Bimodal Control of Fear-Coping Strategies by CB₁Cannabinoid Receptors

Abstract

To maximize their chances of survival, animals need to rapidly and efficiently respond to aversive situations. These responses can be classified as active or passive and depend on the specific nature of threats, but also on individual fear coping styles. In this study, we show that the control of excitatory and inhibitory brain neurons by type-1 cannabinoid (CB₁) receptors is a key determinant of fear coping strategies in mice. In classical fear conditioning, a switch between initially predominant passive fear responses (freezing) and active behaviors (escape attempts and risk assessment) develops over time. Constitutive genetic deletion of CB₁ receptors in CB₁⁻/⁻ mice disrupted this pattern by favoring passive responses. This phenotype can be ascribed to endocannabinoid control of excitatory neurons, because it was reproduced in conditional mutant mice lacking CB₁ receptors from cortical glutamatergic neurons. CB₁ receptor deletion from GABAergic brain neurons led to the opposite phenotype, characterized by the predominance of active coping. The CB₁ receptor agonist Δ⁹-tetrahydrocannabinol exerted a biphasic control of fear coping strategies, with lower and higher doses favoring active and passive responses, respectively. Finally, viral re-expression of CB₁ receptors in the amygdala of CB₁⁻/⁻ mice restored the normal switch between the two coping strategies. These data strongly suggest that CB₁ receptor signaling bimodally controls the spontaneous adoption of active or passive coping strategies in individuals. This primary function of the endocannabinoid system in shaping individual behavioral traits should be considered when studying the mechanisms of physiological and pathological fear.