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. The mechanism underlying caffeine consumption inversely correlation with depression is unclear. Here, authors identified adenosine A2A receptor in the lateral septum mediating depressive symptoms via direct outputs to the habenula and the hypothalamus.