The bladder-brain connection: putative role of corticotropin-releasing factor

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.

Figure 1

Barrington’s nucleus neurons are transsynaptically-linked to both the bladder and colon. Fluorescent photomicrograph of a rat brain section at the level of Barrington’s nucleus 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. These appear as either yellow or orange (arrows) or cells the have a red nucleus and green cytoplasm (arrowhead). Reproduced from reference with permission from John Wiley and Sons, LTD).

Figure 2

Schematic depicting the circuitry centered around Barrington’s nucleus that links the brain and pelvic viscera. A. Signals from pelvic viscera are conveyed to Barrington’s nucleus either directly or indirectly. Barrington’s nucleus modulates visceral activity via spinal efferents and cortical activity via its projections to the locus coeruleus. B. Through the same circuitry signals related to pathology in the pelvic viscera can be relayed to the cortex via Barrington’s nucleus projections to the LC. Psychogenic stimuli, such as social stress can potentially impact on the pelvic viscera through projections from the periaqueductal gray or other afferents to Barrington’s nucleus. Abbreviations: IBS (irritable bowel syndrome), LC (locus coeruleus) and OAB (Overactive bladder).

Figure 3

CRF is a major neurotransmitter in Barrington’s nucleus neurons. A. Brightfield photomicrograph of a rat brain section at the level of Barrington’s nucleus showing CRF-immunoreactive neurons (blue) and neurons that are retrogradely labeled with the tracer fluorogold from the lumbosacral spinal cord (brown). Note that most neurons have the hybrid 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 4

Effect of partial bladder obstruction on the relationship between bladder pressure and cortical EEG. A. Simultaneous EEG and cystometry recordings from sham and obstructed rats. From top to bottom, the traces show raw EEG, bladder pressure (BP, mm Hg), bladder capacity (BC, ml), micturition volume (MV, ml), and EEG power spectrum (PSD). An obstructed rat (1) has a similar urodynamic pattern as the sham rat with the exception of spontaneous non-voiding contractions but has a distinct EEG pattern characterized by a peak at 7.5 Hz (theta oscillation). Obstructed rat 2 does not exhibit non-voiding contractions, but shows increased micturition frequency. In this case the EEG is characterized by lower amplitude and a shift towards higher frequencies. B1 and B2 show peri-event spectrograms generated from the same subjects as in A, indicating how power in different EEG frequency bands co-varies with bladder pressure during individual micturition cycles. In B1, the traces represent mean bladder pressure over 4–5 micturition cycles and centered at the micturition threshold (time=0). The heat map above each trace represents bladder pressure for each micturition cycle. For the sham rat, a uniform increase in bladder pressure up to micturition threshold can be seen. In contrast, for Obstructed (1) non-voiding contractions are indicated in the heat map as sporadic episodes (lighter blue blocks interspersed within darker blue) that occur up to the point at which micturition threshold is reached. Obstructed (2) does not exhibit non-voiding contractions. B2 shows heat maps that indicate the mean relative power in different EEG frequency bands (0–20 Hz, ordinate) and these are time-locked with B1, such that time=0 indicates the point of the micturition threshold. Note how the different patterns of bladder activity produced by obstruction impact on the relationship between bladder pressure and cortical EEG activity. In sham rats a decrease in power in all frequencies (i.e., desynchronization) precedes the micturition threshold and is maintained. Obstructed 1 with non-voiding contractions has greater power in higher frequencies (7–10 Hz and 14–15 Hz) that fluctuate like the contractions. In Obstructed 2 that has frequent micturition cycles and no non-voiding contractions, cortical EEG is desynchronized throughout the session and increases in bladder pressure up to the micturition threshold are without effect. Reproduced with permission from reference .

Figure 4

Effect of partial bladder obstruction on the relationship between bladder pressure and cortical EEG. A. Simultaneous EEG and cystometry recordings from sham and obstructed rats. From top to bottom, the traces show raw EEG, bladder pressure (BP, mm Hg), bladder capacity (BC, ml), micturition volume (MV, ml), and EEG power spectrum (PSD). An obstructed rat (1) has a similar urodynamic pattern as the sham rat with the exception of spontaneous non-voiding contractions but has a distinct EEG pattern characterized by a peak at 7.5 Hz (theta oscillation). Obstructed rat 2 does not exhibit non-voiding contractions, but shows increased micturition frequency. In this case the EEG is characterized by lower amplitude and a shift towards higher frequencies. B1 and B2 show peri-event spectrograms generated from the same subjects as in A, indicating how power in different EEG frequency bands co-varies with bladder pressure during individual micturition cycles. In B1, the traces represent mean bladder pressure over 4–5 micturition cycles and centered at the micturition threshold (time=0). The heat map above each trace represents bladder pressure for each micturition cycle. For the sham rat, a uniform increase in bladder pressure up to micturition threshold can be seen. In contrast, for Obstructed (1) non-voiding contractions are indicated in the heat map as sporadic episodes (lighter blue blocks interspersed within darker blue) that occur up to the point at which micturition threshold is reached. Obstructed (2) does not exhibit non-voiding contractions. B2 shows heat maps that indicate the mean relative power in different EEG frequency bands (0–20 Hz, ordinate) and these are time-locked with B1, such that time=0 indicates the point of the micturition threshold. Note how the different patterns of bladder activity produced by obstruction impact on the relationship between bladder pressure and cortical EEG activity. In sham rats a decrease in power in all frequencies (i.e., desynchronization) precedes the micturition threshold and is maintained. Obstructed 1 with non-voiding contractions has greater power in higher frequencies (7–10 Hz and 14–15 Hz) that fluctuate like the contractions. In Obstructed 2 that has frequent micturition cycles and no non-voiding contractions, cortical EEG is desynchronized throughout the session and increases in bladder pressure up to the micturition threshold are without effect. Reproduced with permission from reference .

Figure 5

Social stress alters bladder urodynamics. A and B show representative cystometry recordings of bladder pressure and bladder capacity of a control rat (A) and a rat that was exposed to the resident-intruder stress for 7 consecutive days (B). Note that the bladder of the stressed rat shows numerous non-micturition contractions, longer intermicturition intervals and greater bladder capacity. (Reproduced from ref , Wood et al., Am J Physiol Regul Integr Comp Physiol, 2009 with permission of the American Physiological Society).