Endocannabinoid Signaling at Distinct Regions and Circuits Bidirectionally Modulates Stress: Implications for Cannabis Treatments in Psychiatric Disorders
Kondev, Veronika
0000-0002-0860-9027
:
2023-03-29
Abstract
The endocannabinoid (eCB) system, which consists of the cannabinoid receptor type 1 (CB1R) and its endogenous ligand, 2-arachidonoylglycerol (2-AG), as well as key synthesis and degradation enzymes, can promote bidirectional, sometimes opposing effects on behavior. Here, we test the hypothesis that the neurobiological mechanism underlying eCB-dependent changes in behavior relies on eCB recruitment and signaling within distinct brain regions, neural circuits, and cell-types. Using rodent behavioral models for anxiety-like and depressive-like phenotypes, stress exposure models, in vivo fiber photometry, chemogenetics, optogenetics, and ex vivo electrophysiology, we parse apart the contribution of eCB/CB1R signaling in ventral hippocampus (vHPC) circuitry, including downstream regions such as the amygdala and the nucleus accumbens (NAc). First, we confirm that systemic, pharmacological 2-AG augmentation can indeed produce biphasic effects on stress responding using an acute stress exposure to predator odor; we reveal that the timing of administration and context both play a role in the behavioral output following drug administration. Furthermore, we reveal that while 2-AG signaling in the vHPC promotes anxiogenesis, eCB signaling at vHPC terminals in the basolateral amygdala (BLA) ultimately protects against the negative effects of stress. Furthermore, we demonstrate that stress promotes reorganization of vHPC input to somatostatin interneurons in the nucleus accumbens (NAc), which can be reversed by CB1R blockade. Together, these data ultimately shed light on how eCB regulation of distinct regions, circuits, and cells can have divergent and opposing effects on behavior and have broad implications for cannabis/eCB-based therapies for stress-related disorders, including anxiety, depression, and posttrarumatic stress disorder (PTSD).