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Bridging The Sex Divide: Chronic Non-Discriminatory Social Defeat Stress Paradigm Induces Altered Voiding Phenotypes In Both Male And Female Mice
Stephan Butler, MA, Joanna Fesi, BS, Sanghee Yun, PhD, Amelia Eisch, PhD, Jason P. Van Batavia, MD, MSTR.
The Children's Hospital of Philadelphia, Philadelphia, PA, USA.


Background: Lower urinary tract dysfunction (LUTD) in children varies by sex in terms of symptoms and etiologies. These sex differences may be at the level of the CNS, PNS, or bladder. Chronic social defeat stress in rodents produces LUTD but almost all paradigms are male exclusive. Recently, a paradigm involving both male and female rodents simultaneously exposed to the same stress has been described (chronic non-discriminatory social defeat stress, CNSDS). Here we describe voiding phenotypes in male and female mice after CNSDS. We hypothesized that both male and female stressed mice would have an altered voiding phenotype characterized by fewer, larger voids and exhibit stress-induced social avoidance.
Methods: For the CNSDS paradigm (Figure 1B), each “test” mice (7week old C57BL/6J male and female pair, n=16/sex) is placed in home cage of novel CD-1 ”aggressor” mouse for 5min/day of physical interaction for 10days (“social defeat” phase). After defeat, each test mouse is housed separately with a new CD-1 mouse separated by a perforated plastic divider for continuous sensory exposure. Control female and male pairs (n=10/sex) interact for 5 min in the CNSDS cage (no CD-1 mouse present) for 5min/day over 10days and separately housed on either side of the divider. The voiding pattern of all female and male mice was assessed for 24hrs in a metabolic chamber pre- and post-CNSDS (Figure 1A). To measure response to the defeat stress, a social interaction (SI) test was performed and allows classification of mice as “susceptible” or “resilient” to CNSDS (Figure 1C).
Results:There were no differences in mean voiding parameters in control mice (Table1). Compared to baseline, female mice had significant increase in mean number of voids per 24hrs and mean voided volumes after CNSDS. Male mice only had significant increase in mean voided volumes after CNSDS compared to baseline. After completion of CNSDS protocol, 8 female mice were found to be resilient and 8 were susceptible; while 10 male mice were found to be resilient and 6 were susceptible. Resilient vs. susceptible status did not affect altered voiding parameters after CNSDS (Figure 2).
Conclusions:CNSDS led to a significant increase in voided volumes in both female and male mice. We did note a sex difference in altered voiding pattern, as only female mice had an increase in voids per 24hr after CNSDS. Previous studies have shown that mice susceptible to SDS display a depressive-like phenotype, which includes social anxiety. When we analyzed voiding data of susceptible vs resilient mice we saw no significant differences suggesting that changes in the voiding phenotype and depressive-like behavior are not mutually inclusive phenomenon.



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