Circuit mechanisms governing endocannabinoid modulation of affective behaviour and stress adaptation.

Anxiety and stress-related psychiatric disorders are highly prevalent, have uncertain aetiologies and are only partially responsive to available therapies. Elucidating fundamental mechanisms that regulate anxiety, fear and stress responsivity could reveal new insights into disease mechanisms and offer opportunities for therapeutic development. Endocannabinoid (eCB) signalling has been shown to modulate innate avoidance behaviour, conditioned defensive behaviour and responsivity to stress in preclinical and human experimental studies. Furthermore, recent studies utilizing eCB biosensors, intersectional genetics and optogenetic-assisted circuit mapping have identified synaptic, cellular and circuit-level mechanisms by which eCBs affect these biobehavioural processes. These data suggest that eCB-deficient states could represent a stress-susceptibility endophenotype while pharmacological eCB augmentation could represent emerging approaches for the treatment of affective and stress-related neuropsychiatric disorders. In addition, several cortical-cortical and cortical-subcortical circuits have been identified as key substrates by which eCB signalling affects avoidance behaviour and stress responsivity. Taken together, the reviewed data offer new insights into the potential contribution of eCB signalling systems to the pathophysiology of anxiety and stress-related disorders and reveal fundamental roles for eCB signalling in the modulation of anxiety, fear and stress responsivity.