Bladder Voiding After Stress Defeat Stress: Impact of Sex and Gonadal Hormones - PROJECT SUMMARY/ABSTRACT Lower urinary tract symptoms (LUTS) and disorders of voiding are among the most common reasons for referral to the urologist and affect ~20% of school-aged children. LUTS can be caused by one of several different LUT conditions, including voiding postponement, and the prevalence of these conditions varies by sex. Neuropsychiatric comorbidities, especially depression and anxiety, occur in 20-40% of children with LUTS and school bullying can lead to bladder holding. Despite the known sex differences in terms of psychosocial factors and underlying LUTS etiology, almost all basic science research on LUTS and stress is limited by male only animal models. Chronic social defeat stress (SDS) in male mice leads to a voiding phenotype similar to that seen in children with voiding postponement, as well as to increased expression of the stress neuropeptide corticotropin releasing hormone (CRH) in Barrington's nucleus (BN), the brainstem region considered the voiding “command center.” Data from the candidate's NIDDK K08 aims identified a sexual dimorphism in voiding phenotype changes when the CRH neurons in BN are stimulated: female mice bladder sizes increase ~2x the amount seen in males. These clinical and basic science data fuel this R03's central hypotheses: that SDS will induce sex- specific voiding, bladder, and brain phenotypes and that gonadal hormones are required for these changes. The proposed research is an extension of the candidate's K08 grant conducted in primary mentor Dr. Stephen Zderic's laboratory using mice and will facilitate the candidate's research independence. In Aim 1, we will establish sex-specific effects of a novel chronic non-discriminatory social defeat stress (CNSDS) paradigm on bladder voiding, histology, and contractility, and on neurohormone and receptor expression in BN, a brain region that the candidate has studied extensively in his K08 grant. Through collaboration with Drs. Eisch and Yun (CHOP neuroscientists), the candidate will gain new skillsets in chronic social defeat stress models and behavioral assays in mice. CNSDS allows study of both male and female mice exposed to identical stress and will help overcome the knowledge gap that exists on sex-specific SDS effects on LUT dysfunction. In Aim 2, we will determine the effects of gonadectomy in female and male mice on CNSDS susceptibility to bladder and brain changes. Female and male mice will undergo gonadectomy prior to CNSDS followed by bladder and brain measures as in Aim 1. Successful completion of these Aims will result in the first characterization of an altered voiding phenotype in socially-stressed female mice, allow direct comparison with male mice, define neurohormone changes in BN, and reveal if gonadal hormones play a role in sex-specific stress-induced bladder voiding phenotype. As such, the data lay critical groundwork for future translational assessment of sex-specific LUTS and their personalized treatment in clinical populations. As a supplement to the candidate's K08 grant, these aims will provide preliminary data to help launch an R01 application and formalize collaborations with Drs. Eisch and Yun, who will support the candidate's research independence.
