Mitochondrial cannabinoid receptors gate corticosterone impact on novel object recognition

Corticosteroid-mediated stress responses require the activation of complex brain circuits involving mitochondrial activity, but the underlying cellular and molecular mechanisms are scantly known. The endocannabinoid system is implicated in stress coping, and it can directly regulate brain mitochondrial functions via type 1 cannabinoid (CB₁) receptors associated with mitochondrial membranes (mtCB₁). In this study, we show that the impairing effect of corticosterone in the novel object recognition (NOR) task in mice requires mtCB₁ receptors and the regulation of mitochondrial calcium levels in neurons. Different brain circuits are modulated by this mechanism to mediate the impact of corticosterone during specific phases of the task. Thus, whereas corticosterone recruits mtCB₁ receptors in noradrenergic neurons to impair NOR consolidation, mtCB₁ receptors in local hippocampal GABAergic interneurons are required to inhibit NOR retrieval. These data reveal unforeseen mechanisms mediating the effects of corticosteroids during different phases of NOR, involving mitochondrial calcium alterations in different brain circuits.