Abstract
Stress plays a role in the exacerbation and possibly the development of functional lower urinary tract disorders. Chronic water avoidance stress (WAS) in rodents is a model with high construct and face validity to bladder hypersensitive syndromes, such as interstitial cystitis/bladder pain syndrome (IC/BPS), characterized by urinary frequency and bladder hyperalgesia and heightened stress responsiveness. Given the overlap of the brain circuits involved in stress, anxiety, and micturition, we evaluated the effects chronic stress has on bladder function, as well as its effects on regional brain activation during bladder filling. Female Wistar-Kyoto rats were exposed to WAS (10 days) or sham paradigms. One day thereafter, cystometrograms were obtained during titrated bladder dilation, with visceromotor responses (VMR) recorded simultaneously. Cerebral perfusion was assessed during passive bladder distension (20-cmH2O) following intravenous administration of [14C]-iodoantipyrine. Regional cerebral blood flow was quantified by autoradiography and analyzed in 3-dimensionally reconstructed brains with statistical parametric mapping. WAS animals compared to controls demonstrated a decreased pressure threshold and visceromotor threshold triggering the voiding phase. At 20-cmH2O, VMR was significantly greater in WAS animals compared to controls. WAS animals showed greater activation in cortical regions of the central micturition circuit, including the posterior cingulate, anterior retrosplenial, somatosensory, posterior insula, orbital, and anterior secondary (“supplementary”) motor cortices, as well as in the thalamus, anterior hypothalamus, parabrachial and Barrington nuclei, and striatum. Seed analysis showed increased functional connectivity of WAS compared to control animals of the posterior cingulate cortex to the pontine parabrachial nucleus; of the Barrington nucleus to the anterior dorsal midline and ventrobasilar thalamus and somatosensory and retrosplenial cortices; and of the posterior insula to anterior secondary motor cortex. Our findings show a visceral hypersensitivity during bladder filling in WAS animals, as well as increased engagement of portions of the micturition circuit responsive to urgency, viscerosensory perception and its relay to motor regions coordinating imminent bladder contraction. Results are consistent with recent findings in patients with interstitial cystitis, suggesting that WAS may serve as an animal model to elucidate the mechanisms leading to viscerosensitive brain phenotypes in humans with IC/BPS.
Highlights
Chronic emotional stress plays a role in the exacerbation and possibly the development of functional lower urinary tract disorders (LUTD) [1,2,3,4,5]
The current study addresses this in an animal model by prospectively examining the relationship between chronic stress exposure, bladder function, hyperalgesia and functional brain activation
The visceromotor responses (VMR) evoked by bladder distension in water avoidance stress (WAS) animals appeared at a lower IVP during bladder filling compared to controls (P = 0.01, Fig 1E)
Summary
Chronic emotional stress plays a role in the exacerbation and possibly the development of functional lower urinary tract disorders (LUTD) [1,2,3,4,5] These disorders can be viewed as a spectrum of bladder hypersensitivity syndromes sharing the common symptoms of urinary frequency and urgency, with bladder pain syndrome/interstitial cystitis (IC/BPS) patients experiencing pain as an additional symptom. Our prior work has shown that chronic psychological stress in high-anxiety rats induces urinary frequency, sustained bladder hyperalgesia, tactile hindpaw allodynia and suprapubic hyperalgesia [16,17]. Using this animal model, we examine the effects chronic psychological stress has on functional bladder dynamics, as well as functional brain responses during bladder filling. We hypothesize that rats exposed to water avoidance stress compared to non-stressed controls will during passive bladder filling show abnormal bladder function and sensitivity, as well as increased activation of brain regions within the micturition circuit
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