Lateral septum adenosine A2A receptors control stress-induced depressive-like behaviors via signaling to the hypothalamus and habenula

Muran Wang, Peijun Li, Zewen Li, Beatriz S. 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 () and Wei Guo ()
Additional contact information
Muran Wang: Wenzhou Medical University
Peijun Li: The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University
Zewen Li: Wenzhou Medical University
Beatriz S. Silva: University of Coimbra
Wu Zheng: Wenzhou Medical University
Zhenghua Xiang: Ministry of Education, Naval Medical University
Yan He: Wenzhou Medical University
Tao Xu: Wenzhou Medical University
Cristina Cordeiro: University of Coimbra
Lu Deng: The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University
Yuwei Dai: Wenzhou Medical University
Mengqian Ye: Wenzhou Medical University
Zhiqing Lin: Wenzhou Medical University
Jianhong Zhou: Wenzhou Medical University
Xuzhao Zhou: Wenzhou Medical University
Fenfen Ye: Wenzhou Medical University
Rodrigo A. Cunha: University of Coimbra
Jiangfan Chen: Wenzhou Medical University
Wei Guo: Wenzhou Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37601-x

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