TY - JOUR
T1 - Ventral hippocampal diacylglycerol lipase-alpha deletion decreases avoidance behaviors and alters excitation-inhibition balance
AU - Kondev, Veronika
AU - Bluett, Rebecca
AU - Najeed, Mustafa
AU - Rosas-Vidal, Luis E.
AU - Grueter, Brad A.
AU - Patel, Sachin
N1 - Funding Information:
This work was supported by the National Institutes of Health [ R01MH107435 (S.P.); and K08MH126166 (L.R.V.) and a NARSAD Young Investigator Award (L.R.V.)]
Publisher Copyright:
© 2022
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
KW - Anxiety
KW - Endocannabinoid
KW - Fear conditioning
KW - Stress
KW - Ventral hippocampus
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U2 - 10.1016/j.ynstr.2022.100510
DO - 10.1016/j.ynstr.2022.100510
M3 - Article
C2 - 36594052
AN - SCOPUS:85144746715
VL - 22
JO - Neurobiology of Stress
JF - Neurobiology of Stress
SN - 2352-2895
M1 - 100510
ER -