Please use this identifier to cite or link to this item: https://hdl.handle.net/10316/111185
Title: Lateral septum adenosine A2A receptors control stress-induced depressive-like behaviors via signaling to the hypothalamus and habenula
Authors: Wang, Muran
Li, Peijun
Li, Zewen
Silva, Beatriz S. da 
Zheng, Wu
Xiang, Zhenghua
He, Yan
Xu, Tao
Cordeiro, Cristina
Deng, Lu
Dai, Yuwei
Ye, Mengqian
Lin, Zhiqing
Zhou, Jianhong
Zhou, Xuzhao
Ye, Fenfen
Cunha, Rodrigo A. 
Chen, Jiang-Fan 
Guo, Wei
Issue Date: 5-Apr-2023
Publisher: Springer Nature
Project: LCF/PR/HP17/52190001 
CENTRO-01-0246-FEDER-000010 
POCI-01-0145- FEDER-03127 
info:eu-repo/grantAgreement/UIDB/04539/2020 
IF/01492/2015 
Serial title, monograph or event: Nature Communications
Volume: 14
Issue: 1
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 A2A receptors (A2AR)-positive neurons mediating depressive symptoms via direct projects to the lateral habenula (LHb) and the dorsomedial hypothalamus (DMH). Activation of A2AR in the LS augmented the spiking frequency of A2AR-positive neurons leading to a decreased activation of surrounding neurons and the bi-directional manipulation of LS-A2AR activity demonstrated that LS-A2ARs are necessary and sufficient to trigger depressive phenotypes. Thus, the optogenetic modulation (stimulation or inhibition) of LS-A2AR-positive neuronal activity or LS-A2AR-positive neurons projection terminals to the LHb or DMH, phenocopied depressive behaviors. Moreover, A2AR are upregulated in the LS in two male mouse models of repeated stress-induced depression. This identification that aberrantly increased A2AR 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 A2AR antagonists, prompting their clinical translation.
URI: https://hdl.handle.net/10316/111185
ISSN: 2041-1723
DOI: 10.1038/s41467-023-37601-x
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais
FMUC Medicina - Artigos em Revistas Internacionais

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