A body of clinical evidence has linked psychological stress with bladder disorders, including post-traumatic stress disorder and witness trauma.  Many of these bladder disorders have been associated with voiding dysfunction, particularly in people with a history of abuse. Stress appears to cause or worsen symptoms of bladder dysfunction, and around 40% of people with bladder dysfunction have poor outcomes from current treatments (1). In spite of this strong clinical link between psychological stress and bladder dysfunction, there is little understanding of the mechanism contributing to voiding changes.  The aim of this study was to determine the effects of stress, caused by social defeat or witness trauma on voiding behaviour and bladder function using in vivo voiding pattern analysis and an ex vivo bladder preparation.

A validated model of physical and emotional stress (social defeat and witness trauma respectively) was used.  Male ex-breeder ARC1 mice were screened for aggressive behaviour and house individually. Male C57Bl/6J mice (12-14 weeks) were housed in pairs for 3-days prior and during the 10-day stress protocol, each being randomly allocated to either the 1) social defeat or 2) witness trauma experimental group.  C57Bl/6J pairs were placed in a custom-made plexiglass chamber with the aggressor mouse for 1 hour/day for 10 days.  The social defeat mouse was in physical contact with the aggressor for 5 minutes and then separated by a transparent perforated barrier for 55 minutes.  The witness mouse was physically separated (transparent perforated wall) but could observe interactions between its cage mate and the aggressor.  Age matched control pairs were housed under normal conditions for the duration of the study.  Voiding pattern analysis was conducted on days 0, 1, 3, 7 and 10.  Mice were euthanised 24-hours after final stress exposure and a blood sample was taken for analysis of corticosterone.  Bladders were then removed, catheterised and intravesical pressure responses recorded during distension with saline and in response to stimulation of purinergic and cholinergic agonists, and following electrical field stimulation.

Plasma corticosterone levels were significantly increased following 10-days of social defeat or witness trauma stress when compared to unstressed controls (p<0.001) (Fig. 1A).  Voiding pattern analysis revealed no significant difference in total voided volume between groups; however, a significant increase in the average void size was observed in the social defeat group from day 3 compared to unstressed control animals (Fig. 1B), indicating an altered voiding phenotype.  Witness trauma did not alter voiding behaviour at any timepoint tested.  Bladder contractile responses to cholinergic or purinergic stimulation (carbachol and ATP respectively) were not significantly altered by stress, nor was the pressure response to KCl or bladder relaxation to the beta-adrenoceptor agonist isoprenaline.  However, nerve evoked contractile responses to EFS were significantly increased at all frequencies in bladders from social defeat but not witness trauma mice (Fig. 1C).   The response to EFS (20Hz) was reduced by 51.2 ± 8.5% in the presence of atropine, with a further decrease of 39.5 ± 2.8% following addition of αβ-mATP in control bladders.  The relative contribution of acetylcholine and ATP to nerve evoked contractions was not significantly altered by social defeat or witness trauma.

Exposure to physical or emotional stress produces a similar hormonal stress response in both models of stress (social defeat and witness trauma).  However, the changes in voiding behaviour and local functional changes in the bladder appear to be dependent on the type of stressor.  The increase in average void size observed in the social defeat group is consistent with previous reports of urine retention in this model when using male mice (2). This is in contrast to the increased voiding frequency and decreased average void size which we have observed in female mice following water avoidance stress (3). The increase in contractility to EFS may indicate local changes in efferent innervation rather than detrusor contractility.

Stress induced functional bladder changes are dependent on stressor type. This study reports a male model of social defeat with reduced urinary frequency, with no voiding changes observed in the witness.

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