NAc-VTA circuit underlies emotional stress-induced anxiety-like behavior in the three-chamber vicarious social defeat stress mouse model

Guangjian Qi,Qian Zhang,Jie Ming,Pei Zhang,Lijun Zhang,Ming Li,Haifa Qiao,Feng He,Xinyuan Lv,Tongxia Li,Bo Tian,Xiaoqian Chen,Hongwei Cai

doi:10.1038/s41467-022-28190-2

Abstract

Emotional stress is considered a severe pathogenetic factor of psychiatric disorders. However, the circuit mechanisms remain largely unclear. Using a three-chamber vicarious social defeat stress (3C-VSDS) model in mice, we here show that chronic emotional stress (CES) induces anxiety-like behavior and transient social interaction changes. Dopaminergic neurons of ventral tegmental area (VTA) are required to control this behavioral deficit. VTA dopaminergic neuron hyperactivity induced by CES is involved in the anxiety-like behavior in the innate anxiogenic environment. Chemogenetic activation of VTA dopaminergic neurons directly triggers anxiety-like behavior, while chemogenetic inhibition of these neurons promotes resilience to the CES-induced anxiety-like behavior. Moreover, VTA dopaminergic neurons receiving nucleus accumbens (NAc) projections are activated in CES mice. Bidirectional modulation of the NAc-VTA circuit mimics or reverses the CES-induced anxiety-like behavior. In conclusion, we propose that a NAc-VTA circuit critically establishes and regulates the CES-induced anxiety-like behavior. This study not only characterizes a preclinical model that is representative of the nuanced aspect of CES, but also provides insight to the circuit-level neuronal processes that underlie empathy-like behavior.

Highlights

Emotional stress is considered a severe pathogenetic factor of psychiatric disorders
The current study combined viral tracing, in vivo electrophysiological and Ca2+ recordings, and chemogenetic and optogenetic methods in the 3C-vicarious social defeat stress (VSDS) model to demonstrate that VTADA neurons are essential for the chronic emotional stress (CES)-induced anxiety-like behavior
The results revealed that many brain areas have projections to VTADA neurons, but among them, VTADA neurons receive fewer inputs from the nucleus accumbens (NAc) area in CES mice compared with controls (Fig. 6e), suggesting that the structural plasticity of axons of direct inputs from NAc to VTADA neurons was changed after CES

Summary

Introduction

Emotional stress is considered a severe pathogenetic factor of psychiatric disorders. Using a three-chamber vicarious social defeat stress (3C-VSDS) model in mice, we here show that chronic emotional stress (CES) induces anxiety-like behavior and transient social interaction changes. This study characterizes a preclinical model that is representative of the nuanced aspect of CES, and provides insight to the circuit-level neuronal processes that underlie empathy-like behavior. In the following set of experiments, we improved the previous vicarious social defeat stress (VSDS) model[14,15] and redesigned the threechamber VSDS (3C-VSDS) model with high face, construct, and predictive validity, to study the neurobiological consequences of emotional stress In this animal model, the observer mouse is conditioned vicariously for scene-dependent emotion (chronic emotional stress, CES) by observing a demonstrator mouse that receives repetitive social defeats (chronic social defeat stress, CSDS). Whether VTADA neurons mediate or modulate CESinduced behaviors is currently unknown

Methods

Results

Conclusion