Lateral septum adenosine A 2A receptors control stress-induced depressive-like behaviors via signaling to the hypothalamus and habenula.

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 2A R)-positive neurons mediating depressive symptoms via direct projects to the lateral habenula (LHb) and the dorsomedial hypothalamus (DMH). Activation of A 2A R in the LS augmented the spiking frequency of A 2A R-positive neurons leading to a decreased activation of surrounding neurons and the bi-directional manipulation of LS-A 2A R activity demonstrated that LS-A 2A Rs are necessary and sufficient to trigger depressive phenotypes. Thus, the optogenetic modulation (stimulation or inhibition) of LS-A 2A R-positive neuronal activity or LS-A 2A R-positive neurons projection terminals to the LHb or DMH, phenocopied depressive behaviors. Moreover, A 2A R are upregulated in the LS in two male mouse models of repeated stress-induced depression. This identification that aberrantly increased A 2A R 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 2A R antagonists, prompting their clinical translation.