Sex Differences in Chronic Variable Stress Effects on Oxytocin and the HPA Axis in the Mouse

Presentation Number: OR02-2
Date of Presentation: April 4th, 2017

Amanda P Borrow* and Robert J Handa
Colorado State University, Fort Collins, CO

Abstract

Chronic variable stress (CVS) exposure, a common model of affective disorders, produces a number of behavioral and neurobiological deficits in the rodent. Exposure to CVS induces anxiety- and depressive-like behavior and alters the responsivity of the hypothalamo-pituitary-adrenal (HPA) axis following an acute stressor. Despite the disproportionately higher prevalence of affective disorders in women relative to men, much of the research utilizing the CVS model to date has focused exclusively on male rodents, leaving the need for research using both sexes to elucidate the mechanisms underlying CVS’s detrimental effects. One potential mediator, the hypothalamic neuropeptide oxytocin (OT), may contribute to the alterations in HPA axis function following CVS exposure. Under basal conditions, OT generally serves to inhibit the HPA axis at the level of the paraventricular n. (PVN) by suppressing secretion of corticotropin releasing hormone (CRH) neurons, but OT has also been found to enhance the ACTH response to an acute stressor by acting at the anterior pituitary gland. In the male rat, CVS has been shown to either increase or decrease PVN OT mRNA. However, sex differences in the effects of CVS on hormone secretion and OT expression in mice have not been examined. In the present set of experiments, intact male and female mice underwent six weeks of unpredictable exposure to a variety of mild stressors. Neuropeptide expression was examined in adult males and diestrus females using immunohistochemistry (IHC). Quantification of OT-ir neurons in the PVN showed a significant decrease in OT-ir in CVS treated female, but not male, subjects. These effects were largely restricted to the anterior and middle regions of the PVN. In addition, plasma was collected from males and diestrus females immediately following twenty minutes of restraint stress or from home cage controls. CVS treatment prevented the restraint-induced elevation in corticosterone in female mice, but this elevation was not altered by CVS in male subjects. The neuroendocrine phenotype of the OT neurons affected by CVS in female mice is being determined utilizing IHC to examine the colocalization of PVN OT-ir neurons with the peripherally-injected retrograde tracer Fluorogold. Our findings reveal that CVS may be a more potent modulator of HPA function in female mice, strengthening this paradigm’s translational validity as a model for affective disorders. These data also suggest a novel mechanism through which CVS impacts the HPA axis in the rodent.

 

Nothing to Disclose: APB, RJH