Endocannabinoid Release at Ventral Hippocampal-Amygdala Synapses Regulates Stress-Induced Behavioral Adaptation

Abstract

The endocannabinoid (eCB) system is a key modulator of glutamate release within limbic neurocircuitry and is heavily implicated in the modulation of stress responsivity and adaptation. The ventral hippocampus (vHPC)–basolateral amygdala (BLA) circuit has been previously implicated in the expression of negative affective states following stress exposure and is modulated by retrograde eCB signaling. However, the mechanism governing eCB release, and whether eCB signaling within vHPC-BLA circuits is causally related to stress-induced affective pathology, are not known. Here we utilized in vivo optogenetic- and biosensor-based approaches to reveal the temporal dynamics of BLA neuron activity-dependent and stress-induced eCB release at vHPC-BLA synapses. Furthermore, we demonstrate that genetic deletion of cannabinoid type-1 receptors selectively at vHPC-BLA synapses decreases active coping responses to acute stressors and exacerbates subsequent anxiety- and depressive-like phenotypes. These data reveal novel insight into in vivo determinants of eCB release at limbic synapses and suggest eCB signaling within the vHPC-BLA circuit serves to counteract adverse behavioral consequences of stress exposure.

Note:
Funding Information: These studies were supported by NIH grants MH107435 (S.P.) and MH119817 (S.P.).

Declaration of Interests: SP is a scientific consultant for Psy Therapeutics, Janssen Pharmaceuticals, and Jazz Pharmaceuticals unrelated to the present work. All other authors declare no conflicts of interest.

Ethics Approval Statement: All experiments were approved by the Vanderbilt University Institutional Animal Care and Use Committees and were conducted in accordance with the National Institute of Health guidelines for the Care and Use of Laboratory Animals.

Keywords: CB1 receptor, 2-arachidonoylglycerol, posttraumatic stress disorder, anxiety, depression, Cannabis