The BladderBrain Connection

Putative Role of Corticotropin-releasing Factor

Rita J. Valentino; Susan K. Wood; Alan J. Wein; Stephen A. Zderic
Authors and Disclosures
Posted: 03/10/2011; Nat Rev Urol. 2011;8(1):19-28. 2011 Nature Publishing Group

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Abstract and Introduction

The Barrington's Nucleus Circuit

Corticotropin-releasing Factor

Central Symptoms of Bladder Pathology

Social Stress-induced Bladder Dysfunction

Conclusions

References

Sidebar 1

Sidebar 2

Abstract and Introduction

Abstract

The coordination of pelvic visceral activity with appropriate elimination behaviors is a

complex task that requires reciprocal communication between the brain and pelvic organs.
Barrington's nucleus, located in the pons, is central to a circuit involved in this function.
Barrington's nucleus neurons project to both pelvic visceral motorneurons and cerebral
norepinephrine neurons that modulate behavior. This circuit coordinates the descending limb
of the micturition reflex with a central limb that initiates arousal and shifts the focus of
attention to facilitate elimination behavior. The same circuitry that links the bladder and brain
enables pathological processes in one target of the circuit to be expressed in the other.
Urological disorders can, therefore, have cognitive and behavioral consequences by affecting
components of this circuit; and in the opposing direction, psychosocial stressors can produce
voiding dysfunctions and bladder pathology. The stress-related neuropeptide, corticotropinreleasing factor, which is prominent in Barrington's nucleus neurons, is a potential mediator
of these effects.
Introduction

Clinical assessment of patients with pelvic visceral disorders is often exclusively directed
towards specific viscera, including the colon, bladder, and reproductive organs. However, the
activity of these viscera must be coordinated and they do not function independently of the
brain. The coexistence of multiple pelvic visceral symptoms and their frequent association
with psychiatric symptoms highlights the interrelationships between the brain and pelvic
viscera.[18] Underlying these interrelationships are reciprocal endocrine and neural lines of
communication. For example, reciprocal communication between the brain and bladder
enables bladder pressure to be communicated to brain nuclei that serve to increase arousal,
redirect attention and modify behavior so that micturition is coordinated with voiding
behaviors. Conversely, the brain is poised to directly modify visceral activity so that these
responses can be attuned to specific circumstances (for example, in response to stress or
when urination is used to mark territory or as a part of a sexual repertoire).[9] These reciprocal
lines of communication provide routes through which visceral pathology can affect brain
activity and conversely, routes through which changes in brain activity can influence visceral
function. Despite the physiological importance of communication between the brain and
bladder and the role this interchange can have in urological disorders, our understanding of
the underlying mechanisms for this is sparse.
One circuit that underlies communication between the brain and pelvic viscera is centered
around Barrington's nucleus, the pontine micturition center. Initially considered to be the
switch that initiates the descending limb of the micturition reflex, Barrington's nucleus
neurons that project to bladder motorneurons diverge to innervate the locus coeruleus, the
major norepinephrine-containing brain nucleus.[10] Locus coeruleus neurons, in turn,
collateralize extensively throughout the forebrain to densely innervate the cortex. Through
this projection system, locus coeruleus activation increases arousal and shifts attention
towards salient stimuli.[1114] This structural organization enables neurons from Barrington's
nucleus to co-regulate the parasympathetic tone of the bladder and noradrenergic tone of the
cortex, which provides a mechanism for coordinating elimination behaviors with bladder
voiding.
A notable characteristic of Barrington's nucleus neurons is that they express high levels of
the stress-related neuropeptide, corticotropin-releasing factor (CRF).[1517] Although CRF was
first characterized as the hypothalamic neurohormone released in response to stressors to
initiate the endocrine limb of the stress response,[18] it also acts as a neurotransmitter that is
released from neurons in limbic brain regions to mediate behavioral responses to stress.
[19]
The substantial expression of CRF by Barrington's nucleus neurons has been speculated
to be involved in regulation of bladder or colonic motility as a component of the stress
response.[20]Given its prominence in this pathway, which coordinates central and pelvic
visceral functions, clarifying the actions of CRF could pave the way for the development of
novel pharmacological methods for treating pelvic visceral disorders.
In this Review, we consider the convergent anatomical and physiological evidence for the
Barrington's nucleus network linking the brain and bladder and discuss its role in coordinating
a behavioral limb of the micturition reflex with the descending limb. We present evidence that
partial bladder outlet obstruction adversely affects cortical activity, and that psychosocial
stress induces voiding dysfunction and bladder pathology through the same circuit. Finally

we discuss the evidence for a role of Barrington's nucleus CRF in pelvic visceral disorders
and as a target for treating such disorders.

The Bladder-brain Connection: The Barrington's Nucleus

Circuit
Authors and Disclosures

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Abstract and Introduction

The Barrington's Nucleus Circuit

Corticotropin-releasing Factor

Central Symptoms of Bladder Pathology

Social Stress-induced Bladder Dysfunction

Conclusions

References

Sidebar 1

Sidebar 2

The Barrington's Nucleus Circuit

Descending Limb of the Micturition Reflex

Early studies in cats and rats demonstrated that lesions in the dorsal pons abolished
micturition and, conversely, that electrical stimulation of the same region elicited bladder
contractions and voiding.[2124] These studies suggested that a micturition center was located
in the dorsal pons, and anatomical tracing studies then localized the area critical to
micturition as an oval cluster of neurons just ventral to the fourth ventriclethis area was
named Barrington's nucleus, after the physician who first determined that dorsal pons lesions
disrupted micturition.[2426] Anterograde tracers injected into Barrington's nucleus labeled axon
terminals in the preganglionic parasympathetic column of the lumbosacral spinal cord, in the
vicinity of neurons that innervate the bladder.[27] Consistent with this, Barrington's nucleus
neurons were retrogradely labeled from the lumbosacral spinal cord. The finding that
chemical stimulation of Barrington's nucleus elicited bladder contractions physiologically
confirmed the identification of Barrington's nucleus as a micturition center.[22,23] Barrington's
nucleus neurons are activated as bladder pressure increases and receive bladder afferent
information directly from the spinal cord as well as from the periaqueductal gray region.[28

The input from the periaqueductal gray region is particularly relevant to the effects of social
stress on the regulation of micturition by Barrington's nucleus.
30]

Coordinated Regulation of Visceral Functions

Following the initial studies identifying the role of Barrington's nucleus as a switch in the
micturition reflex, more complex functions for the nucleus were suggested through
transsynaptic tracing, which used labeled pseudorabies virus to identify neurons with
synaptic links to viscera. These studies indicated that Barrington's nucleus neurons were
synaptically linked to (and were thereby able to influence) the distal colon and genitals, as
well as the bladder.[3134] Of particular clinical relevance, the majority of Barrington's nucleus
neurons have synaptic links to both the bladder and distal colon, which enables co-regulation
of these viscera (Figure 1).[31] By contrast, few Barrington's nucleus neurons are transsynaptically linked to the stomach, which suggests that brain regulation of the distal colon is
likely to be coordinated with pelvic viscera, such as the bladder, rather than with other
gastrointestinal viscera.[31] The finding that the same Barrington's nucleus neurons are
positioned to co-regulate both the bladder and colon may seem at odds with the idea that
these viscera should function in a reciprocal manner. However, this observation is consistent
with embryological development as the bladder and rectum both arise from the same part of
the hindgut, which undergoes a coronal partition owing to the insertion of the urorectal
septum by 6 weeks of fetal development.[35] Unlike the bladder, the distal colon is regulated
by multiple factors that control its motility in addition to innervation from Barrington's nucleus.
These factors include propulsive forces from the proximal gastrointestinal tract that are under
vagal control; these forces are likely to exert a greater influence over distal colonic motility
than the spinal parasympathetic tone regulated by Barrington's nucleus. Nonetheless, coactivation of both bladder and colon could occur under certain conditions, such as stress.
Importantly, many Barrington's nucleus neurons are activated by nonpainful distention of both
bladder and colon, indicating that bladder and colonic information converge onto common
Barrington's nucleus neurons.[28]This convergence provides a means through which multiple
pelvic visceral symptoms could coexist: for example, irritable bowel syndrome and irritable
bladder.[1,4,5,36]

Figure 1.

(Enlarge Image)

Fluorescent photomicrograph of a rat brain section at the level of

Barrington's nucleus. The section is labeled with pseudorabies
virus expressing green fluorescent protein that was injected into
the bladder (green) and pseudorabies virus expressing galactosidase (red) that was injected into the distal colon. Many
Barrington's nucleus neurons are labeled with both viruses, and
appear as either yellow or orange (arrows) or cells that have a
red nucleus and green cytoplasm (arrowheads). Thus,
Barrington's nucleus neurons are transsynaptically linked to both
the bladder and colon. Permission obtained from John Wiley &
Sons Ltd Rouzade-Dominguezet al. Eur. J. Neurosci. 18,
33113324 (2003).

Central Limb of the Micturition Reflex

Our understanding of the functions of Barrington's nucleus was changed by the discovery
that many Barrington's nucleus neurons projecting to the spinal cord also project to the major
norepinephrine-containing brain nucleus, the locus coeruleus.[10] This finding suggested that
Barrington's nucleus neurons serve a larger function in the regulation of micturition. The
locus coeruleus is a cluster of norepinephrine-containing neurons that serves as the major
source of norepinephrine in the brain.[11,12,37] These cells have extensive collateral projections
that innervate the entire neuraxis, particularly the forebrain.[12] The locus coeruleus
norepinephrine system initiates and maintains arousal in response to stimuli and facilitates
shifts between scanning and focused modes of attention.[13,14,38] Locus coeruleus neurons are
activated by multimodal sensory stimuli and, importantly, by visceral stimuli such as bladder
and colonic distention.[3943] Locus coeruleus activation by these pelvic visceral stimuli is
temporally related to cortical electroencephalographic indices of arousal, such as
desynchronization and a shift from high-amplitude, low-frequency activity to low-amplitude,
high-frequency activity.[42,43] Activation of the locus coeruleus provides the means by which
increases in bladder or colon pressure can initiate arousal and shift the focus of attention,
such that behaviors unrelated to these stimuli will be interrupted and behaviors appropriate to
the stimuli will be facilitated. Through their projections to the locus coeruleus, Barrington's
nucleus neurons are central to coordinating the descending limb of the micturition reflex with
a central limb that facilitates the switch from ongoing (voiding-unrelated) behavior to voiding
behaviors. As these neurons are also excited by increases in colonic intraluminal pressure,
this circuit is also likely to facilitate behaviors related to defecation.[42] Barrington's nucleus,
with its divergent projections to the spinal cord and locus coeruleus, is poised to integrate
ongoing signals from multiple pelvic viscera and to coordinate the activity of each of these
viscera with the activity in forebrain regions that underlies behavior (Figure 2a).

Figure 2.

(Enlarge Image)

Schematic diagram of the circuitry centered around BN that links

the brain and pelvic viscera. a | Signals from the pelvic viscera
are conveyed to BN either directly or indirectly. This brain region
modulates visceral activity via spinal efferents, and cortical
activity via projections to the locus coeruleus. b | Signals related
to pathology in the pelvic viscera can be relayed through the
same circuitry to the cortex via BN projections to the locus
coeruleus and in turn, locus coeruleus projections to the cortex.
Psychogenic stimuli, such as social stress can potentially
influence the pelvic viscera through projections from the
periaqueductal gray or other afferents to BN and from BN to the
spinal cord. Abbreviations: BN, Barrington's nucleus; IBS,
irritable bowel syndrome; LC, locus coeruleus; OAB, overactive
bladder; PAG, periaqueductal gray.

Corticotropin-releasing Factor

CRF serves as a neurohormone and neurotransmitter that orchestrates the stress response.
Release of CRF from hypothalamic neurons terminating in the median eminence initiates the
cascade of adrenocorticotropin and corticosteroid secretion that is the hallmark of stress.
[18]
CRF in neurons outside the hypothalamusparticularly in limbic regions that are involved
in the expression of emotionserves as a neurotransmitter that mediates emotional,
cognitive and behavioral aspects of the stress response.[19,44] The locus coeruleus is a target
of CRF neurotransmission; in response to stress, CRF is released into this area from limbic
regions and excites locus coeruleus neurons, which results in forebrain activation and
arousal that is detectable by electroencephalography.[4548] This reaction is thought to form the
emotional arousal component of the stress response.
CRF is also prominently expressed in Barrington's nucleus neurons. CRF axons from
Barrington's nucleus terminate not only within the locus coeruleus, but also within the
preganglionic parasympathetic nucleus that gives rise to pelvic innervation, indicating that
CRF is an important neurotransmitter in this circuit (Figure 3).[10,17,49] The discovery of CRF in a
circuit regulating micturition is of interest from an evolutionary and phylogenetic standpoint,
because CRF functioned as an osmoregulatory peptide in early species (for example,
teleost) and CRF analogs act as diuretic hormones in insects.[50,51] As is the case in rats and
cats, CRF is prominent in the human brain in the region that corresponds to Barrington's
nucleus and PET imaging studies have associated this region with micturition.[52,53]

Figure 3.

(Enlarge Image)

Corticotropin-releasing factor (CRF) is a major neurotransmitter

in Barrington's nucleus neurons.a | Bright-field photomicrograph
of a rat brain section at the level of Barrington's nucleus showing
CRF-immunoreactive neurons (blue) and neurons that are
labeled from the lumbosacral spinal cord with the retrograde
tracer fluorogold (brown). Most neurons have a mixed
blue/brown color, indicating that they are CRF neurons that
project to the spinal cord (example indicated by arrow). The
arrowhead points to a neuron that is labeled for CRF only.
Dorsal is at the top and medial is to the right. V indicates the
fourth ventricle. b | Section at the level of the lumbosacral spinal
cord showing dense CRF-immunoreactive terminal fields (blue)
in the region of the preganglionic parasympathetic neurons
(arrows). The section is counterstained with Neutral Red. Dorsal
is at the top.

The CRF-expressing neurons of Barrington's nucleus respond to both bladder and colonic
distention.[28] In Barrington's nucleus projections to the locus coeruleus, CRF has excitatory
effects and mediates locus coeruleus neuronal activation in response to pelvic visceral
stimuli which in turn, elicits cortical arousal.[42,54] These CRF neurons are an important step in
communication of pelvic visceral information to the cortex, which initiates behavioral
responses to these stimuli. Via spinal projections from Barrington's nucleus, CRF has been
speculated to have excitatory effects on colonic motorneurons, which perhaps contribute to
stress-related increases in colonic motility and the symptoms of irritable bowel syndrome.

Cystometric studies in rats examining the effect of CRF or CRF antagonists administered
systemically or intrathecally suggest both excitatory and inhibitory effects of CRF on
micturition.[5658] These conflicting findings may be a result of the use of different rat strains
and sexes. Additionally, the state of arousal, which is difficult to standardize between
laboratories, is an important determinant of urodynamic end points and of the effect of CRF.
[58]
An important consideration when interpreting the role of CRF in urodynamic function on
the basis of cystometric studies is that cystometry end points represent the net effect of
activity of spinal afferents and efferents as well as neural activity in bladder urothelium. CRF
is present in multiple sites that could influence each of these end points, including the
urothelium and dorsal horn of the spinal cord, as well as in spinal projections of Barrington's
nucleus neurons that regulate the micturition reflex.[5961] CRF can influence urodynamics at
multiple sitesthus interpreting the role of CRF in urodynamics is difficult.
[20,55]

The specific role of CRF in Barrington's nucleus spinal projections has been directly studied
using recordings of bladder pressure during localized chemical stimulation of Barrington's
nucleus neurons. These studies demonstrated that blocking the effects of CRF at the level of
the spinal cord increased the magnitude of Barrington's-nucleus-stimulated contractions of
the bladder, supporting an inhibitory influence of CRF in this spinal pathway.[22] The inhibitory
influence of CRF in these projections may result from a direct action on preganglionic
parasympathetic neurons or inhibition of excitatory amino acid neurotransmitters such as
glutamate from Barrington's nucleus that stimulate preganglionic parasympathetic neurons.[22]
An inhibitory influence of CRF on the bladder may seem counterintuitive, as urination is often
considered a response to fear, which is equated with stress. However, urination is inhibited in
response to some stressors. Urinary retention is a particularly prominent response to social
stress in rodents, in which it is likely to be adaptive. When this fact is considered in
conjunction with the ability of CRF to engage the locus coeruleuscortical pathway and to
initiate arousal in response to pelvic visceral stimuli, the inhibitory influence of CRF in the
spinal cord may help to maintain continence by allowing arousal to occur before the initiation
of bladder contraction (Figure 4). If bladder contraction and cortical arousal occurred
simultaneously, insufficient time would be provided to interrupt ongoing behavior and
mobilize motor systems for voiding behaviors. By creating a lag between arousal and the
visceral response, continence can be maintained. Although speculative at this point, this
putative role for CRF in continence provides interesting options for future research, given the
prevalence of disorders of continence and their cost to the individual and to society.

Figure 4.

(Enlarge Image)

Simultaneous EEG and cystometry recordings obtained from a

sham-treated rat and two PBOO rats. PBOO rat 1 shows
spontaneous nonvoiding contractions and an EEG pattern
characterized by a theta oscillation peak at 7.5 Hz. PBOO rat 2
does not exhibit nonvoiding contractions, but shows increased
micturition frequency and an EEG pattern characterized by
reduced amplitude and a shift towards higher frequencies.
Abbreviations: BC, bladder capacity; BP, bladder pressure; EEG,
electroencephalography; MV, micturition volume; PBOO, partial

bladder outlet obstruction; PSD, EEG power spectrum density.

Permission obtained from The National Academy of Sciences
Rickenbacher, E. et al. Proc. Natl Acad. Sci. USA 105, 10589
10594 (2008).
Central Symptoms of Bladder Pathology
Partial Bladder Outlet Obstruction

The Barrington's nucleus circuit is clearly important in the coordination of behavior with
visceral activity. However, the same lines of communication can also act as a conduit to
convey signals from pathological events occurring in the viscera to the brain, providing a
structural basis for neurobehavioral sequelae of pelvic visceral disorders (Figure 2b). This
concept has been investigated in rats with partial bladder outlet obstruction (PBOO), an
animal model that has been used to examine the consequences of outlet obstruction on
bladder function and structure.[62] An initial neuronal consequence of partial bladder outlet
obstruction was the loss of Barrington's nucleus and locus coeruleus responses to increases
in bladder pressure up to the micturition threshold.[63] This loss of response is relevant to the
ongoing visceral pathology as it represents a loss of central regulation of bladder function.
Analogous to the effects of spinal cord injury on micturition, the loss of central control could
contribute to the development of local spinal regulation of the micturition reflex, which is
thought to underlie bladder hyperactivity.[64] Thus, the consequences of partial bladder outlet
obstruction with regard to Barrington's nucleus neuronal activity might exacerbate the
bladder dysfunction. Importantly, this hypothesis accounts for the finding that some
individuals can have chronic urinary retention and an enlarged bladder, yet have no
sensation of bladder fullness or urge to urinate.
Although locus coeruleus neurons of rats with partial bladder outlet obstruction were not
activated by acute increases in bladder pressure up to the micturition threshold, their rate of
spontaneous discharge was tonically elevated compared to that of rats that underwent sham
surgery.[63] Theories about the function of the locus coeruleusnorepinephrine system in
relation to behavior suggest that it has a role in facilitating decisions related to task-directed
behavior (that is, whether to maintain behavior in an ongoing task or to disengage and seek
alternative strategies in a dynamic environment).[13] Tonic locus coeruleus activation favors
disengagement from ongoing behavior and tasks involving focused attention, and promotes
scanning of the environment for alternate strategies. From this perspective, the transient
tonic excitation of locus coeruleus neurons elicited as bladder pressure rises towards the
micturition threshold in control rats is speculated to represent a central limb of the micturition
reflex. This serves to increase arousal and facilitate disengagement from ongoing behavior to
initiate elimination-related behaviors. The persistent elevation of locus coeruleus discharge
that is observed in rats with partial bladder outlet obstruction may translate in humans to
hyperarousal, sleep disorders, altered attention and inability to stay on task, all of which
would disrupt normal behavior.
The persistent effects of partial bladder outlet obstruction on locus coeruleus activity and
responses to bladder distention are reflected in cortical electroencephalography as

desynchronization and a shift from high-amplitude, low-frequency activity to low-amplitude,

high-frequency activityeffects indicative of hyperarousal (Figures 4 and 5).[63] A salient
electroencephalographic feature of partial bladder outlet obstruction is a theta frequency
oscillation that is particularly prominent in rats with a urodynamic profile characterized by
numerous nonvoiding contractions (Figure 4).[63] Theta oscillations are involved in
sensorimotor integration and are hypothesized to coordinate activity in different brain regions
in preparation for motor responses to sensory input.[65] Their persistence in subjects with an
overactive bladder may reflect constant or disordered processing of bladder signals. Theta
oscillations in PBOO rats are present even when selective responses to the major micturition
event are attenuated, which suggests a loss of ability to discriminate between different
magnitudes of bladder pressure changes (Figure 5).

Figure 5.

(Enlarge Image)

The heat maps indicate time-averaged bladder pressure and

corresponding EEG generated over 45 micturition cycles from
the same rats as in Figure 4. Time 0 represents the micturition
threshold. The sham-treated rat demonstrates a steady increase
in bladder pressure up to the micturition threshold. In shamtreated rats, a decrease in power at all frequencies
(desynchronization) precedes the micturition threshold,
illustrating that arousal precedes micturition. By contrast, PBOO
rat 1 has nonvoiding contractions that appear in the bladder
pressure heat map as lighter blue blocks interspersed within
darker blue. This obstructed rat has increased power in the high
frequencies (710 Hz and 1415 Hz) that fluctuate with the
nonvoiding contractions. In PBOO rat 2, desynchronization is
evident in the cortical EEG throughout the micturition cycle
regardless of the changes in bladder pressure. Abbreviations:
BP, bladder pressure; EEG, electroencephalography; PBOO,
partial bladder outlet obstruction. Permission obtained from The
National Academy of Sciences Rickenbacher, E. et al. Proc.
Natl Acad. Sci. USA 105, 1058910594 (2008).

Importantly, an effect of partial bladder outlet obstruction on sensorimotor processing could

affect cortical processing of stimuli unrelated to the bladder, and have an adverse effect on
functions requiring focused attention. Selective chemical lesions of forebrain locus coeruleus
projections abrogates the effects of partial bladder outlet obstruction on cortical activity seen
on electroencephalography without altering urodynamics, suggesting that tonic locus
coeruleus activation is necessary for these effects to occur.[63] The potential role of CRF in the
changes in locus coeruleus activity induced by partial bladder outlet obstruction is a
compelling area of research that could lead to new targets for therapeutic intervention in
patients with voiding dysfunction.
Simultaneous electroencephalography and cystometric recordings are beginning to reveal
how bladder and cortical activity are coordinated and how this relationship is altered in
disease states, such as partial bladder outlet obstruction. These data show that, in normal

animals, arousal (which manifests as desynchronization) increases with bladder pressure

and precedes the voiding event, a relationship that is important for continence. In PBOO rats,
the relationship between bladder pressure and cortical activity is markedly altered. In
particular, the temporal relationship between EEG desynchronization and micturition
threshold is not so clear and this could affect continence (Figure 5). In the rat with many
nonmicturition contractions, the bursts of theta rhythm could affect processing of information
not related to bladder (Figure 5).
Clinical Translation

The PBOO rat model demonstrates that pathology originating in the bladder can have
pronounced adverse central consequences via the Barrington's nucleus circuit. In the clinic,
central sequelae of bladder disorders might go unrecognized if urologists focus solely on
bladder complaints, and psychiatrists will not typically link neurobehavioral symptoms to the
bladder. Nonetheless, some evidence indicates that anxiety and sleep disorders occur in
men with benign prostatic hypertrophy and in men and women with various bladder
disorders.[66,67]Notably, attention deficit hyperactivity disorder, which has been linked to
excessive activation of the locus coeruleusnorepinephrine system,[6870] is highly associated
with enuresis in children.[71] Impairment of cognitive function, as tested in the Cambridge
cognitive exam, is seen in elderly patients with urge incontinence and the Barrington's
nucleus circuit could contribute to this.[72] Overactive bladder is notably prevalent in the
elderly, a population that is also vulnerable to neurobehavioral deficits and sleep
disturbances.[73] This model leads to the speculation that improvement of bladder symptoms
may also improve cognition. Importantly, evidence for a causal role of the locus coeruleus
norepinephrine system in the central consequences of partial bladder outlet obstruction in
rats suggests that fine-tuning the activity of this pathway may provide a useful therapeutic
approach for neurobehavioral symptoms in humans.
The link between Barrington's nucleus neurons and other pelvic viscera implies that
pathology arising from pelvic viscera other than the bladder could have similar central
consequences to those reported for the bladder. For example, this circuit might underlie the
well-documented coexistence of psychiatric and colonic symptoms that characterizes irritable
bowel syndrome.[2,3,36]

Social Stress-induced Bladder Dysfunction

As described above, the Barrington's nucleus circuitry enables bladder pathology to
adversely affect cortical activity. This circuit also provides a structure through which
psychogenic stimuli can affect the pelvic viscera and result in voiding dysfunction. Regulation
of pelvic visceral activity in response to sexual signals, predators and social hierarchy is an
adaptive brain function in animals that has been conserved throughout evolution. Social
stress or competition in male rodents causes urinary retention that is likely to be adaptive.[9,74
76]
However, if the urinary retention persists, it results in bladder enlargement and, in some
cases, leads to death from nephritis.[74] In a rodent model of social stress (the resident
intruder model), subordinate rats develop a urodynamic profile that resembles that produced
by partial bladder outlet obstruction, with prolonged intermicturition intervals, increased
bladder capacity and micturition volume, and numerous nonvoiding bladder contractions

(Figure 6).[77] The urodynamic profile associated with social stress is distinguishable from that
of partial bladder outlet obstruction by its lack of an elevated micturition threshold pressure,
implying that social stress results in a loss of central drive to the detrusor as opposed to
increased sphincter tone. Like partial bladder outlet obstruction, social stress increases
bladder mass and the magnitude of this effect is negatively correlated to the tendency to
become subordinate, suggesting that rodents that are prone to defeat in a social conflict are
more vulnerable to bladder dysfunction. Urinary retention might be a visceral component of a
defensive response mediated by the periaqueductal gray, a brain structure that organizes
defensive behaviors and is a major input to Barrington's nucleus.[78,79]

Figure 6.

(Enlarge Image)

Social stress alters bladder urodynamics. Cystometric

recordings of bladder pressure and bladder capacity of a | a
control rat and b | a rat that was exposed to resident-intruder
stress for a period of 7 days. The bladder of the stressed rat
shows numerous nonvoiding contractions, prolonged
intermicturition intervals and greater bladder capacity, compared
to the unstressed control rat. Permission obtained from the
American Physiological Society Wood et al. Am. J. Physiol.
Regul. Integr. Comp. Physiol. 296, R1671R1678 (2009).

In line with the observed increase in bladder mass, social stress causes upregulation of
some of the same transcription factors that are upregulated by partial bladder outlet
obstruction. These factors are thought to be important in the structural remodeling of the
bladder that occurs during partial bladder outlet obstruction, and include nuclear factor of
activated T cells (NFAT) and myocyte enhancer factor 2 (MEF2).[80] The induction of these
molecules by social stress is a striking example of how a social signal can induce visceral
restructuring that has important biological and clinical implications.
The role of CRF in stress and its inhibitory effect on Barrington's nucleus projections to
bladder motor neurons led to speculation that CRF would be intrinsically involved in socialstress-induced voiding dysfunction. Consistent with this hypothesis, social stress upregulates
CRF protein and messenger RNA expression in Barrington's nucleus neurons, an effect that
can account for the urinary retention.[77] Notably, repeated restraint stress does not produce
urinary dysfunction, or increase expression of either CRF protein or messenger RNA in
Barrington's nucleus neurons. This observation indicates that visceral dysfunction might be
specific to social stress, and further implicates CRF neurons of Barrington's nucleus in this
association.
The specific nature of the association between the effects on bladder and social stress is not
surprising given that different stressors engage distinct circuits in the brain and can have very
different effects on transcription in the same neurons.[81,82] Social stress engages the
periaqueductal gray region to mediate defensive responses and this brain region has
prominent projections to Barrington's nucleus, suggesting a pathway by which social
stressors could also affect this nucleus.[78,79,83]

Clinical Translation

Social-stress-induced voiding dysfunction in rodent models is characterized by urinary

retention, a problem seen in individuals of both sexes and all age groups.[8488] Dysfunctional
voiding remains the most common reason for referral to a pediatric urologist.[89] In children,
dysfunctional voiding associated with detrusor hypoactivity is hypothesized to arise from
adverse events that occur before or at around the time of toilet training.[90,91]Consistent with
this hypothesis, children with voiding postponement have a less balanced family environment
and more psychiatric comorbidity than children with other types of voiding dysfunction.
[92,93]
The effect of childhood social stress on bladder function can extend into adulthood
childhood sexual or physical abuse is associated with urinary disorders characterized by
retention in adults,[94,95] and adult urinary retention is associated with a history of sexual
abuse, depression and social anxiety.[6,94] As in the rat model, persistent urinary retention can
have severe structural consequences on the genitourinary system and result in chronic renal
insufficiency.[85]Even in the absence of such severe consequences, the importance of social
stress in urological health is emphasized by a study of >1,000 women, which demonstrated
associations between urinary incontinence and psychosocial problems that included feelings
of vulnerability.[96]
To date, the mechanisms that determine how social stressors adversely affect bladder
function have remained unknown, which makes their treatment difficult. Evidence for an
involvement of CRF in the Barrington's nucleus circuit suggests that this peptide hormone
could provide a target for the treatment of these disorders.

Conclusions
The divergent projections of Barrington's nucleus neurons to the major brain norepinephrine
nucleus (the locus coeruleus) and the lumbosacral spinal preganglionic neurons that give
rise to parasympathetic innervation of the pelvic viscera provide a mechanism for
coordinating behavior with pelvic visceral activity. This structural organization also enables
signals from dysfunctional viscera to affect cortical activity and produce the neurobehavioral
effects that are associated with visceral pathology. Similarly, psychogenic stimuli, particularly
social stress, can induce pelvic visceral dysfunction by affecting components of the same
circuit.
In the bladder, this circuit helps to coordinate voiding behaviors with elimination. At the same
time, it provides a means by which bladder disorders can produce hyperarousal, anxiety and
inattentiveness, and by which social adverse events can induce bladder dysfunction. The
stress-related neuropeptide, CRF, is an important component of this circuit, and might
constitute a novel target for the treatment of urological disorders, particularly those with a
psychogenic component.
The findings discussed in this Review emphasize the importance of considering central
components in the etiology of urological disorders. Elucidating the mechanisms through
which the brain and bladder communicate could lead to a holistic and effective approach to
the treatment of human urinary disorders, and offer new avenues for the development of
novel agents for treating these disorders.

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MORE ON THIS TOPIC

Voiding Dysfunction
Urological Management in
Neurological Disease
Overactive Bladder in Children
Sidebar 1

Urinary Incontinence & OAB News

& Perspecti

Key Points

Barrington's nucleus in the pons coordinates the descending visceral limb of the
micturition reflex with a central limb that initiates arousal and facilitates elimination
behavior

The stress-related neurotransmitter, corticotropin-releasing factor, regulates both

limbs of the micturition reflex owing to its actions in the central and spinal projections
of Barrington's nucleus neurons

Pelvic visceral disorders can affect the major brain norepinephrine nucleus, the locus
coeruleus and have neurobehavioral consequences

Psychosocial stressors can produce voiding dysfunctions and bladder pathology via
spinal projections of Barrington's nucleus neurons

Neural circuits linking the brain and bladder provide a basis for the coexistence of
bladder and neurobehavioral symptoms

Pharmacological modulation of neurotransmitters expressed by Barrington's nucleus

neuronssuch as corticotropin-releasing factoroffers a novel approach for the
treatment of bladder disorders

Sidebar 2
Review Criteria

We searched PubMed for original articles focusing on the role of corticotropin-releasing

factor in bladderbrain interactions, using the search terms "Barrington's nucleus", "locus
coeruleus", "corticotropin-releasing factor", "pseudorabies virus" and "trans-synaptic tracing".
All articles selected for inclusion were full-text papers in English. In addition, the reference
lists of selected papers were checked to identify further relevant articles. The translational
aspects of this Review were based on papers identified by searching PubMed using the
following terms: "pelvic comorbidity", "social stress urination", "partial bladder outlet
obstruction", "social stress voiding dysfunction", "incontinence" and "social stress overactive
bladder".