Differential Influence of Early Life and Adult Stress on Urogenital Sensitivity and Function in Male Mice

Abstract

Experiences of adverse childhood events have been associated with improper output of the hypothalamic-pituitary-adrenal (HPA) axis in adulthood, as well as development of comorbid functional pain disorders. Symptoms of chronic prostatitis/chronic pelvic pain syndrome frequently overlap with those of interstitial cystitis/painful bladder syndrome and symptom severity is often triggered by stress. The objective of this study was to investigate the influence early life stress and acute adult stress on (1) perigenital sensitivity, (2) micturition, (3) anhedonia, and (4) HPA axis regulation and output in male C56Bl/6 mice. Neonatal maternal separation (NMS) was performed for 3 h a day from postnatal day 1 to 21 and naïve pups remained unhandled during this time. As adults, male mice were tested for referred prostate sensitivity and micturition patterning prior to and 1 and 8 days after exposure to 1 h of water avoidance stress (WAS). Following testing, prostate and bladder tissues were used for mast cell and Western blot analysis and RT-PCR was performed on mRNA from hypothalamus, amygdala, and hippocampus. Serum corticosterone (CORT) was also measured by enzyme-linked immunosorbent assay (ELISA). A significant increase in perigenital sensitivity and micturition frequency was observed in NMS mice and these measures were exacerbated by WAS exposure. Exposure to NMS significantly increased mast cell degranulation in both the bladder and prostate. Mast cell degranulation was also increased in naïve prostate tissue following WAS exposure. Cytokine mRNA levels were influenced by both NMS and WAS exposure, though WAS had a larger impact on central gene expression. Protein levels of CRF1 were differentially regulated by NMS and WAS in the bladder and prostate and serum CORT levels were significantly diminished following stress exposure. Taken together, these data suggest that NMS results in neurogenic inflammation and hypersensitivity within the urogenital organs, coupled with diminished gene expression and output from the HPA axis. Future studies of NMS in male mice may provide a useful tool as a preclinical model of male chronic urological pain syndromes for investigating potential pharmacological and interventional therapies.

Voluntary wheel running improves outcomes in an early life stress-induced model of urologic chronic pelvic pain syndrome in male mice

“…Importantly, a history of being physically active, particularly having a higher level of moderate-and high-intensity physical activity, was associated with a lower risk of developing CP/CPPS in older men (67) and endometriosis in young adult women (68). Here, we report that male NMS mice display significant mechanical allodynia in the perigenital region, a finding that supports our previous research (45). Allodynia in the perigenital or pelvic region has been consistently reported in other mouse models of CP/CPPS (19,69).…”

“…Consistent with our previous studies (39,45), NMS induced significant perigenital hypersensitivity ( Figure 2). Sedentary NMS mice exhibited significantly lower withdrawal thresholds in response to mechanical, monofilament stimulation to the scrotum compared to their naïve-Sed counterparts.…”

“…Here, we report that male NMS-Sed mice have a significantly lower serum CORT level than naïve-Sed mice. We have previously reported lower CORT levels in male NMS mice (45), but increased CORT levels in female NMS mice, which were decreased following a similar voluntary wheel running intervention (38). In this study, voluntary wheel running significantly reduced serum CORT in naïve mice and had relatively little impact on CORT levels in NMS mice.…”

Early life stress reduces voluntary exercise and its prevention of diet-induced obesity and metabolic dysfunction in mice

“…Although running distance was significantly lower, we have observed an attenuation of urogenital hypersensitivity and bladder overactivity due to voluntary wheel running in female NMS mice [47]. We hypothesize that differences in running distance could be due to changes in reward pathways, as we have also observed gene expression changes indicative of reduced hippocampal regulation of the HPA axis [27,28,47,73]. Lovallo [74], explains that early life stress in humans can lead to altered dopaminergic signaling, which influences motivated behaviors [75], including physical activity.…”

Early life voiding dysfunction leads to lower urinary tract dysfunction through alteration of muscarinic and purinergic signaling in the bladder

“…A previous study showed that about one-third of rats exposed to NMS but none in the control group retained perigenital reflex at 7 wk old suggesting an incomplete maturation of voiding control in the NMS animals (38), which agrees with the findings in this study. More recent studies demonstrated that 1) NMS mice had a significantly higher sensitivity upon urinary bladder distension in adulthood compared with the control group, 2) the hypersensitivity to urinary bladder distension mice was further increased after exposure to water avoidance stress in adult NMS mice but not in control mice, and 3) NMS mice had an increase in the number of voids compared with the control mice at 8 wk old (19,29,30). These results suggest the effects from NMS on bladder sustained in young adulthood, which also support our findings.…”