Establishment of a repeated social defeat stress model in female mice

Aki Takahashi,Georgia E Hodes,Hongxing Zhang,Yael Grossman,Madeline L Pfau,Song Zhang,Ming-Hu Han,Dani Dumitriu,Hossein Aleyasin,Meghan E Flanigan,Bruce S Mcewen,Scott J Russo,Eric J Nestler,Jia-Ru Chung,Caroline Menard

doi:10.1038/s41598-017-12811-8

Abstract

Numerous studies have employed repeated social defeat stress (RSDS) to study the neurobiological mechanisms of depression in rodents. An important limitation of RSDS studies to date is that they have been conducted exclusively in male mice due to the difficulty of initiating attack behavior directed toward female mice. Here, we establish a female mouse model of RSDS by inducing male aggression toward females through chemogenetic activation of the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl). We demonstrate that females susceptible to RSDS display social avoidance, anxiety-like behavior, reduction of body weight, and elevated levels of circulating interleukin 6. In contrast, a subset of mice we term resilient only display anxiety-like behaviors after RSDS. This model allows for investigation of sex differences in the neurobiological mechanisms of defeat‒induced depression‒like behaviors. A robust female social defeat model is a critical first step in the identification and development of novel therapeutic compounds to treat depression and anxiety disorders in women.

Highlights

Violence against women is a major public health problem—an estimated 35% of women worldwide have experienced physical and/or sexual violence at some point in their lives[1]
Histological examination indicated that animals lacking attack behavior had low or no infection of virus in the VMHvl area as only 20% of mice showing aggression had expression of AAV-Gq-designer receptors exclusively activated by designer drugs (DREADDs) within the VMHvl (Fig. 1C)
Despite higher lifetime prevalence rates of depression and anxiety disorders in women, the majority of rodent studies examining the mechanisms of mood disorders have been conducted exclusively in males

Summary

Introduction

Violence against women is a major public health problem—an estimated 35% of women worldwide have experienced physical and/or sexual violence at some point in their lives[1]. There is increasing evidence of sex differences in the underlying biology of stress-related disorders in men and women[9,10,11]. Despite these important issues, the majority of preclinical studies of stress-related disorders focus heavily on male rodents. RSDS yields a pool of rodents that exhibit large individual differences in response to defeat, with 50-60% of mice displaying stress susceptibility and about 30% of mice displaying stress resilience[17,18], allowing for the study of biological mechanisms underlying susceptibility and resilience to social stress[27,28]. Our results describe a reliable and reproducible method of RSDS to induce depression-like behavioral responses in both female and male mice

Objectives

Methods

Results

Conclusion