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

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 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.

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.