Acetylcholine Muscarinic Receptors in Ventral Hippocampus Modulate Stress-Induced Anxiety-Like Behaviors in Mice.

Li Mei,Hong Liu,Yi Sun,Yu Zhou,Haihua Shu,Pingping Liu,Dengwen Zhang

doi:10.3389/fnmol.2020.598811

Abstract

Chronic stress exposure increases the risk of developing various neuropsychiatric illnesses. The ventral hippocampus (vHPC) is central to affective and cognitive processing and displays a high density of acetylcholine (ACh) muscarinic receptors (mAChRs). However, the precise role of vHPC mAChRs in anxiety remains to be fully investigated. In this study, we found that chronic restraint stress (CRS) induced social avoidance and anxiety-like behaviors in mice and increased mAChR expression in the vHPC. CRS increased the vHPC ACh release in behaving mice. Moreover, CRS altered the synaptic activities and enhanced neuronal activity of the vHPC neurons. Using pharmacological and viral approaches, we showed that infusing the antagonist of mAChRs or decreasing their expression in the vHPC attenuated the anxiety-like behavior and rescued the social avoidance behaviors in mice probably due to suppression of vHPC neuronal activity and its excitatory synaptic transmission. Our results suggest that the changes of neuronal activity and synaptic transmission in the vHPC mediated by mAChRs may play an important role in stress-induced anxiety-like behavior, providing new insights into the pathological mechanism and potential pharmacological target for anxiety disorders.

Highlights

Maladaptive responses to chronic stress are associated with the onset and exacerbation of emotional abnormalities, including anxiety disorders and social avoidance (Dias-Ferreira et al, 2009; McEwen and Morrison, 2013; McEwen et al, 2015; Sandi and Haller, 2015)
After 10-day restraint, at the end of stress, emotional behaviors were assessed with the social interaction (SI), open-field test (OFT), and elevated plus maze (EPM) test (Figure 1A); each behavior test was detected 1 day apart
We found that C57BL/6J mice showed social avoidance behavior after chronic restraint stress (CRS), as they showed less desire for interaction in the SI test (Figures 1B,C; F(1,56) = 5.631, p < 0.001) and showed a smaller SI ratio compared with no stress mice (Figure 1D; t(28)s = 4.086, p < 0.001)

Summary

Introduction

Maladaptive responses to chronic stress are associated with the onset and exacerbation of emotional abnormalities, including anxiety disorders and social avoidance (Dias-Ferreira et al, 2009; McEwen and Morrison, 2013; McEwen et al, 2015; Sandi and Haller, 2015). During postsurgical recovery, anxiety negatively influences the intensity of postoperative pain and analgesia requirement and even increases postoperative morbidity and mortality in certain types of surgery (Kassel et al, 2018). Various treatments, such as acceptance and commitment therapy, cognitive therapy, music therapy, and pharmacological interventions, have been applied to patients suffering from anxiety disorder. ACh muscarinic receptor (mAChR) family is one of the two ACh receptors, with subtypes M1, M2, M3, M4, and M5 (Volpicelli and Levey, 2004) They are expressed in many regions of the CNS including the prefrontal cortex, amygdala, and hippocampus. Our results suggest that increased expression of mAChRs in the vHPC contributed to stress-induced anxiety-like behavior via promoting excitatory synaptic transmission in the vHPC

Methods

Results

Conclusion