Sex-Dependent Effects of Chronic Social Defeat on Emotional and Social Behaviors, and Parameters of Oxytocin and Vasopressin Systems in Mandarin Voles (Microtus mandarinus).

Fadao Tai,Rui Jia,Huan Ma,Xin Zhang,Wenjuan Hou,Zhixiong He,Shuying Huang,Yufeng Xun,Wenqi Cai

doi:10.3389/fnins.2021.625116

Abstract

In the regulation of emotional and social behaviors, both oxytocin (OT) and vasopressin (AVP) are sex specific. Although significant sex differences have been reported in the context of behavioral and hormonal responses to social stress, such differences in response to chronic social defeat stress (CSDS) and the underlying neural mechanisms remain largely unknown. By investigating monogamous mandarin voles (Microtus mandarinus), CSDS was found to decrease the percentages of time spent in the central area of the open field, in the open arms of the elevated plus maze, as well as in the light area of the light and dark boxes in both male and female voles. CSDS also increased the observed level of social withdrawal in both sex groups. However, CSDS exposure increased the percentages of immobile time in both the tail suspension test and the forced swim test and reduced the locomotor activity in the open field (in females only). Along with these behavioral changes, the oxytocin receptor (OTR) levels in the nucleus accumbens (NAc) were significantly lower in CSDS-exposed voles of both sexes; however, in males, the levels of OTR in the paraventricular nucleus (PVN) were reduced. CSDS-exposed males showed lower levels of V1aR in the NAc than CSDS-exposed females. Furthermore, induced by a single social defeat event, CSDS reduced c-Fos and OT double labeling in the PVN of females but increased c-Fos and AVP double-labeled neurons in the PVN of males exposed to a single social defeat event. Collectively, the present study indicates that OT and AVP systems may play important regulatory roles in the sex differences of behavioral performances in response to CSDS. These findings suggest mandarin voles as a useful animal model for studying sex-specific behavioral performance and the underlying neurobiological mechanisms of stress-related mental disorders in preclinical studies.

Highlights

Grievous and stressful life experiences have been reported to increase the risk for depression or anxiety (Klinsey et al, 2007; Franklin et al, 2018)
chronic social defeat stress (CSDS) caused a significant decrease in the percentage of time spent in the central area compared with the controls in both males (p < 0.01) and females (p < 0.01); sex differences were observed between males and females in CSDS groups (CSDS male versus female: p < 0.01) (Figure 2A)
Improved CSDS models need to be developed in the future to overcome this limitation. Both male and female mandarin voles displayed changes in emotional behaviors as well as increased social avoidance when exposed to CSDS

Summary

Introduction

Grievous and stressful life experiences have been reported to increase the risk for depression or anxiety (Klinsey et al, 2007; Franklin et al, 2018). As an etiologically valid stressor, chronic social defeat stress (CSDS) provides a relevant model for investigating the etiology of stress-related disorders (Koolhaas et al, 1999; Steinman and Trainor, 2017). The CSDS paradigm has been widely applied as an animal model of depression and anxiety disorders (Blanchard et al, 2001). The mechanisms with which these stressful experiences are translated into behaviors are poorly understood, and the influencing factors should be investigated further. While males and females generally tend to exhibit very similar behaviors, they often use different mechanisms when responding to social and emotional challenges and opportunities (Bangasser and Wicks, 2017; Palanza and Parmigiani, 2017). To understand the mechanisms with which the brain regulates these behaviors, many variables need to be considered, and sex is one of the prominent variables

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