Sex-Specific Adaptations to VTA Circuits Following Subchronic Stress

Abstract

Dysregulation of the mesolimbic reward circuitry is implicated in the pathophysiology of stress-related illnesses such as depression and anxiety. These disorders are more frequently diagnosed in females, and sex differences in the response to stress are likely to be one factor that leads to enhanced vulnerability of females. In this study, we use subchronic variable stress (SCVS), a model in which male and female mice exhibit distinct behavioral, transcriptional, and immunological alterations, to investigate sexually divergent mechanisms of regulation of the ventral tegmental area by stress. Using slice electrophysiology, we find that female, but not male, mice have a reduction in the ex vivo firing rate of VTA dopaminergic neurons following SCVS. Surprisingly, both male and female animals show an increase in inhibitory tone onto VTA dopaminergic neurons and an increase in the firing rate of VTA GABAergic neurons. In males, however, this is accompanied by a robust increase in excitatory synaptic tone onto VTA dopamine neurons. This supports a model by which SCVS recruits VTA GABA neurons to inhibit dopaminergic neurons in both male and female mice, but males are protected from diminished functioning of the dopaminergic system by upregulation of excitatory synapses. Thus, SCVS leads to both shared and disparate changes in the organization of the VTA in males and females.

Keywords: GABA; dopamine; stress; ventral tegmental area.