Ventral hippocampal diacylglycerol lipase-alpha deletion decreases avoidance behaviors and alters excitation-inhibition balance.

The endogenous cannabinoid, 2-arachidonoylglycerol (2-AG), plays a key role in the regulation of anxiety- and stress-related behavioral phenotypes and may represent a novel target for the treatment of anxiety disorders. However, recent studies have suggested a more complex role for 2-AG signaling in the regulation of stress responsivity, including increases in acute fear responses after 2-AG augmentation under some conditions. Thus, 2-AG signaling within distinct brain regions and circuits could regulate anxiety-like behavior and stress responsivity in opposing manners. The ventral hippocampus (vHPC) is a critical region for emotional processing, anxiety-like behaviors, and stress responding. Here, we use a conditional knock-out of the 2-AG synthesis enzyme, diacylglycerol lipase α (DAGLα), to study the role of vHPC 2-AG signaling in the regulation of affective behavior. We show that vHPC DAGLα deletion decreases avoidance behaviors both basally and following an acute stress exposure. Genetic deletion of vHPC DAGLα also promotes stress resiliency, with no effect on fear acquisition, expression, or contextual fear generalization. Using slice electrophysiology, we demonstrate that vHPC DAGLα deletion shifts vHPC activity towards enhanced inhibition. Together, these data indicate endogenous 2-AG signaling in the vHPC promotes avoidance and increases stress reactivity, confirming the notion that 2-AG signaling within distinct brain regions may exert divergent effects on anxiety states and stress adaptability.