Lateral septum adenosine A_2A receptors control stress-induced depressive-like behaviors via signaling to the hypothalamus and habenula.

Authors

Muran Wang, Peijun Li, Zewen Li, Beatriz S da Silva, Wu Zheng, Zhenghua Xiang, Yan He, Tao Xu, Cristina Cordeiro, Lu Deng, Yuwei Dai, Mengqian Ye, Zhiqing Lin, Jianhong Zhou, Xuzhao Zhou, Fenfen Ye, Rodrigo A Cunha, Jiangfan Chen, Wei Guo

Published in

Nature communications. Volume 14. Issue 1. Pages 1880. Apr 05, 2023. Epub Apr 05, 2023.

Abstract

Major depressive disorder ranks as a major burden of disease worldwide, yet the current antidepressant medications are limited by frequent non-responsiveness and significant side effects. The lateral septum (LS) is thought to control of depression, however, the cellular and circuit substrates are largely unknown. Here, we identified a subpopulation of LS GABAergic adenosine A_2A receptors (A_2AR)-positive neurons mediating depressive symptoms via direct projects to the lateral habenula (LHb) and the dorsomedial hypothalamus (DMH). Activation of A_2AR in the LS augmented the spiking frequency of A_2AR-positive neurons leading to a decreased activation of surrounding neurons and the bi-directional manipulation of LS-A_2AR activity demonstrated that LS-A_2ARs are necessary and sufficient to trigger depressive phenotypes. Thus, the optogenetic modulation (stimulation or inhibition) of LS-A_2AR-positive neuronal activity or LS-A_2AR-positive neurons projection terminals to the LHb or DMH, phenocopied depressive behaviors. Moreover, A_2AR are upregulated in the LS in two male mouse models of repeated stress-induced depression. This identification that aberrantly increased A_2AR signaling in the LS is a critical upstream regulator of repeated stress-induced depressive-like behaviors provides a neurophysiological and circuit-based justification of the antidepressant potential of A_2AR antagonists, prompting their clinical translation.

PMID:
37019936
Bibliographic data and abstract were imported from PubMed on 06 Apr 2023.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.