Urinary Bladder Dysfunction in a Novel Model of Neuroendocrine Stress
Authors: Husain Jenan , Pace Anna , Bakhareva Sasha , Fallon Hannah , Herrera Gerald , Heppner Thomas , Erdos Benedek 
Published: May 2024

Chronic stress can lead to urinary bladder dysfunction and pain either through actions within the central nervous system or by mechanisms that are locally induced in the bladder. Prolonged upregulation of brain-derived neurotrophic factor (BDNF) in the paraventricular nucleus of the hypothalamus (PVN) has been shown to induce hypertension and chronically elevate activities of the sympathetic nervous system and hypothalamus-pituitary-adrenal axis. Taking advantage of this mechanism, we created a novel model of chronic neuroendocrine stress by subjecting male Sprague Dawley rats to bilateral PVN injections of AAV2 viral vectors expressing either BDNF or GFP (for control). We tested the hypothesis that model-induced chronic neuroendocrine stress would impair bladder function. Bladder activity was assessed 10 weeks post-injections by monitoring the number of urinary voids and average urinary void volume along with water intake over a 48-hour period. To further characterize changes in the urinary bladder, bladder weights were recorded, and in vitro bladder strip experiments were conducted 14 weeks after viral vector injections. BDNF overexpression in the hypothalamus led to significantly lower daily urine output even though water intake remained unaffected, suggesting that BDNF-treated animals showed a significantly higher non-urine-related fluid compared to GFP controls (daily urine output = GFP: 33.85±4.94, BDNF: 14.82±2.18, p < 0.01. Interestingly, despite a lower total daily urine volume, BDNF-treated animals had a significantly higher number of urinary voids (GFP: 7.50±1.42, BDNF: 15.38±2.76; GFP vs. BDNF: p < 0.001) and lower average void volume (GFP: 1.19±0.15, BDNF: 0.27±0.07; GFP vs. BDNF: p < 0.01), thus emulating the overactive bladder phenotype, a common complication in humans with chronic stress. These findings were complemented by in vitro experiments where bladder strips from BDNF rats showed significantly higher contractility as tested with high K+ concentration and electric field stimulation. Moreover, Carbachol-induced stimulation of muscarinic receptors in BDNF bladder strips also trended towards higher contractility. However, urinary bladder weights were unaffected by BDNF overexpression. In summary, we demonstrated that prolonged hypothalamic BDNF overexpression, a model of chronic neuroendocrine stress, leads to significant alterations in bladder function such that BDNF-treated rats exhibited a higher number of urinary voids and lower average void volume compared to GFP controls, and bladder strip experiments suggest that enhanced smooth muscle contractility may contribute to this overactive bladder phenotype. These findings from our novel experimental model will help elucidate pathways through which neuroendocrine stress mechanisms contribute to the development of the overactive bladder syndrome.

Funded by R01HL166464, R03AG072016 and R01DK125543.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.