A model of lower urinary tract dysfunction in female mice: Utilizing a novel chronic social defeat stress paradigm to alter voiding phenotype
Stephan Butler, MS, Sanghee Yun, PhD, Joanna Fesi, BS, Amelia Eisch, PhD, Stephen Zderic, MD, Jason P. Van Batavia, MD, MSTR.
The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
BACKGROUND: Lower urinary tract dysfunction (LUTD) is a common reason for referral to pediatric urologists, affecting ~20% of school-aged children. Psychosocial factors and sex differences have been associated with specific LUT conditions, yet despite the potential importance of the mechanistic differences in LUTD between the sexes, most basic science research has focused on male animals as a reliable model of chronic social defeat stress (CSDS) in female rodents has been elusive. While we previously found male CSDS results in prolonged altered voiding phenotype, here we utilize a novel CSDS paradigm, “rival aggression,” in female mice to assess the effect of CSDS on voiding. Our hypothesis was that CSDS in female mice would lead to an altered voiding phenotype characterized by larger, infrequent voids.
METHODS: Recently, a novel CSDS model for female mice has been described in which female Swiss Webster mice housed with castrated CFW male will readily attack an unfamiliar C57BL/6J female (Newman et al, Biol Psychiatry, 2019). CSDS was induced in females over 10 consecutive days of 5 minutes of physical interaction with novel aggressor females. Voiding parameters including voids per 24hr, intermicturition interval, voided volumes per void, and total voided volume per 24hr were obtained pre- and post-CSDS by placing female mice in metabolism chambers (UroVoid, MedAssociates, VT) (Figure 1A). Mice were placed in chambers for 72hr with first 48hr used for acclimation and voiding data obtained during the last 24hr. Social interaction testing was also performed pre- and post-CSDS to determine the susceptibility to CSDS and stress coping mechanism. This allowed characterization of female mice into two groups: resilient (no effect of CSDS) and susceptible. C57BL/6J female mice who were not exposed to the CSDS protocol were used as controls.
RESULTS: Baseline voiding parameters were obtained in 11 control female and 17 experimental female mice. After completion of CSDS protocol, 8 mice were found to be resilient to CSDS and 9 mice were found to be susceptible. All results shown in figure 1. Control and resilient mice had no change in voiding parameters between pre and post voiding sessions, while susceptible mice had significantly fewer voids per 24hr period, larger mean voided volumes, and longer mean intermicturition interval post-CSDS compared to pre-CSDS (Figure 1B-D). For each group, total voided volume per 24hr period was similar pre- and post-CSDS (Figure 1E). Representative voiding graphs for each group are shown in Figure 1F.
CONCLUSIONS:
To our knowledge, this is the first description of a CSDS-induced voiding phenotype in female mice. Female mice susceptible to CSDS had an altered voiding phenotype characterized by larger, infrequent voids, similar to what has been documented in male CSDS mice and seen clinically in children with voiding postponement. Future studies to analyze brain and bladder changes in these CSDS female mice and comparison to male CSDS models may help shed light on sex differences in LUTD. 
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