Adaptive responses to danger are essential for survival and involve a balance between passive defensive behaviors, such as freezing, and active responses, such as escape. This balance, known as the active-passive trade-off, allows individuals to cope effectively with threats. Disruptions in the active-passive trade-off can lead to maladaptive coping strategies that are characteristic of anxiety and mood disorders, among the most burdensome psychiatric conditions worldwide. Despite their importance, the neural mechanisms regulating this active-passive trade-off remain poorly understood.
This project addressed this gap by investigating how the endocannabinoid system, and specifically cannabinoid type-1 (CB1) receptors in the striatum, regulate defensive behavioral choices under innate and learned threat conditions. The striatum is known to play a central role in action selection and behavioral flexibility, with striatal CB1 receptors acting as key modulators of these processes. However, their contribution to adaptive coping strategies had not been systematically explored.
The project aimed to: (1) establish robust behavioral paradigms to study active-passive trade-off in innate and learned configurations; (2) determine how distinct striatal CB1 receptor populations regulate active and passive defensive responses; and (3) identify the underlying synaptic and molecular mechanisms. To achieve these goals, the project combined advanced behavioral analysis with genetic, optogenetic, telemetry, and molecular approaches.
By uncovering the mechanisms through which endocannabinoid signaling shaped responses to threat, the project advanced understanding of the biological basis of adaptive and maladaptive coping. In the longer term, the knowledge generated was expected to support the identification of new therapeutic targets for anxiety and mood disorders. The project also generated novel experimental tools and paradigms that could facilitate future research in the stress and mental health fields.
