ReViewS

The bladder–brain connection: putative role

of corticotropin-releasing factor
Rita J. Valentino, Susan K. Wood, Alan J. Wein and Stephen A. Zderic
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, corticotropin‑releasing factor, which is prominent in Barrington’s nucleus neurons,
is a potential mediator of these effects.
Valentino, R. J. et al. Nat. Rev. Urol. 8, 19–28 (2011); published online 7 December 2010; doi:10.1038/nrurol.2010.203

Introduction
Clinical assessment of patients with pelvic visceral dis­
orders 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 psychi­
atric symptoms highlights the interrelationships between
the brain and pelvic viscera.1–8 underlying these inter­
relationships are reciprocal endocrine and neural lines
of communication. For example, reciprocal communica­
tion between the brain and bladder enables bladder pres­
sure to be communicated to brain nuclei that serve to
increase arousal, redirect attention and modify behavior
so that micturition is coordinated with voiding behav­
iors. 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
Competing interests
The authors declare no competing interests.
nucleus, the pontine micturition center. initially consid­
ered to be the switch that initiates the descending limb
of the micturition reflex, Barrington’s nucleus neurons
that project to bladder motorneurons diverge to inner­
vate 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.11–14 this structural
organization enables neurons from Barrington’s nucleus
to co­regulate 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
Department of
is that they express high levels of the stress­related Anesthesia and Critical
neuropeptide, corticotropin­releasing factor (CrF).15–17 Care Medicine
although CrF was first characterized as the hypo­ (r. J. Valentino,
S. K. Wood),
thalamic neurohormone released in response to stres­ Department of Surgery
sors to initiate the endocrine limb of the stress response,18 (S. A. Zderic), The
Children’s Hospital of
it also acts as a neurotransmitter that is released from Philadelphia, Civic
neurons in limbic brain regions to mediate behavioral Center Boulevard,
responses to stress.19 the substantial expression of CrF Philadelphia,
PA 19104, USA.
by Barrington’s nucleus neurons has been speculated to be Division of Urology,
involved in regulation of bladder or colonic motility as a University of
Pennsylvania, Civic
component of the stress response.20 Given its prominence Center Boulevard,
in this pathway, which coordinates central and pelvic vis­ Philadelphia,
ceral functions, clarifying the actions of CrF could pave PA 19014, USA
(A. J. Wein).
the way for the development of novel pharmacological
methods for treating pelvic visceral disorders. Correspondence to:
R. J. Valentino
in this review, we consider the convergent anatomical valentino@
and physiological evidence for the Barrington’s nucleus e‑mail.chop.edu

nature reviews | urology volume 8 | JanuarY 2011 | 19

© 2011 Macmillan Publishers Limited. All rights reserved
reVieWS
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 neurons—such as corticotropin‑releasing factor—offers a novel
approach for the treatment of bladder disorders
4V
Figure 1 | 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 β‑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‑Dominguez et al.
Eur. J. Neurosci. 18, 3311–3324 (2003).
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
20 | JANUARY 2011 | volUme 8
© 2011 Macmillan Publishers Limited. All rights reserved
Barrington’s nucleus CrF in pelvic visceral disorders and
as a target for treating such disorders.
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.21–24 these studies
suggested that a micturition center was located in the
dorsal pons, and anatomical tracing studies then local­
ized the area critical to micturition as an oval cluster of
neurons just ventral to the fourth ventricle—this area was
named Barrington’s nucleus, after the physician who first
determined that dorsal pons lesions disrupted micturi­
tion.24–26 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.28–30 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.
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.31–34 of particular clinical
relevance, the majority of Barrington’s nucleus neurons
have synaptic links to both the bladder and distal colon,
which enables co­regulation of these viscera (Figure 1).31
By contrast, few Barrington’s nucleus neurons are trans­
synaptically linked to the stomach, which suggests that
brain regulation of the distal colon is likely to be coordi­
nated 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 co­regulate 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 con­
sistent 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 inser­
tion of the urorectal septum by 6 weeks of fetal develop­
ment.35 unlike the bladder, the distal colon is regulated
by multiple factors that control its motility in addition
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to innervation from Barrington’s nucleus. these factors
include propulsive forces from the proximal gastro­
intestinal 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 condi­
tions, 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
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 norepinephrine­containing 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 norepinephrine­containing 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 main­
tains 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.39–43 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, low­frequency activity to low­amplitude,
high­frequency activity.42,43 activation of the locus coer­
uleus 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 micturi­
tion reflex with a central limb that facilitates the switch
from ongoing (voiding­unrelated) 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 activ­
ity of each of these viscera with the activity in forebrain
regions that underlies behavior (Figure 2a).
Corticotropin-releasing factor
CrF serves as a neurohormone and neurotransmitter
that orchestrates the stress response. release of CrF from
nature reviews | urology
© 2011 Macmillan Publishers Limited. All rights reserved
reVieWS
a
Central effects of BN activation:
■ Arousal
■ Shift in attention
■ Facilitation of voiding-related behaviors
■ Inhibition of nonvoiding-related behaviors
LC
BN
Visceral effects of BN activation:
■ Detrusor contraction Pelvic viscera
■ Distal colon contraction
b Stress
Psychogenic stimuli (social stress)
can impact on pelvic visceral activity
PAG to cause voiding dysfunction, and IBS
LC
BN
Pelvic stimuli (IBS, OAB, pelvic pain) Pelvic viscera
can impact on cortical activity to
cause hyperarousal, sleep
disturbance, and disrupted attention
Figure 2 | 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.
hypothalamic neurons terminating in the median emi­
nence initiates the cascade of adrenocorticotropin and
corticosteroid secretion that is the hallmark of stress.18
CrF in neurons outside the hypothalamus—particularly
in limbic regions that are involved in the expression of
emotion—serves 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 coer­
uleus neurons, which results in forebrain activation and
arousal that is detectable by electroencephalography.45–48
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
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reVieWS
a V b urothelium and dorsal horn of the spinal cord, as well
Figure 3 | 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.
(Figure 3).10,17,49 the discovery of CrF in a circuit regu­
lating 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 promi­
nent 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
the CrF­expressing 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 coer­
uleus 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 projec­
tions from Barrington’s nucleus, CrF has been specu­
lated to have excitatory effects on colonic motorneurons,
which perhaps contribute to stress­related increases in
colonic motility and the symptoms of irritable bowel
syndrome.20,55 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.56–58 these con­
flicting 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 func­
tion on the basis of cystometric studies is that cysto­
metry 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
22 | JANUARY 2011 | volUme 8
© 2011 Macmillan Publishers Limited. All rights reserved
as in spinal projections of Barrington’s nucleus neurons
that regulate the micturition reflex.59–61 CrF can influ­
ence urodynamics at multiple sites—thus interpreting
the role of CrF in urodynamics is difficult.
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 demon­
strated that blocking the effects of CrF at the level of
the spinal cord increased the magnitude of Barrington’s­
nucleus­stimulated contractions of the bladder, sup­
porting an inhibitory influence of CrF in this spinal
pathway.22 the inhibitory influence of CrF in these pro­
jections 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 adap­
tive. when this fact is considered in conjunction with
the ability of CrF to engage the locus coeruleus–cortical
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 allow­
ing arousal to occur before the initiation of bladder con­
traction (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 inter­
esting options for future research, given the prevalence
of disorders of continence and their cost to the individual
and to society.
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 struc­
tural 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 con­
sequences 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 pathol­
ogy as it represents a loss of central regulation of bladder
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Figure 4 | Simultaneous eeG and cystometry recordings ▶ Sham treated

obtained from a sham‑treated rat and two PBOO rats. 1–

MV (ml) BC (ml) BP (mmHg) EEG (V)

PBOO rat 1 shows spontaneous nonvoiding contractions
0–
and an eeG pattern characterized by a theta oscillation
peak at 7.5 Hz. PBOO rat 2 does not exhibit nonvoiding –1 –
30 –
contractions, but shows increased micturition
frequency and an eeG pattern characterized by reduced
amplitude and a shift towards higher frequencies. 0–
Abbreviations: BC, bladder capacity; BP, bladder pressure; 500 –
eeG, electroencephalography; MV, micturition volume;
PBOO, partial bladder outlet obstruction; PSD, eeG power 0–
spectrum density. Permission obtained from The National 0.6 –
Academy of Sciences © Rickenbacher, e. et al. Proc. Natl
Acad. Sci. USA 105, 10589–10594 (2008). 0–
0 1,000 2,000
Time (s)
–
6 –
function. analogous to the effects of spinal cord injury on –

PSD (%)
micturition, the loss of central control could contribute to 4 –
–
the development of local spinal regulation of the micturi­ 2 –
tion reflex, which is thought to underlie bladder hyper­ –
0 –
activity.64 thus, the consequences of partial bladder outlet 0 10 20
obstruction with regard to Barrington’s nucleus neu­ Frequency (Hz)
ronal activity might exacerbate the bladder dysfunction. PBOO 1
importantly, this hypothesis accounts for the finding that 1–
MV (ml) BC (ml) BP (mmHg) EEG (V)

some individuals can have chronic urinary retention and 0–

an enlarged bladder, yet have no sensation of bladder –1 –
fullness or urge to urinate. 30 –
although locus coeruleus neurons of rats with partial
bladder outlet obstruction were not activated by acute 0–
increases in bladder pressure up to the micturition 500 –
threshold, their rate of spontaneous discharge was toni­
cally elevated compared to that of rats that underwent 0–
sham surgery.63 theories about the function of the locus 0.6 –
coeruleus–norepinephrine system in relation to behavior
0–
suggest that it has a role in facilitating decisions related 0 1,000 2,000
to task­directed behavior (that is, whether to maintain Time (s)
–
behavior in an ongoing task or to disengage and seek 6 –
–
PSD (%)

alternative strategies in a dynamic environment).13 tonic 4 –

–
locus coeruleus activation favors disengagement from 2 –
ongoing behavior and tasks involving focused atten­ –
0 –
tion, and promotes scanning of the environment for 0 10 20
alternate strategies. From this perspective, the transient Frequency (Hz)
tonic excitation of locus coeruleus neurons elicited as PBOO 2
bladder pressure rises towards the micturition threshold 1–
MV (ml) BC (ml) BP (mmHg) EEG (V)

in control rats is speculated to represent a central limb 0–

of the micturition reflex. this serves to increase arousal –1 –
and facilitate disengagement from ongoing behavior to 30 –
initiate elimination­related behaviors. the persistent
elevation of locus coeruleus discharge that is observed 0–
in rats with partial bladder outlet obstruction may trans­ 500 –
late in humans to hyperarousal, sleep disorders, altered
attention and inability to stay on task, all of which would 0–
disrupt normal behavior. 0.3 –
the persistent effects of partial bladder outlet obstruc­ 0–
tion on locus coeruleus activity and responses to bladder 0 1,000 2,000
Time (s)
distention are reflected in cortical electroencephalo­ –
6 –
graphy as desynchronization and a shift from high­ –
PSD (%)

amplitude, low­frequency activity to low­amplitude, 4 –

–
high­frequency activity—effects indicative of hyper­ 2 –
arousal (Figures 4 and 5).63 a salient electroencephalo­ –
–
0
graphic feature of partial bladder outlet obstruction is a 0 10 20
theta frequency oscillation that is particularly prominent Frequency (Hz)

nature reviews | urology volume 8 | JanuarY 2011 | 23

© 2011 Macmillan Publishers Limited. All rights reserved
reVieWS

Sham treated Bladder pressure ◀ Figure 5 | The heat maps indicate time‑averaged bladder
28 – pressure and corresponding eeG generated over 4–5
micturition cycles from the same rats as in Figure 4.

BP (mmHg)
24 – Time 0 represents the micturition threshold. The sham‑
treated rat demonstrates a steady increase in bladder
27 – pressure up to the micturition threshold. in sham‑treated
rats, a decrease in power at all frequencies
23 – (desynchronization) precedes the micturition threshold,
–100 0 100 illustrating that arousal precedes micturition. By contrast,
PBOO rat 1 has nonvoiding contractions that appear in the
EEG bladder pressure heat map as lighter blue blocks
25 – 20 –
interspersed within darker blue. This obstructed rat has
Frequency (Hz)

increased power in the high frequencies (7–10 Hz and

10 – 14–15 Hz) that fluctuate with the nonvoiding contractions.
in PBOO rat 2, desynchronization is evident in the cortical
0– 0– eeG throughout the micturition cycle regardless of the
–100 0 100 changes in bladder pressure. Abbreviations: BP, bladder
pressure; eeG, electroencephalography; PBOO, partial
PBOO 1 Bladder pressure bladder outlet obstruction. Permission obtained from The
28 –
National Academy of Sciences © Rickenbacher, e. et al.
Proc. Natl Acad. Sci. USA 105, 10589–10594 (2008).
BP (mmHg)

24 –

27 –
importantly, an effect of partial bladder outlet obstruc­
24 –
tion on sensorimotor processing could affect corti­
cal processing of stimuli unrelated to the bladder, and
–100 0 100
have an adverse effect on functions requiring focused
50 – 20 –
EEG attention. selective chemical lesions of forebrain locus
coeruleus projections abrogates the effects of partial
Frequency (Hz)

bladder outlet obstruction on cortical activity seen on

10 – electroencephalography without altering urodynamics,
suggesting that tonic locus coeruleus activation is neces­
0– 0– sary for these effects to occur.63 the potential role of CrF
–100 0 100
in the changes in locus coeruleus activity induced by
PBOO 2 Bladder pressure partial bladder outlet obstruction is a compelling area
30 – of research that could lead to new targets for therapeutic
intervention in patients with voiding dysfunction.
BP (mmHg)

10 –
simultaneous electroencephalography and cystometric
30 – recordings are beginning to reveal how bladder and cortical
activity are coordinated and how this relationship is altered
10 – in disease states, such as partial bladder outlet obstruction.
40 0 60 these data show that, in normal animals, arousal (which
manifests as desynchronization) increases with bladder
EEG
12.5 – 20 – pressure and precedes the voiding event, a relationship
that is important for continence. in PBoo rats, the
Frequency (Hz)

relationship between bladder pressure and cortical activity

10 –
0– 0–
40 0 60
Time (s)
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 process­
ing 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).
is markedly altered. in particular, the temporal relation­
ship between eeG desynchronization and micturition
threshold is not so clear and this could affect continence
(Figure 5). in the rat with many nonmicturition contrac­
tions, 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

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© 2011 Macmillan Publishers Limited. All rights reserved

men and women with various bladder disorders.66,67
notably, attention deficit hyperactivity disorder, which
has been linked to excessive activation of the locus
coeruleus–norepinephrine system,68–70 is highly associ­
ated 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 fine­tuning 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 well­documented
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, preda­
tors and social hierarchy is an adaptive brain function
in animals that has been conserved throughout evolu­
tion. 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 cap acity
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 nega­
tively 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
nature reviews | urology
© 2011 Macmillan Publishers Limited. All rights reserved
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a
20 –
Pressure
0–
700 –
Capacity
350 –
0–
2,100 2,250 2,400
b
20 –
Pressure
0–
700 –
Capacity
350 –
0–
3,000 3,300 3,600 3,900
Time (s)
Figure 6 | 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, R1671–R1678 (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 intrinsi­
cally involved in social­stress­induced voiding dys­
function. Consistent with this hypothesis, social stress
upregulates CrF protein and messenger rna expres­
sion 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 messen­
ger rna in Barrington’s nucleus neurons. this observa­
tion 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 surpris­
ing given that different stressors engage distinct cir­
cuits in the brain and can have very different effects
on transcription in the same neurons.81,82 social stress
volume 8 | JanuarY 2011 | 25
reVieWS

engages the periaqueductal gray region to mediate
defensive responses and this brain region has promi­
nent projections to Barrington’s nucleus, suggesting
a pathway by which social stressors could also affect
this nucleus.78,79,83
Clinical translation
social­stress­induced voiding dysfunction in rodent
models is characterized by urinary retention, a problem
seen in individuals of both sexes and all age groups.84–88
Dysfunctional voiding remains the most common
reason for referral to a pediatric urologist.89 in children,
dysfunctional voiding associated with detrusor hypo­
activity 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 child­
hood social stress on bladder function can extend into
adulthood—childhood sexual or physical abuse is associ­
ated 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 associa­
tions 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 coordinat­
ing behavior with pelvic visceral activity. this structural
organization also enables signals from dysfunctional
viscera to affect cortical activity and produce the neuro­
behavioral effects that are associated with visceral pathol­
ogy. 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 hyper­
arousal, anxiety and inattentiveness, and by which social
adverse events can induce bladder dysfunction. the
stress­related neuropeptide, CrF, is an important com­
ponent 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 mecha­
nisms through which the brain and bladder communi­
cate 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.
Review criteria
we searched PubMed for original articles focusing on
the role of corticotropin‑releasing factor in bladder–brain
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”.

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Acknowledgments
The authors acknowledge funding provided by an
National institute of Diabetes and Digestive and
Kidney Diseases (NiDDK) George O’Brien Center Grant
(PO5‑DK052620‑13) that was essential in facilitating
discussions and collaborations between the
neuroscientists and urologists involved in this Review.
Author contributions
R. J. Valentino, S. K. wood and S. A. Zderic
researched data for the article, and R. J. Valentino
wrote the article. All authors provided a substantial
contribution to discussions of the content, and
reviewed and edited the article before submission.
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