A DORSOSTRIATAL-CANNABINOID CIRCUIT FOR IMMINENT THREAT PROCESSING IN THE BRAIN

Survival requires the selection of appropriate behaviors in response to threats. Defensive behaviors, including freezing (passive) and fleeing (active), are controlled by multiple neuronal circuits; however, the mechanisms controlling the active-passive trade-off (APT) in defensive responses have only been scantly investigated. The endocannabinoid system, and particularly cannabinoid type-1 (CB1) receptors, has been proposed to participate in this effect, but the neuronal basis of this interaction has not been addressed. Herein, using a combination of semi-naturalistic behavioral paradigms, computational behavior tracking, pharmacogenetics, and viral approaches, we observe that escape behaviors require the activation of CB1 receptors specifically located at dorso-striatopallidal terminals. Imminent threat stimuli increase dorsostriatal neuronal activity in wild-type animals, an effect that quickly resolves thereafter but persists in animals lacking striatopallidal CB1 receptors. Remarkably, the neuronal activity of this circuit correlates directly with escape behavior. Functional manipulations show that reinstating the inhibitory tone of striatopallidal CB1 neurons is sufficient to restore the ability to cope with imminent threatful stimuli. Our findings uncover a circuit motif within the dorsal striatum regulating threat response and offer insights into a local circuit critically involved in innate defensive control.