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.

重度抑郁症是世界范围内的主要疾病负担，但目前的抗抑郁药物因频繁的无反应和显着的副作用而受到限制。侧隔膜（LS）被认为可以控制抑郁症，然而，其细胞和电路基质在很大程度上是未知的。在这里，我们鉴定了 LS GABA 能腺苷 A _2A受体 (A _2A R) 阳性神经元的亚群，它们通过直接投射到外侧缰核 (LHb) 和下丘脑背内侧 (DMH) 介导抑郁症状。 LS 中 A _2A R 的激活增加了 A _2A R 阳性神经元的尖峰频率，导致周围神经元的激活减少，并且 LS-A _2A R 活性的双向操纵表明 LS-A _2A R 是必要的，并且足以引发抑郁表型。因此，LS-A _2A R 阳性神经元活动或 LS-A _2A R 阳性神经元的光遗传学调节（刺激或抑制）将末端投射到 LHb 或 DMH，表型抑郁行为。此外，在两只重复应激诱发抑郁的雄性小鼠模型中，LS 中的 A _2A R 上调。 LS 中异常增加的 A _2A R 信号传导是反复应激诱发的抑郁样行为的关键上游调节因子，这一发现为 A _2A R 拮抗剂的抗抑郁潜力提供了神经生理学和基于回路的合理性，从而促进了它们的临床转化。