An Amygdala‐hippocampus Circuit for Endocannabinoid Modulation of Anxiety Avoidance

Recent studies indicate a therapeutic potential of increased brain endocannabinoids (eCBs) in anxiety disorders, but the underlying brain circuits are still elusive. Here, it is observed that optogenetic inhibition and activation of anterior basolateral amygdala (aBLA) - ventral hippocampus (vHPC) glutamatergic projections respectively decrease and increase anxiety avoidance behaviors. Then, the contributions of eCBs in aBLA-vHPC projections to anxiety avoidance are investigated by employing three newly developed synapse- and circuit-specific eCB-targeted viral strategies to achieve real-time monitoring of eCB release, in vivo optogenetic activation of CB1 receptors, and CRISPR-Cas9 gene knockdown of eCB biosynthesis enzymes. Prominent eCB release are surprisingly found at aBLA-vHPC glutamatergic synapses during anxiety avoidance, suggesting inhibitory effects of increased eCBs in aBLA-vHPC projections on anxiety avoidance. This idea is further supported by findings that specific activation of CB1 receptors at aBLA-vHPC synapses inhibit presynaptic glutamate release and reduce anxiety avoidance. In contrast, specific knockdown of eCB biosynthesis enzymes at aBLA-vHPC synapses reduce eCB levels at aBLA-vHPC glutamatergic synapses and increase anxiety avoidance. Additionally, inhibition of aBLA-innervated vHPC glutamatergic neurons alleviates anxiety avoidance. Together, these findings reveal counteracting effects of increased eCB signaling in aBLA-vHPC circuits on anxiety avoidance.