Deciphering the role of striatal CB1 receptors in defensive behaviours

Projektinformationen

DefenCB1

ID Finanzhilfevereinbarung: 101150763

DOI

10.3030/101150763

Projekt abgeschlossen

EK-Unterschriftsdatum 15 März 2024

Startdatum 1 Mai 2024

Enddatum 30 April 2026

Finanziert unter

• Marie Skłodowska-Curie Actions (MSCA)

Gesamtkosten

Keine Daten

EU-Beitrag

€ 210 742,88

Koordiniert durch

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 1 - DefenCB1 (Deciphering the role of striatal CB1 receptors in defensive behaviours)

Berichtszeitraum: 2024-05-01 bis 2026-04-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

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.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

DefenCB1 generated significant advances in understanding how the brain copes with threatening situations. Prior to this project, the neural mechanisms underlying the active-passive trade-off remained poorly understood, particularly regarding the contribution of the endocannabinoid system and striatal circuits.
During the project, novel behavioral paradigms were established and optimized to study innate and learned defensive responses under comparable conditions. These experimental tools provide a novel framework for studying adaptive and maladaptive coping behaviors.
A major achievement of the project was the identification of a previously uncharacterized dorsostriatal endocannabinoid circuit involved in threat processing. Experimental evidence revealed the existence of a previously uncharacterized dorsostriatal endocannabinoid circuit involved in threat processing by identifying striatopallidal CB1 receptors as important regulators of innate threat responses and adaptive behavioural regulation. These findings provide the first mechanistic evidence linking specific striatal cannabinoid pathways to the control of defensive coping strategies. By integrating behavioural, genetic, circuit-level and molecular approaches, the project generated a multiscale understanding of how endocannabinoid signaling shapes adaptive responses to danger. This represents a substantial advance beyond the state of the art, moving from descriptive observations of defensive behaviors towards the identification of specific cellular and circuital mechanisms controlling behavioural adaptation. The expected long-term impact of these findings lies in their potential to inform the development of novel therapeutic approaches for psychiatric disorders characterized by maladaptive coping, including anxiety and mood disorders.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

The project significantly advanced the state of the art by moving beyond descriptive studies of defensive behaviour and providing mechanistic evidence linking the endocannabinoid system to the regulation of adaptive coping strategies. Prior to DefenCB1, the neural mechanisms governing active-passive trade-off remained poorly understood, and the contribution of specific striatal CB1 receptor populations had not been directly investigated. Thus, DefenCB1 provided the first evidence that a specific dorsostriatal cannabinoid circuit regulates imminent threat-coping responses and influences the selection of defensive strategies. In particular, the project identified striatopallidal CB1 receptors as critical determinants of innate defensive behaviour and established a mechanistic framework linking endocannabinoid signaling, striatal circuitry and adaptive behavioral responses. Beyond its scientific contributions, the project has important long-term translational potential since maladaptive coping strategies are central features of anxiety and mood disorders. By identifying novel cellular and molecular targets involved in defensive responses, the project provides a foundation for the development of more precise therapeutic interventions aimed at restoring adaptive coping mechanisms. The project also generated methodological advances, including refined behavioural paradigms and computational tools that can be adopted by other researchers studying stress, emotion and decision-making. These resources will remain available through open science practices, maximizing their scientific impact and reusability.