Lateral septum adenosine A2A receptors control stress-induced depressive-like behaviors via signaling to hypothalamus and habenula
作者机构：Wenzhou Medical University University of Coimbra NavalMedicalUniversity
出 版 物：《中国药理学与毒理学杂志》 (Chinese Journal of Pharmacology and Toxicology)
年 卷 期：2023年第37卷第7期
页 面：547-548页
学科分类：1002[医学-临床医学] 100205[医学-精神病与精神卫生学] 10[医学]
摘 要：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 LSA2AR-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.
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