Social stress in mice induces voiding dysfunction and bladder wall remodeling

Abstract

Several studies have anecdotally reported the occurrence of altered urinary voiding patterns in rodents exposed to social stress. A recent study characterized the urodynamic and central changes in a rat model of social defeat. Here, we describe a similar voiding phenotype induced in mice by social stress and in addition we describe potential molecular mechanisms underlying the resulting bladder wall remodeling. The mechanism leading to the altered voiding habits and underlying bladder phenotype may be relevant to the human syndrome of dysfunctional voiding which is thought to have a psychological component. To better characterize and investigate social stress-induced bladder wall hypertrophy, FVB mice (6 wk old) were randomized to either social stress or control manipulation. The stress involved repeated cycles of a 1-h direct exposure to a larger aggressive C57Bl6 breeder mouse followed by a 23-h period of barrier separation over 4 wk. Social stress resulted in altered urinary voiding patterns suggestive of urinary retention and increased bladder mass. In vivo cystometry revealed an increased volume at micturition with no change in the voiding pressure. Examination of these bladders revealed increased nuclear expression of the transcription factors MEF-2 and NFAT, as well as increased expression of the myosin heavy chain B isoform mRNA. BrdU uptake was increased within the urothelium and lamina propria layers in the social stress group. We conclude that social stress induces urinary retention that ultimately leads to shifts in transcription factors, alterations in myosin heavy chain isoform expression, and increases in DNA synthesis that mediate bladder wall remodeling. Social stress-induced bladder dysfunction in rodents may provide insight into the underlying mechanisms and potential treatment of dysfunctional voiding in humans.

Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression

“…Thus future studies should be pursued in anesthetized rats where potential effects of the outlet including the urethra and EUS can be evaluated after RVS. RVS-induced increases in voiding frequency are similar to other reports regarding several other animal models of stress including social defeat (4,15,46,74), nontraumatic immobilization/restraint (11,74), and WAS (14,54,62). We suggest that the 7-day RVS model has several advantages compared with other stress models.…”

“…Therefore, patients diagnosed with IC/BPS and other functional urinary tract disorders may have abnormalities in the HPA axis, and stress could contribute to bladder symptoms, including frequency, urgency, and/or pain, reported by these patient populations (47). The pathophysiology underlying stress-induced effects on micturition reflex function remain undetermined.The most well-established animal models of stress used to examine effects on urinary bladder structure and function include the resident-intruder model (15,22,74), immobilization stress (10, 11), water avoidance stress (WAS) (14,54,55,62), and electrical footshock (7,55). Although these stress paradigms produce bladder dysfunction and target tissue (i.e., urinary bladder) abnormalities similar to conditions like IC/BPS, the data in some cases are conflicting, and the stress models used in these studies may not be relevant to the variety of life stressors experienced by humans on a daily basis.…”

A corticotropin-releasing factor receptor antagonist improves urodynamic dysfunction produced by social stress or partial bladder outlet obstruction in male rats

“…Thus, discrete chemical activation of Barrington's nucleus neurons elicited bladder contractions that were increased by intrathecal administration of a CRF antagonist, and conversely, decreased by intrathecal CRF. An inhibitory role for CRF in Barrington's nucleus regulation of the bladder is consistent with reports that social stress in rodents leads to urinary retention, abnormal urodynamics, and bladder hypertrophy (4,6,12,13,45), and this is associated with increased expression of CRF in Barrington's nucleus neurons (45). These findings suggest that pharmacological manipulation of CRF may improve bladder dysfunctions associated with stress or other conditions.…”

“…Although fear has been anecdotally associated with micturition, numerous studies have documented that rodents that become subordinate by exposure to social stress develop urinary retention that is sufficient to increase bladder mass (4,6,12,22,45). In some cases, this can be sufficiently severe as to result in death due to nephritis (12).…”

Objective versus subjective outcome measures of biofeedback: What really matters?

“…Clinical evaluation and treatment of these patients consumes a great deal of time and resources, and requires commitment and considerable effort for a parent to bring the child to the clinic for frequent visits. Epidemiologic studies [1] and experimental evidence from mouse models of voiding dysfunction [2] suggest that, once established, voiding dysfunction can become a lifelong condition if not treated early in life. It is therefore important to identify optimal clinical management and outcome measures for this condition to allow for the best allocation of office and healthcare system resources.…”