Chronic neuroendocrine stress reduces urinary bladder capacity, increases bladder wall thickness and induces overactive voiding behavior

Chronic stress can lead to urinary bladder dysfunction through centrally and locally induced mechanisms. Prolonged upregulation of brain-derived neurotrophic factor (BDNF) in the paraventricular nucleus of the hypothalamus (PVN) has been shown to chronically activate all major stress pathways including the sympathetic nervous system, the hypothalamus-pituitary-adrenal axis and vasopressin (AVP) signaling. 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 alter voiding behavior and induce bladder wall remodeling. Non-invasive voiding behavior tests were conducted for 48 h at weeks 3, 6, 10 and 14 after vector injections. In addition, in vitro bladder wall mechanics and compliance measures as well as Masson's trichrome histology were conducted at 18-19 weeks post injections. Hypothalamic overexpression of BDNF led to an emerging overactive bladder phenotype and altered urine voiding behavior. Remarkably, BDNF overexpression significantly increased voiding frequency and decreased average void volume both during daytime and nighttime from week 3 to 14. For instance, BDNF voiding frequency during daytime was more than twice as high as that of GFP at week 3 (GFP: 4.7 ± 0.8 voids per light cycle, BDNF: 11.1 ± 2.7 voids per light cycle; p < 0.01) and the difference increased to more than 3x by week 14 (GFP: 3.8 ± 0.3 voids per light cycle, BDNF: 12.6 ± 1.6 voids per light cycle; p < 0.0001). On the other hand, average void volumes showed the opposite trajectory where daytime BDNF average void volumes remained 3x lower than in GFP rats for the whole duration of the experiments ( Week 14 : GFP: 2.3 ± 0.2 ml, BDNF: 0.7 ± 0.1 ml; p < 0.0001). Histological analysis revealed increased bladder wall thickness in BDNF (173.9 ± 10.0 μm) vs GFP (125.1 ± 2.9 μm, p < 0.01) and bladder compliance tests suggested a reduced bladder capacity in BDNF rats (GFP: 2.7 ± 0.3 ml, BDNF: 1.1 ± 0.2 ml; p < 0.01) without any alteration in bladder wall tensile stress and compliance mechanics. In conclusion, we demonstrated that in our novel model of chronic neuroendocrine stress, we could emulate overactive bladder syndrome, a common complication in humans experiencing chronic stress that is characterized by higher urinary void frequency and lower average void volume. Our results suggest that bladder wall hypertrophy and reduced bladder capacity may play significant roles; however, bladder compliance didn’t seem to be affected. These findings can help elucidate pathways through which neuroendocrine stress mechanisms contribute to the development of the overactive bladder syndrome. Funded by R01HL166464, R03AG072016 and R01DK125543 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.