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Neurobiology of Learning and Memory xxx (2014) xxxxxx

1

Contents lists available at ScienceDirect

Neurobiology of Learning and Memory

journal homepage: www.elsevier.com/locate/ynlme

2 Review
5
4 Forgetfulness during aging: An integrated biology q,qq
6

7 Q1 Paul E. Gold , Donna L. Korol

8 Q2 Department of Biology, Syracuse University, Syracuse, NY 13244, United States

9
10
a r t i c l e i n f o a b s t r a c t
1 7
2 2
13 Article history: Age-related impairments in memory are often attributed to failures, at either systems or molecular levels, 28
14 Received 16 December 2013 of memory storage processes. A major characteristic of changes in memory with increasing age is the 29
15 Revised 10 March 2014 advent of forgetfulness in old vs. young animals. This review examines the contribution of a dysfunction 30
16 Accepted 13 March 2014
of the mechanisms responsible for modulating the maintenance of memory in aged rats. A memory- 31
17 Available online xxxx
modulating system that includes epinephrine, acting through release of glucose from liver glycogen 32
stores, potently enhances memory in young rats. In old rats, epinephrine loses its ability to release 33
18 Keywords:
glucose and loses its efcacy in enhancing memory. Brain measures of extracellular levels of glucose in 34
19 Aging
20 Age-related memory impairments
the hippocampus during memory testing show decreases in glucose in both young and old rats, but 35
21 Epinephrine the decreases are markedly greater in extent and duration in old rats. Importantly, the old rats do not 36
22 Glucose have the ability to increase blood glucose levels in response to arousal-related epinephrine release, which 37
23 Astrocytes is retained and even increased in aged rats. Glucose appears to be able to reverse fully the increased rate 38
24 Brain metabolism and memory of forgetting seen in old rats. This set of ndings suggests that physiological mechanisms outside of the 39
25 Memory consolidation and modulation brain, i.e. changes in neuroendocrine functions, may contribute substantially to the onset of rapid 40
26
forgetting in aged animals. 41
2014 Elsevier Inc. All rights reserved. 42
43

44
45

46 Q3 1. Introduction 2. Background: epinephrine and glucose modulation of 57

memory processing 58
47 Aging is accompanied by rapid forgetting in humans (e.g., Craik,
48 Anderson, Kerr, & Li Karen, 1995; Craik & Salthouse, 1992; Davis It has been known since at least the early 20th century that 59
49 et al., 2003; Kausler, 1994; Mary, Schreiner, & Peigneux, 2013) there is an optimal level of arousal that facilitates information pro- 60
50 and increased forgetfulness with aging is also evident in animals cessing and promotes memory formation (Yerkes & Dodson, 1908). 61
51 other than humans, as detailed below. In particular, studies using Epinephrine is perhaps the best-studied example of a hormonal 62
52 laboratory rodents show age-related increases in rates of forgetting mediator of the modulation of memory by arousal. Epinephrine 63
53 and provide reliable and valid models with which to study the bio- administered near the time of behavioral testing enhances learning 64
54 logical bases of forgetfulness during aging. The issue of the rapid and memory across a wide spectrum of tasks in rodents (cf. Gold, 65
55 forgetting that characterizes memory in aged animals is the focus 2008, in press) and also enhances the durability of long-term 66
56 of this paper. potentiation (Korol & Gold, 2008). Administration of epinephrine 67
also enhances memory in humans (Cahill & Alkire, 2003; Cahill, 68
Gorski, & Le, 2003). Together, the results suggest that the condi- 69
tions under which epinephrine enhances cognitive functions are 70
very broad. 71

q
Epinephrine is released from the adrenal medulla in graded 72
Research described here was supported by NIA R01 AG07648, NIDA DA024129,
fashion during times of arousal and thus is physiologically well- 73
NSF IOS 08-43175 and 13-18490, the Syracuse University Center for Aging and
Policy Studies (NIA P30 AG034464) and the Alzheimers Association. positioned to play an important role in the sequelae that modulate 74
qq
Submitted to: Stress and the regulation of memory: from basic mechanisms to memory (Gold & McGaugh, 1975). Plasma levels of the hormone 75
clinical implications for Neurobiology of Learning and Memory, D. de Quervain and increase about twofold above baseline when rats are placed in a 76
J.L. McGaugh, Eds. novel environment, increasing several fold after footshock or after 77
Corresponding author. Address: Department of Biology, Syracuse University,
immersion in water, as in inhibitory avoidance and swim tasks, 78
Life Sciences Complex, 107 College Place, Syracuse, NY 13244, United States.
Fax: +1 315 443 2012. respectively (Mabry, Gold, & McCarty, 1995a, 1995b). The large dy- 79
E-mail address: pegold@syr.edu (P.E. Gold). namic range of the physiological responses of epinephrine support 80

http://dx.doi.org/10.1016/j.nlm.2014.03.005
1074-7427/ 2014 Elsevier Inc. All rights reserved.

Please cite this article in press as: Gold, P. E., & Korol, D. L. Forgetfulness during aging: An integrated biology. Neurobiology of Learning and Memory (2014),
http://dx.doi.org/10.1016/j.nlm.2014.03.005
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2 P.E. Gold, D.L. Korol / Neurobiology of Learning and Memory xxx (2014) xxxxxx

81 a role for regulating brain functions across a range of arousing and

82 emotional situations that can readily match the many instances
83 when epinephrine enhances memory.
84 Because circulating epinephrine is largely excluded from the
85 brain (Axelrod, Weil-Malherbe, & Tomchick, 1959; Hardebo &
86 Owman, 1980; Weil-Malherbe, Whitby, & Axelrod, 1961), a periph-
87 eral mechanism likely serves as an intermediate step between in-
88 creases in plasma epinephrine levels and the hormones effects
89 on brain functions such as learning and memory. There is now
90 substantial evidence, as reviewed recently (Gold, in press; Gold &
91 Korol, 2012), showing that increased blood glucose levels in re-
92 sponse to increases in epinephrine levels reects a key mechanism
93 linking epinephrine to memory. In a set of fundamental and classic
94 experiments in biology, Sutherland and Rall (1960) showed that
95 epinephrine activates hepatic adrenergic receptors to initiate the Fig. 1. Age-related differences in forgetting rates. Rats were trained on a one-trial
inhibitory avoidance task and memory was assessed at different times after
96 breakdown of glycogen to glucose with subsequent release of
training. Note that the rate of forgetting increased with age (from Gold et al., 1982).
97 glucose into blood; it is these experiments that provided the rst
98 evidence for second-messenger systems in response to activation
99 of cell membrane receptors. the training trial and the memory test. Forgetting was evident at 144
100 The evidence that glucose mediates epinephrine effects on 7 days of training in 1-year-old rats and reached the low latencies 145
101 memory takes several forms (Gold, in press). Like epinephrine, sys- of untrained rats (not shown) at 21 days. In 2-yr-old rats, forgetting 146
102 temic administration of glucose enhances memory on a wide vari- emerged after 1 day and was considerable at 7 days after training. 147
103 ety of tasks (cf.: Gold, 2008, in press; Korol & Gold, 2007; Messier, As mentioned before, rapid forgetting is also evident after training 148
104 2004). The glucose doses that enhance memory result in blood glu- in many other tasks, including swim (Gage, Dunnett, & Bjorklund, 149
105 cose levels comparable to those seen after epinephrine doses that 1984; Lindner, Balch, & VanderMaelen, 1992; Mabry, McCarty, 150
106 enhance memory. Also, peripheral adrenergic receptor antagonists Gold, & Foster, 1996; Rapp, Rosenberg, & Gallagher, 1987), reward 151
107 block epinephrine effects on memory and also block the associated reduction (Salinas & Gold, 2005), visual discriminated avoidance 152
108 increases in blood glucose levels; however, the adrenergic receptor (Gold et al., 1982), spatial (Barnes & McNaughton, 1985; Mark- 153
109 antagonists do not block glucose enhancement of memory (Gold, owska, 1999), spatial reversal (Zornetzer, Thompson, & Rogers, 154
110 Vogt, & Hall, 1986; Hall & Gold, 1992). Additional evidence sup- 1982), odor-reward association (Roman, Alescio-Lautier, & Soumi- 155
111 porting the view that increases in blood glucose contribute impor- reu-Mourat, 1996), social transmission of food preference (Coun- 156
112 tantly to and are downstream from epinephrine enhancement of tryman & Gold, 2007) tasks, and object location (Wimmer et al., 157
113 memory is that epinephrine loses its ability to enhance memory 2012) tasks. 158
114 in rats that are deprived of food, with subsequent loss of liver gly- In experiments examining age-related differences in memory 159
115 cogen stores and of the ability to generate glucose in response to across time after training, forgetting rates are often assessed after 160
116 epinephrine injections (Talley, Kahn, Alexander, & Gold, 2000). In 24-h or longer intervals between training and test trials and there- 161
117 contrast, glucose effects on memory are retained in food-restricted fore can be characterized as a failure of long-term maintenance of 162
118 rats (e.g., Messier & Destrade, 1988; Packard & White, 1990; Wino- new memories. However, the same general principle of rapid for- 163
119 cur & Gagnon, 1998). Additional evidence derived from studies of getting is also evident in tasks that tap working memory and that, 164
120 aging and memory is described below. by their nature, have shorter forgetting times even in young rats. 165
For example, in a test of spatial working memory, spontaneous 166
alternation scores in a Y-maze are similar in young and two- 167
121 3. Rapid forgetting in aged rats and mice year-old mice permitted to move freely through the maze but 168
not when an interval of 60 s was imposed between arm choices 169
122 Across many studies, the ndings show that aged rats and mice (Stone, Rudd, & Gold, 1992). Rapid deterioration of spatial working 170
123 exhibit learning and memory performance comparable to that of memory, tested in a swim task, can also be observed after 3-min 171
124 young adults when tests are administered soon after training but delays in 2-yr-old females shown to be reproductively senescent 172
125 show poor memory relative to young animals when tests are (Markowska, 1999). 173
126 administered at later times after training (Barnes, 1991; Foster, Rapid forgetting may also explain results seen in classical con- 174
127 1999; Gold, 2001, 2005; Gold & Stone, 1988; Korol, 2002; Morris, ditioning experiments. These experiments show that trace condi- 175
128 Chang, Mohler, & Gold, 2010; Morris & Gold, 2012, 2013; Wimmer, tioning, with a delay between the conditioned and unconditioned 176
129 Hernandez, Blackwell, & Abel, 2012; Winocur, 1988). While there stimuli, is more impaired by aging in both laboratory animals 177
130 are many examples of accelerated forgetting in aged rodents, it is and humans than is delay conditioning, where the unconditioned 178
131 of interest that the specic time courses of forgetting differ by task. stimulus occurs at the end of a conditioned stimulus (e.g., Graves 179
132 Memory for inhibitory avoidance training, which remains stable & Solomon, 1985; Solomon & Groccia-Ellison, 1996; Thompson, 180
133 for weeks after training in young rats, is intact soon after training Moyer, & Disterhoft, 1996). Moreover, the age-related impairment 181
134 but then deteriorates over the next several days in aged rats; mid- increases as the time between the conditioned and unconditioned 182
135 dle-aged rats have intermediate rates of forgetting (Gold, stimulus increases, suggestive of rapid forgetting of the condi- 183
136 McGaugh, Hankins, Rose, & Vasquez, 1982). A clear example of tioned stimulus. The eeting quality of memory for new informa- 184
137 age-related increases in forgetting rates can be seen across young tion in old animals, evident for both short- and long-lasting types 185
138 adult (70-day-old), middle-aged (1-yr-old), and senescent (2-yr- of memories, suggests that there is impaired maintenance or 186
139 old) male rats trained on an inhibitory avoidance task (Fig. 1). After enhanced forgetting of new information that transcends the clas- 187
140 a single training trial, independent groups of rats were tested for sically dened stages of memory formation, e.g. short- and long- 188
141 memory at different post-training times. As shown in Fig. 1, young term memory. 189
142 adult rats showed good memory for several weeks after training, The pervasiveness of rapid forgetting across many tasks and 190
143 with some forgetting appearing after a 6-week delay between across species also suggests age-related changes across different 191

Please cite this article in press as: Gold, P. E., & Korol, D. L. Forgetfulness during aging: An integrated biology. Neurobiology of Learning and Memory (2014),
http://dx.doi.org/10.1016/j.nlm.2014.03.005
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192 brain areas that are employed for different tasks. In many experi- anisms needed to form and to maintain memories are intact in 255
193 ments, there has been an emphasis on age-related changes in hip- aged rats but are not effectively engaged by modulators of memory 256
194 pocampal functioning, with many using the hidden-platform to promote optimal memory formation. The perspective offered 257
195 version of the swim task for behavioral assessments (cf. Robitsek, here is that alterations in brain functions that underlie rapid for- 258
196 Fortin, Koh, Gallagher, & Eichenbaum, 2008). These experiments getting are secondary to loss of adequate blood glucose responses 259
197 have resulted in a wide array of biological correlates of individual to arousing events. 260
198 differences in learning on this task. As assessed by neuroendocrine
199 responses to stress, some of which are discussed below, immersion
200 in water is more stressful than is training-related footshock and 5. Uncoupling of epinephrine and glucose in aged rats 261
201 substantially so in older rats (Mabry et al., 1995a). Differential
202 stress responses across ages, such as elevated epinephrine release One way in which epinephrine and glucose modulation of 262
203 to water immersion, may therefore alter learning strategies in memory might contribute to age-related accelerated forgetting 263
204 the swim task by increasing thigmotaxis. Thus, age-related mem- would be if the neuroendocrine system were dysregulated in aged 264
205 ory loss may reect an age difference in stress responses, age dif- rats. Perhaps, release of epinephrine from the adrenal medulla dur- 265
206 ferences in learning strategies, age differences in mechanisms of ing and after training is impaired in aged rats. However, the nd- 266
207 memory formation, or all of these. Whether the focus on a single ings indicate exactly the opposite is true: Release of epinephrine 267
208 task, e.g. the swim task, and the derived focus on a single brain is exaggerated in aged rats. In undisturbed young adult and aged 268
209 area, e.g. the hippocampus, is a good strategy is somewhat unclear (2-yr-old) rats, baseline levels of epinephrine were about the same. 269
210 (cf. Lindner, 1997; Nicolle, Prescott, & Bizon, 2003). This is an espe- Despite similar baseline values, epinephrine levels in old rats rose 270
211 cially important issue when viewed in the context of evidence that about twice as much as in young rats when rats were placed in a 271
212 age-related decits are also evident under behavioral conditions of water tank (Mabry et al., 1995a) (Fig. 2). 272
213 low stress as in spatial reversal, social transmission of food prefer- Results consistent with greater release of epinephrine in old 273
214 ence, and object location tasks noted above. Moreover, it is clear rats were also obtained using footshocks during inhibitory avoid- 274
215 that brain areas other than the hippocampus also exhibit changes ance training (Mabry et al., 1995b). In this experiment, baseline 275
216 during aging and these may contribute to the broad spectrum of epinephrine levels (100 pg/ml) were again similar at both ages 276
217 tasks in which memory changes are evident. The intersection of re- (not shown). As illustrated in Fig. 3(left), plasma epinephrine levels 277
218 search on the neurobiological underpinnings of age-related mem- increased markedly more in aged rats than in young rats at all 278
219 ory impairments with information from research based on shock levels. Note that there is a difference by age evident even 279
220 approaches of multiple memory systems (cf.: Gold, Newman, in the non-shocked rats after they were placed in the novel training 280
221 Scavuzzo, & Korol, 2013; Kathirvelu & Colombo, 2013; Konishi apparatus (i.e., 0 mA footshock level). Thus, circulating epinephrine 281
222 et al., 2013; Korol, Gold, & Scavuzzo, 2013; Mizumori & Jo, 2013; responses to training and to training-related arousal are markedly 282
223 Packard & Goodman, 2013; Poldrack & Packard, 2003; White & increased, not decreased, in aged rats. When viewed alone, these 283
224 McDonald, 2002) needs more attention. results suggest that if anything these adrenal modulatory pro- 284
cesses shown to support memory in young adults are increased, 285
not decreased with age. 286
225 4. Age-related forgetfulness as a failure of memory modulation: However, even in the face of increased epinephrine release into 287
226 peripheral mechanisms the circulation, blood glucose responses to training or stress are se- 288
verely attenuated in aged rats (Mabry et al., 1995a; Morris et al., 289
227 The extensive neurobiological changes during aging, together 2010). An example of the discrepant responses of epinephrine 290
228 with the similar failures to hold new memories across tasks and and glucose is shown in Fig. 3 (compare left and right panels) par- 291
229 species, suggest that the underlying mechanisms may involve pro- ticularly at the 1.0 mA shock level. Similarly, as shown in Fig. 4, in- 292
230 cesses that are pervasive across brain areas and across neurochem- creases in blood glucose levels in response to epinephrine 293
231 ical mediators of memory formation. An outcome of this injections are severely depleted in aged rats. Blood glucose levels 294
232 perspective is the possibility that the dysfunctions in memory hardly increase after injections of a memory-enhancing dose 295
233 may be mediated by impairments not in the anatomical or neuro- (0.1 mg/kg) of epinephrine. These results suggest that epinephrine 296
234 chemical substrates of memory but instead in the modulators of
235 memory formation, i.e. processes responsible for up-regulating
236 the substrate mechanisms of memory, thereby engaging and
237 amplifying the neural mechanisms of memory formation.
238 Both classes of research on substrates and on modulators of
239 substrates have considered changes in the brain to be the key ele-
240 ments responsible for age-related memory impairments. At a level
241 of analysis examining the machinery of memory formation,
242 changes in brain function are undoubtedly appropriate targets for
243 research. However, it is important to note that modulation of
244 memory involves, in part at least, hormones such as epinephrine
245 that are released outside the brain. Therefore, it is possible that
246 physiological changes that initiate brain dysfunctions may reside
247 outside the brain. This review will describe ndings suggesting
248 that an important locus of dysfunction may involve epinephrine
249 regulation of memory processing specically via an uncoupling be-
250 tween epinephrine and subsequent release of glucose from hepatic
251 stores. The results demonstrate that a loss of arousal-initiated in-
Fig. 2. Plasma levels of epinephrine (EPI) at baseline and at timed intervals after
252 creases in blood glucose levels is associated with rapid forgetting swimming for 15 min. Values are means for groups of 710 rats. Old rats had
253 in aged rats. The rapid forgetting can apparently be reversed by substantially greater levels of epinephrine after immersion in water than did young
254 glucose administration. These results suggest that the brain mech- rats [from Mabry et al., 1995a).

Please cite this article in press as: Gold, P. E., & Korol, D. L. Forgetfulness during aging: An integrated biology. Neurobiology of Learning and Memory (2014),
http://dx.doi.org/10.1016/j.nlm.2014.03.005
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Fig. 3. Plasma epinephrine (left panel) and glucose (right panel) levels after administration of a single footshock at the intensity shown. Note that old rats exhibited
exaggerated release of epinephrine compared to young rats but diminished increases in blood glucose levels across the same shock intensities. P < 0.05 vs. young (from
Mabry et al., 1995b).

(median +semi-interquartile range

*

LATENCY TO CROSS (sec)

300
* *
250

200

150

100

50

0
SAL EPI GLU SAL EPI GL
U
YOUNG OLD

Fig. 5. Enhancement of inhibitory avoidance memory (48 h) by immediate post-

training injections of epinephrine and glucose. Although the treatments were
equally effective at enhancing memory in young rats, glucose was more effective
than epinephrine in old rats (from Morris et al., 2010).

Systemic injections of glucose enhance memory in aged rodents 319

Fig. 4. Effects of epinephrine injections on blood glucose levels in aged vs. young
not only for inhibitory avoidance tasks, but also in reward reduc- 320
rats. Epinephrine injections increased glucose levels more substantially in young
than in old rats, particularly at an epinephrine dose (0.1 mg/kg) that is effective at tion (Salinas & Gold, 2005), spatial (Winocur & Gagnon, 1998), 321
enhancing memory in young rats (from Morris et al., 2010). and spontaneous alternation (McNay & Gold, 2001) tasks, fully 322
reversing age-related memory decits on each of these tasks and 323
in some cases enhancing memory scores to the glucose-enhanced 324
297 release may be increased by loss of negative feedback from the ab- levels of young rats. Importantly, studies in healthy young, aged, 325
298 sent rise in glucose levels. In terms of modulation of memory, it and cognitively impaired humans using orally administered glu- 326
299 may be the case then that decient glucose production by the liver cose have shown complementary results, with glucose enhance- 327
300 represents the impaired step in modulation of memory, contribut- ment characterized by an inverted-U doseresponse curve and 328
301 ing to the relative inability of aged rats to retain new memories. enhancing memory on a range of tasks (cf. Gold, 2005; Korol, 329
302 Supporting this possibility are results showing that epinephrine 2002; Messier, 2004). Some of the largest effects of glucose on 330
303 is less effective at enhancing memory in old vs. young rats while memory in humans have been seen in healthy elderly people and 331
304 glucose is effective at both ages. Rats were trained on a one-trial in people with Alzheimers Disease, with enhancement of memory 332
305 inhibitory avoidance task and memory was tested 48 h later. Epi- for a narrative prose passage of 3040% in healthy individuals and 333
306 nephrine or glucose was administered immediately after the train- 100% in Alzheimers patients above their individual baselines 334
307 ing footshock (Fig. 5). In this experiment, the shock intensity and (Manning, Hall, & Gold, 1990; Manning, Ragozzino, & Gold, 1993; 335
308 the 48-h training-test interval were selected to compare directly cf.: Gold, 2001; Korol, 2002). 336
309 the efcacy of epinephrine and glucose in enhancing memory in In these multiple tasks and from rodents to humans, the 337
310 young vs. old rats, requiring comparable memory at both ages to enhancement of memory by glucose in aged subjects resulted in 338
311 address the question clearly. Therefore, the control memory scores scores equal to or higher than those of the young subjects. These 339
312 did not differ by age after 48 h although rapid forgetting in aged ndings support the view that the aged brain apparently retains 340
313 rats as compared to young rats may have emerged at later times the ability to form and to maintain new memories but that the 341
314 with these training conditions. In addition, the doses of epineph- storage mechanisms are not effectively engaged by endogenous 342
315 rine (0.1 mg/kg) and glucose (100 mg/kg) were selected to match modulators of memory, such as glucose. The ability of exogenous 343
316 enhancement scores in young rats. As shown in Fig. 5, epinephrine systemically administered glucose to improve memory, together 344
317 signicantly enhanced memory in young but not aged rats while, with a failure of epinephrine to initiate release of glucose into 345
318 in contrast, glucose enhanced memory in rats at both ages. blood from hepatic glycogen stores, suggests that a primary cause 346

Please cite this article in press as: Gold, P. E., & Korol, D. L. Forgetfulness during aging: An integrated biology. Neurobiology of Learning and Memory (2014),
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347 of rapid forgetting in aged rats is a peripheral one. Consistent with sions of the hippocampus and is sensitive to pharmacological 389
348 this view, we have preliminary ndings indicating that glycogen manipulations of the hippocampus. The memory decit in aged 390
349 levels in the liver are substantially lower in old vs. young rats. rats was accompanied by depletion of ECF glucose in the hippo- 391
350 Moreover, epinephrine injections reduce liver glycogen concentra- campus during testing that was greater and of longer duration in 392
351 tions in young rats, presumably by signaling the conversion of gly- aged than in young rats, dropping to nearly 50% of baseline values 393
352 cogen to glucose, but do not lower the already depleted glycogen during memory testing in aged rats (Fig. 7). At the same time, the 394
353 concentrations in old rats. If conrmed, the decreased ability of substantial depletion of hippocampal ECF glucose seen during 395
354 epinephrine to initiate the release of glucose from hepatic glycogen memory testing in aged rats, and the smaller depletion seen in 396
355 stores in aged rats may explain why epinephrine very effectively young rats, was fully prevented by injections of glucose (McNay 397
356 enhances memory in young rats but is less effective at doing so & Gold, 2001). As noted above, basal blood glucose levels in aged 398
357 in old rats. rats were comparable to those of young adult rats, but aged rats 399
did not exhibit a signicant increase in blood glucose levels in re- 400

358 6. Age-related forgetfulness as a failure of memory modulation: sponse to training. Thus, in failing to provide sufcient glucose to 401

359 central mechanisms the brain under demand, the absence of a blood glucose response 402
to the arousal of placement in a novel environment appears to be 403

360 6.1. Glucose availability a major contributor to the greater depletion of ECF glucose, the 404
slower return of ECF levels to baseline, and the cognitive decits 405

361 The ndings reviewed above show that circulating glucose lev- observed in old rats. 406

362 els are not responsive to arousal and stress in aged rats and that old To test whether glucose in the hippocampus is critical to mem- 407

363 rats exhibit rapid forgetting. These results are coupled with evi- ory processing, Morris and Gold (2013) examined the effects of 408

364 dence that exogenous glucose treatments enhance memory in aged post-training intra-hippocampal injections of glucose. As shown 409

365 rats. The collective evidence suggests either that circulating glu- in Fig. 8, the infusions of glucose prevented forgetting after inhib- 410

366 cose, like epinephrine, augments memory processes via peripheral itory avoidance training in aged rats, resulting in memory scores 411

367 actions or that the brain requires the additional circulating glucose like those seen in young rats. Together with the neurochemical 412

368 to support cognitive processes. These are certainly not mutually evidence that hippocampal glucose is depleted during memory 413

369 exclusive views. The rst possibility that glucose has peripheral testing in aged rats, the results support the view that the condi- 414

370 signaling or other actions that contribute to memory enhancement tions for maintenance of memory, i.e. the absence of forgetting, in- 415

371 in aged animals has not received much attention. However, the clude availability of extracellular glucose to support neural 416

372 second possibility that glucose acts directly on brain mechanisms functions. The enhancement of memory in aged rats is similar to 417

373 - now has considerable support. that seen in young rats and shares a task  brain target interaction, 418

374 Using zero-net ux methods, glucose levels in brain ECF are i.e., intracerebral infusions of glucose are only effective when glu- 419

375 1 mM in hippocampus and lower in other brain regions and do cose injected into selective structures shown to play a primary role 420

376 not saturate neuronal glucose transporters (Fellows, Boutelle, & in the task (e.g., Canal, Stutz, & Gold, 2005; McNay, Fries, & Gold, 421

377 Fillenz, 1993; McNay & Gold, 1999, 2002). Because in normal states 2000; McNay & Gold, 1998; Parent, Laurey, Wilkness, & Gold, 422

378 the glucose transporter is not saturated, brain extracellular levels 1997; Pych, Kim, & Gold, 2006; Stefani & Gold, 2001). Therefore, 423

379 of glucose are likely to uctuate in response to changing need while it is possible that peripheral actions of glucose contribute 424

380 and are therefore positioned to regulate neuronal function (McNay to memory enhancement, the efcacy of central injections in a task 425

381 & Gold, 2002). by memory system manner indicates that peripheral actions are 426

382 In the absence of blood glucose increases in response to epi- not necessary for glucose enhancement of memory. 427

383 nephrine release, brain functions in aged rats may be compromised

384 by depressed glucose availability. As seen on many tests of spatial 6.2. Acetylcholine 428
385 working memory, aged rats exhibited a memory decit when
386 tested on a 4-arm spontaneous alternation task (Fig. 6); injections In young rats, glucose augments acetylcholine release in a man- 429
387 (i.p.) of glucose restored memory to the levels seen in young rats ner related to enhancement of spatial working memory (Ragozzi- 430
388 treated with glucose. Performance on this task is impaired by le- no, Pal, Unick, Stefani, & Gold, 1998; Ragozzino, Unick, & Gold, 431

Fig. 6. Alternation scores in rats tested for working memory on a 4-arm sponta-
neous alternation task. Young adult rats performed signicantly better than chance
on this task, but 24-month-old rats did not; the aged rats had scores signicantly
lower than those of young adult controls. Glucose enhanced memory in both young
and old rats, bringing the memory scores in old rats to values near those of the
glucose-enhanced memory of young rats (from McNay and Gold, 2001).
Fig. 7. In vivo microdialysis measurements of extracellular glucose levels in the
hippocampus before, during, and after testing on a spontaneous alternation task.
Extracellular glucose levels decreased signicantly at both ages, but signicantly
more so in aged rats (from McNay and Gold, 2001).

Please cite this article in press as: Gold, P. E., & Korol, D. L. Forgetfulness during aging: An integrated biology. Neurobiology of Learning and Memory (2014),
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drugs also impaired working memory assessed in a spontaneous 475

alternation task, a task in which age-related memory impairments 476
are also evident in rats. Additional treatment with intrahippocam- 477
pal glucose was used to challenge the efcacy on memory of the 478
two nicotinic antagonists. The ndings indicated that glucose did 479
not attenuate the effects of the a7 antagonist but did reverse the 480
effect of the a4b2 antagonist in both tasks; the spontaneous alter- 481
nation results are shown in Fig. 9. 482
Thus, glucose is very effective at reversing age-related impair- 483
ments in memory and glucose enhancement of memory appears 484
to include augmented release of acetylcholine as a mediating 485
mechanism, with pharmacological evidence suggesting involve- 486
ment of nicotinic a7 receptors. However, as described below, re- 487

Fig. 8. Effects of intrahippocampal injections of glucose on memory. Immediately cent ndings show that glucose may also act more generally 488
after training on an inhibitory avoidance task, young and old rats received than through cholinergic actions, i.e. supporting metabolic de- 489
injections of aCSF containing either 1 mM or 33.4 mM glucose. These groups are mands of learning and memory that may be important in the 490
designated aCSF and GLUCOSE, respectively, in this gure. The 1 mM glucose mechanisms by which glucose reverses memory impairments dur- 491
concentration in aCSF matches baseline extracellular glucose levels in the hippo-
campus, as measured with zero-net-ux microdialysis methods (McNay and Gold,
ing aging. 492

1999). Memory was assessed 7 days after training. Glucose enhanced memory in
aged rats, bringing the latencies to the ceiling scores of 600 s (from Morris and Gold,
6.3. Astrocytes, glycogen and lactate 493
2013).

Findings described above provide evidence that glucose re- 494

verses the rapid forgetting that characterizes memory in aged ani- 495
432 1996). We compared acetylcholine release after inhibitory avoid- mals and that glucose replenishes extracellular glucose levels that 496
433 ance training in young and old rats that received post-training are severely depleted in aged rats by memory testing. While the 497
434 injections of epinephrine or glucose. The training was conducted evidence of a poor blood glucose response to training or to epi- 498
435 under low footshock conditions that would reveal rapid forgetting nephrine suggests that peripheral glycogen stores and production 499
436 in aged but not young rats. Microdialysis samples were collected of glucose, i.e. in the liver, may be a basis for these effects, the issue 500
437 for measurements of acetylcholine release every 10 min for remains about the brain actions of glucose that mediate the effects 501
438 40 min before training to 60 min after training. Young and old rats on both brain signaling mechanisms and on cognition. Recent nd- 502
439 were trained on an inhibitory avoidance task and received sys- ings suggest that glucose enhances memory by providing a sub- 503
440 temic injections of epinephrine (0.1 mg/kg), glucose (100 mg/kg) strate for astrocytic generation of lactate (Newman, Korol, & 504
441 or saline (1 ml/kg) immediately after training. The effects on ace- Gold, 2011; Suzuki et al., 2011; see Gold et al., 2014, for recent re- Q4 505
442 tylcholine release were consistent with the effects on memory view). Although neurons do not have the capability to store glyco- 506
443 shown above. Epinephrine and glucose similarly augmented the gen, astrocytes do (Brunet, Allaman, Magistretti, & Pellerin, 2009; 507
444 duration of acetylcholine release after training in young rats, mir- Maxwell & Kruger, 1965; Newman et al., 2011; Petersen, 1969; 508
445 roring their comparable efcacy in enhancing memory. However, Pfeiffer-Guglielmi, Fleckenstein, Jung, & Hamprecht, 2003), provid- 509
446 in old rats, glucose was substantially more effective than was epi- ing stores that can supplement glucose availability. In the brain, 510
447 nephrine in augmenting release of acetylcholine after training, astrocytic glycogen is metabolized to lactate, which can be shut- 511
448 again paralleling the relative effects of the two treatments on tled to neurons to provide an additional energy reserve when 512
449 memory. These ndings suggest that the age-related deciency needed (Magistretti, Pellerin, Rothman, & Shulman, 1999). Mea- 513
450 in the ability of epinephrine signaling to increase blood glucose sured in somatosensory cortex, glucose uptake by neurons and 514
451 levels may contribute to diminished neurotransmitter responses astrocytes is similar at baseline but glucose uptake increases in 515
452 to training and thereby contribute to rapid forgetting in aged rats.
453 The augmented release of acetylcholine in response to glucose
454 and training, as seen in both aged and young rats (Morris et al.,
455 2010; Ragozzino et al., 1996, 1998) is consistent with evidence that
456 acetylcholine release may contribute to glucose effects on memory.
457 In particular, nicotinic receptors and associated signaling processes
458 have become important targets for experiments addressing mech-
459 anisms of memory function and dysfunction. Many of these exper-
460 iments have shown that the specic a7 and a4b2 nicotinic
461 receptor antagonists, methyllycaconitine (MLA) and dihydro-
462 beta-erythroidine (DHBE), respectively, impair memory (e.g. Addy,
463 Nakijama, & Levin, 2003; Bettany & Levin, 2001; Chan, Wong, &
464 Sheu, 2007; Levin, Bradley, Addy, & Sigurani, 2002; Nott & Levin,
465 2006). Recent ndings using young adult rats provide pharmaco-
466 logical evidence that glucose enhancement of memory may be
467 mediated, in part, by nicotinic receptors (Morris, Li, Bui, & Gold,
468 2012). Young adult rats received injections (I.P.) of either MLA or Fig. 9. Effects of intrahippocampal infusions of glucose and nicotinic receptor
469 DHBE 30 min prior to inhibitory avoidance training or spontaneous antagonists on working memory assessed in young adult rats using a 4-arm
470 alternation testing. Both drugs impaired memory in these tasks. In spontaneous alternation task. Chance performance is 44% on this task. Rats
471 the inhibitory avoidance task, the memory impairment was evi- pretreated with either an a7 (MLA) or an a4b2 (DHE) nicotinic receptor antagonist
exhibited signicantly impaired memory. Co-administration of glucose reversed the
472 dent as an instance of rapid forgetting similar to observations in impairments produced by the a4b2 antagonist but not the a7 antagonist. P < 0.05
473 aged rats: Memory was intact at 1 h after training but impaired vs. aCSF. MLA: methyllycaconitine; DHE: dihydro-beta-erythroidine; GLU: glu-
474 by 7 days. When injected directly into the hippocampus, these cose; aCSF: articial cerebrospinal uid (from Morris et al., 2013).

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516 astrocytes and not neurons during times of activation (Chuquet,

517 Quilichini, Nimchinsky, & Buzski, 2010). In memory tests, glucose
518 levels in the hippocampus decrease upon activation (McNay &
519 Gold, 2001; McNay, McCarty, & Gold, 2001; McNay & Sherwin,
520 2004; McNay et al., 2000) (as in Fig. 7). The decrease is accompa-
521 nied by an increase in extracellular levels of lactate (McNay & Sher-
522 win, 2004; Newman et al., 2011). The increase in lactate levels is
523 likely generated by glycogenolysis and glycolysis in astrocytes
524 with release of lactate into the extracellular space (Sampol et al.,
525 2013).
526 An example of the uxes in extracellular lactate and glucose
527 during spontaneous alternation tests is shown in Fig. 10. In this
528 experiment (Newman et al., 2011), biosensors were used to mea-
529 sure lactate and glucose levels in the hippocampus, a method that
Fig. 11. Effects of intrahippocampal injections of lactate on working memory scores
530 permits 1-s sampling of the analytes; however, 10-s averages were in a 4-arm spontaneous alternation task. Lactate enhanced memory in an inverted-
531 used in Fig. 10 for display purposes. As seen in earlier studies using U manner, as seen also with glucose (from Newman et al., 2011).
532 microdialysis methods, extracellular levels of glucose decreased
533 after the start of training before recovering later. Previous work avenues for investigation within the realm of glucose reversal of 557

534 showed that the recovery of extracellular glucose levels during forgetfulness during aging. In particular, it is possible that astro- 558

535 testing in young rats, which is not seen in aged rats, is coincident cytes will demonstrate age-related decits in glycogen storage 559

536 with increases in blood glucose levels (McNay et al., 2001). The and carbohydrate delivery for energy use by neurons in a manner 560

537 main new nding was that lactate levels increased at times that similar to what is seen in the periphery. 561

538 mirrored the decrease in glucose values, suggesting that lactate

539 may supplement glucose as a reserve for energy metabolic demand 7. Conclusions 562
540 in support of neural processing needed for optimal cognitive func-
541 tions. Genetic and pharmacological manipulations support this Across tasks, glucose administration appears to fully reverse the 563
542 view (Newman et al., 2011; Suzuki et al., 2011). As shown in effects of aging on memory. Therefore, the results show that an old 564
543 Fig. 11, direct injections of lactate into the hippocampus enhance brain can learn and store new information as well as a young brain 565
544 memory, similar to results obtained with intrahippocampal injec- but apparently does not readily do so because the modulation of 566
545 tions of glucose. In addition, intrahippocampal infusions of a drug, memory is dampened or absent. This conceptual approach is very 567
546 a-cyano-4-hydroxycinnamate, that blocks the entry of lactate into different from that guiding much of aging research in memory, in 568
547 neurons impairs memory (Newman et al., 2011). That impairment which the presumption is that the aged brain has limited capacity. 569
548 is not rescued by coadministration of either glucose or lactate. That perspective includes the ideas that compensatory mecha- 570
549 Astrocytes contain a host of neurotransmitter receptors, including nisms are engaged with less efciency, and that cognitive enhanc- 571
550 both nicotinic receptors noted above (Xiu, Nordberg, Zhang, & ers therefore can only act on limited residual functions or by 572
551 Guan, 2005), that might initiate glycogen breakdown to lactate, effecting downstream molecular cascades. Replacing single signal- 573
552 perhaps opening an opportunity to integrate neurotransmitter ing molecules may be technically and conceptually challenging. 574
553 functions with glucose enhancement of memory. Most memory molecules participate in multiple converging path- 575
554 These recent ndings point to a key role of astrocytes in medi- ways, making it difcult to alter any one molecular pathway and 576
555 ating the enhancement of memory by glucose. Thus far, the work function. Moreover, the pervasiveness of forgetfulness across many 577
556 has not been extended to aged rats but the ndings open clear tasks and their related neural systems suggests a mechanism with 578
more comprehensive functions. Addressing such a mechanism, as 579
that described here, may offer a promising approach to ameliorate 580
age-related increases in forgetting. 581
EXTRACELLULAR CONCENTRATION

Our results suggest that cognitive functions in older adults are 582
remediable simply if adequate glucose is provided to the brain. 583
(PERCENT OF BASELINE)

LACTATE This research may open new avenues for development of drug 584
120 GLUCOSE treatments or lifestyle interventions for age-related memory loss 585
that target regulation of neuroendocrine response. The application 586
110
of endocrine studies to examine bases for age-related memory 587
100 impairments will likely propel these developments, as might 588
experiments that point to altered mechanisms of glycogen storage, 589
90 metabolism, and delivery of intermediary substrates in the periph- 590

80 ery or in the brain. 591

8. Uncited reference 592

TIME FROM START OF SPONTANEOUS
ALTERNATION (MIN) Gold, McIntyre, McNay, Stefani, & Korol (2001). Q5 593

Fig. 10. Effects of spontaneous alternation testing on extracellular glucose (black References 594
diamonds) and lactate (gray circles) levels in the hippocampus of young adult rats.
These levels were measured using bioprobes with 1-s sampling periods, summa- Addy, N. A., Nakijama, A., & Levin, E. D. (2003). Nicotinic mechanisms of memory: 595
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http://dx.doi.org/10.1016/j.nlm.2014.03.005
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Please cite this article in press as: Gold, P. E., & Korol, D. L. Forgetfulness during aging: An integrated biology. Neurobiology of Learning and Memory (2014),
http://dx.doi.org/10.1016/j.nlm.2014.03.005