) had blood drawn prior to a 1-year
exercise intervention. The sample was clotted, incubated and centrifuged to later quantify
serum BDNF using an immunoabsorbant assay. Participant’s aerobic fitness levels were
assessed prior to appointing them to an exercise condition for a 1-year intervention.
The VO2max of all participants - the maximum volume of oxygen used by the subject -
was measured while completing a cardio fitness test. Following the fitness assessment,
subjects were assigned to one of two conditions: 47 participants were assigned to an
experimental condition, a 1-year aerobic exercise intervention and 45 were assigned to
a control condition, a 1-year stretching and toning exercise intervention. Participants
in the aerobic exercise condition were required to walk for 10 minutes daily, thereafter
increasing this duration by 5 minutes until a 40 minute maximum exercise period was
reached. Participants in the stretching-toning condition completed 4 muscle toning
exercises, yoga and one exercise of their choosing, daily. BDNF serum levels were
measured at the end of both 1-year exercise intentions.
Improvements in executive function following the intervention were assessed via a
task-switch paradigm. Numbers were displayed in a square box, where background
colour indicated whether subjects were to make even/odd or lower/higher judgments
about the number presented. When the background was blue, subjects were asked to
determine weather the number was higher (by pressing an X key) or lower (by pressing a
Z key) than 5. When the background was pink however, they were asked to make odd (by
pressing the N key) or even (by pressing the M key) judgments. A Block consisted of the
number presentation for 1500 ms., a fixation period of 3 ms. after which another number
was presented. The task was divided into two conditions. In the single task condition,
participants made high/low judgments in Block 1 and even/odd judgments during Block
2 for 60 trials. The second mixed condition was subdivided into two trials. During a
repeat trial, subjects made one type of judgment (higher/lower or even/odd judgments),
similar to the single task condition. In the switch trial, blocks included both higher/lower
and odd/even judgments. Accuracy - as a measure of executive function -during the
task-switch paradigm was measured based on the difference in percent correct judgments
for the mixed condition and the single task condition.
Task-Switch Paradigm Elucidated
Condition 1: Single Task Condition - 2 blocks, 60 trials each.

Block 1 – Higher/lower than 5 judgment (1500 ms.) - fixation (3 ms.) - Higher/lower than
5 judgment (1500 ms.)
Block 2 – Even/odd judgment (1500 ms.) - fixation (3 ms.) – Even/odd judgment (1500
ms.)
Condition 2: Mixed Condition – 1 block, 120 trials

Repeat Trial (1 Block) - Higher/lower than 5 judgment (1500ms) - fixation (3 ms.) -
Higher/lower than 5 judgment (1500 ms.) OR Even/odd judgment (1500 ms.) - fixation (3
ms.) – Even/odd judgment (1500 ms.)
Switch Trial (1 Block) - Higher/lower than 5 judgment (1500 ms.) - fixation (3 ms.) -
Even/odd judgment (1500 ms.) (can be reversed)
Major Results:
Subjects in the aerobic exercise condition and the stretching and toning condition
did not display differences in the pre-intervention serum BDNF levels and VO2max.
Post-serum BDNF levels were elevated for participants in the aerobic exercise condition,
specifically for subjects > 65 years of age. Thus, age had a moderating effect on aerobic
exercise and BDNF serum levels. Global accuracy (mixed trial accuracy - single trial
accuracy) was greater for subjects >71 years of age in comparison to younger subjects.
Thus, increased BDNF levels due to daily aerobic exercise mediate improvement in
executive function. Participants >65 in the stretching and toning condition did not
display higher BDNF levels, but rather marked decreases in the post-serum levels of
this neurotrophic factor, evidence of age-related neurodegeneration. Subjects in this
flexibility exercise conditioning performed poorly on the task-switch paradigm, particular
for the mixed condition when they were required to make both higher/lower and even/
odd judgments. Thus, decreased BDNF levels in these subjects led to increased apoptosis
of neurons in regions involved in executive function, as demonstrated by the decreased
accuracy in judgments. It is worthy to note that local accuracy, switch trial accuracy -
repeat trial accuracy, was similar for subjects in the aerobic exercise condition and the
stretching and toning condition.
Conclusions:
The age of elderly subjects moderates changes in BDNF serum levels as demonstrated
by significantly higher amounts of neurotrophic factor in adults >65. Subjects in the
1-year aerobic condition, >71 years of age showed better task-switch performance, with
higher accuracy in mixed trials that demand executive function and control. Thus, an
increase in serum BDNF levels due to aerobic exercise mediates the effect of this physical
activity on task-switch performance. Stretching and toning does not elevate BDNF levels
and thus task-switch performance, as mediated by this factor, declines. Thus, elderly
individuals should be encouraged to partake in daily aerobic exercise, rather than
flexibility exercise to prevent the waning of executive function. A limitation of this study
however is the lack of neuroimaging. A similar study should perform fMRI simultaneously
as participants complete the task-switch paradigm to look at activity in the prefrontal
cortex. The subject’s white matter should also be assessed using tractography to look for
neuronal dwindling in regions associated with executive function. Furthermore, subjects
prior to intervention should have completed the task-switch paradigm for comparative
purposes.
Thus, Leckie et al. (2014) found elevated BDNF levels as mitigating factor for
neurodegeneration in regions involved in executive control by mediating the effects of
aerobic exercise on task-switch performance. Furthermore, age moderated the effect of
exercise intervention on BDNF serum levels, with adults >65 showing higher levels of
growth factor.
Leckie, R. L., Oberlin, L. E., Voss, M. W., Parkas, R. S., Szabo-Reed, A., Chaddock-Heyman, L., …
Erickson, K. I. (2014). BDNF mediates improvements in executive function following a 1-year exercise
intervention. Front. Hum. Neurosci, (8) 985, 1-10.
Summary by: Melissa Colaluca
128
Summary of:
Fear of the unexpected: Hippocampus mediates novelty-induced
return of extinguished fear in rats
Authors: Stephen Maren
Many psychological problems such as post-traumatic stress disorder rely on treatments
that attempt to weaken or erase learned fears and memories of traumatic experiences
through cognitive therapy or administration of drugs. Drugs are often ineffective because
their effect on the pathways of the brain involved in fear learning and extinction are still
yet to be fully understood. However, it is well known that the hippocampus is involved
in detecting associative novelty – a phenomenon where a new stimulus is presented
in a familiar context, or a familiar stimulus presented in a new/unfamiliar context.
The purpose of the experiment was to understand the role of the hippocampus in the
renewal of extinguished memories, and how it affected this process through associative
novelty. Normally, when a stimulus or context is familiar to an organism, it will
reactivate memories that were learned or conditioned at an earlier point in time. It was
hypothesized that blocking the hippocampal pathway that detects associative novelty
with the GABAA agonist muscimol would result in the inability to renew previously
extinguished fears in rats.
Rats were trained in three conditions – fear conditioning, extinction, and renewal. In
the first experiment, the rats were first fear conditioned with a foot shock (US) and tone
(CS). 24 hours later their fear was extinguished by presenting the tone without any foot
shock. Another 24 hours later, the rats were injected with either the GABAA agonist
muscimol (to inactivate the hippocampus) or saline (control), and given a retrieval test
(to see if the fear would return) in either the same or different context from where the
extinction occurred. In the second experiment, the conditions were identical with the
exception that the retrieval test was done in the same context as that of the extinction (no
variation in context) but the tone that was presented during this test was either novel or
familiar to the rats.
Major Results:
In experiment one (where the context was manipulated), saline-injected rats showed
higher levels of freezing in the novel context compared to the context where the extinction
occurred during the retrieval test. In contrast, the muscimol-injected rats did not show
any changes in freezing behaviour between the two contexts. In experiment two (where
the conditioned stimulus was manipulated), saline-injected rats showed higher levels of
freezing when the new conditioned stimulus was presented compared to the familiar one.
The muscimol-injected rats showed similar behaviour but to a much lesser degree
Conclusions:
Although the hippocampus detects novel contexts or stimuli and organisms normally
respond strongly to novelty, when the hippocampus is inactivated by the GABAA agonist,
muscimol, rats no longer show an increased response to novelty. There is therefore a
strong correlation between the hippocampus’ detection of associative novelty and the
renewal of extinguished fear responses, because when the hippocampus is inactivated
the fear response declines or disappears entirely. One important point to be noted is that
in experiment two, there was only a small difference between the saline and muscimol
injected rats, most probably because the hippocampus is important in spatial memories
and probably detects novelty in context better than in stimuli.
129
Maren, Stephen “Fear of the unexpected: Hippocampus mediates novelty-induced return of

extinguished fear in rats “ Neurobiology of Learning and Memory (2014) doi:10.1016/j.
nlm.2013.06.004 Published online 17 June 2013
Summary by: Divya Mamootil
130
Summary of:
A neuroprotective role for microRNA miR-1000 mediated by
limiting glutamate excitotoxicity
Authors: Pushpa Verma, George J Augustine, Mohamed-Raafet Ammar, Ayumu Tashiro & Stephen
M Cohen
Recent studies have shown miRNAs as important players in controlling many cellular and
molecular functions. In recent studies, the roles of miRNA in regulating synaptic plasticity,
regulating responsiveness in synaptic transmission and neurodegeneration have been
established and have been shown to act on neurons either in post-synaptic or pre-synaptic
manner via retrograde fashion or through affecting vesicle density. However, the role of miRNA
in pre-synaptic terminals affecting neurotransmitter release has not been well established.
Verma et al., show the regulation of vesicular glutamate transporter (VGlut) by miRNA-1000
in Drosophila and its contribution to early-onset neurodegeneration and glutamate mediated
excitotoxicity. Moreover, the current study draws a potential link in VGlut deregulation by
miRNA-1000 to neurodegenerative disorders like Parkinson’s and Alzheimer’s.
Different combinations of miR-1000 mutant alleles were used in the current study. A knockout
allele, KO1, of the miR-1000 was made using targeted homologous recombination. A second
independent knockout allele, KO2 of the miR-1000 was made using a vector that exchanges GFP,
Gal 4 reporters or 202 bp spanning miRNA hairpin of rescue allele, for the miR-1000 locus by
recombinase-mediated cassette exchange (RMCE). The rescue allele expression produced roughly
half the expression of normal miR-1000 and was used to test the recovery of mutant phenotype.
The mean fold change in VGlut mRNA was determined by quantitative PCR with mRNAs extracted
from animal heads. UAS-RNAi transgene (VGlut-RNAi) was used to reduce vesicular glutamate
transporter mRNA (VGlut). The performance in climbing assay was calculated by measuring
the percentage of flies under each miR-1000 mutants that were able to climb >5 cm in a 30-cm
column and was used as a model for determining neurodegeneration and movement disorder in
Drosophila. The effects of glutamate receptor expression in miR-1000 mutants were determined by
mutating NMDA receptor gene Nmdar1. The effects of suppression of apoptosis in neurons were
studied by expressing Drosophila inhibitor of apoptosis protein (DIAP1).
Major Results:
The current study found deregulation in the presynaptic vesicular glutamate transporter, its
contribution to excess glutamate release and glutamate excitotoxicity and neurodegeneration using
three different combinations of miR-1000 mutant alleles. The level of vesicular glutamate transporter
mRNA was found to be 4 fold in (KO1/KO2) miR-1000 mutant flies compared to control, rescued
and (KO2/+) mutants, confirming deregulation in vesicular glutamate transporter in miR-1000
mutants. Similarly, the median amplitude and frequency of miniature excitatory junction potentials
(mEJPs) were found to be significantly higher in (KO1/KO1) mutants compared to control and
rescued flies. The contribution of VGlut deregulation to excess glutamate release and increased
mEJPs was confirmed by expressing VGlut-RNAi in miRNA-1000 expressing cells. It was found that
KO2/KO2-GAL4 fly mutants had their median mEJP frequency and amplitude significantly higher
than VGlut-RNAi, KO2/KO2-GAL4 expressing mutants, ratifying the presence of excess glutamate
in the synapse. Lastly, it was found that Nmdar1 mutated flies in miR-1000 mutants- Nmdar1,
KO2/KO1 and Nmdar1, KO2/+, had improved survival and performance in climbing assay and
reduced apoptotic death compared to KO2/KO1 mutant flies. miR-1000 mutants expressing DIAP1
in metabotropic glutamate receptor expressing cells- KO1/KO2; mGluRA-GAL4>UAS-DIAP1 showed
increased performance in climbing essay compared to miR-1000 mutants not expressing DIAP1-
KO1/KO2; mGluRA-GAL4, confirming neurodegeneration in miR-1000 mutants.
Conclusions:
The current study established the regulation of glutamate release by miRNA-1000 in
presynaptic terminals by regulating VGlut. It was demonstrated that deregulation in VGlut
in defined miR-1000 knockout mutants leads to glutamate excitotoxicity, increased cell
death and early-onset neurodegeneration. The current study also has found preservation of
similar VGlut regulation in mammals. It’s been found that in a group of Alzheimer’s patients
miR-137 (regulates VGlut in humans) levels were minimal. Thus, the current study draws
the possibility of using miRNA mediated VGlut regulation as plausible targets for treating
neurodegenerative disorders such as Parkinson’s and Alzheimer’s in humans.
131
Figure URLs:
1) http://www.nature.com/nrd/journal/v4/n2/fig_tab/nrd1630_F1.html
2) http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.3935.html
Pushpa Verma, George J Augustine, Mohamed-Raafet Ammar, Ayumu Tashiro & Stephen M Cohen, “A
neuroprotective role for microRNA miR-1000 mediated by limiting glutamate excitotoxicity.” Nature
Neuroscience (2015) doi: 10.1038nn.3935 Published online 02 February 2015
Summary by: Padmanabhan Ramanujam

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