Abstract
Anxiety and stress-related psychiatric disorders are highly prevalent, have uncertain aetiologies and are only partially responsive to available therapies. Elucidating fundamental mechanisms that regulate anxiety, fear and stress responsivity could reveal new insights into disease mechanisms and offer opportunities for therapeutic development. Endocannabinoid (eCB) signalling has been shown to modulate innate avoidance behaviour, conditioned defensive behaviour and responsivity to stress in preclinical and human experimental studies. Furthermore, recent studies utilizing eCB biosensors, intersectional genetics and optogenetic-assisted circuit mapping have identified synaptic, cellular and circuit-level mechanisms by which eCBs affect these biobehavioural processes. These data suggest that eCB-deficient states could represent a stress-susceptibility endophenotype while pharmacological eCB augmentation could represent emerging approaches for the treatment of affective and stress-related neuropsychiatric disorders. In addition, several cortical–cortical and cortical–subcortical circuits have been identified as key substrates by which eCB signalling affects avoidance behaviour and stress responsivity. Taken together, the reviewed data offer new insights into the potential contribution of eCB signalling systems to the pathophysiology of anxiety and stress-related disorders and reveal fundamental roles for eCB signalling in the modulation of anxiety, fear and stress responsivity.
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Acknowledgements
The authors would like to thank their long-time colleagues, M. Hill, C. Hillard, L. Mayo, A. Holmes, O. Gunduz-Cinar, B. Shonesy and others, for their thoughtful and spirited discussions on the topics reviewed here over the years. This work is supported by the National Institutes of Health grant MH107435 (S.P.).
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Glossary
- Allostasis
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The active processes that the body and brain undergo to re-establish homeostasis after stress exposure.
- Anhedonia
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The inability to experience pleasure or enjoyment from activities that would normally be pleasurable.
- Elevated-plus maze
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(EPM). A rodent spatial avoidance task during which rodents can explore closed (safe) and threatening (open) arms, with increases in open-arm exploration suggestive of reduced anxiety-related responses.
- Innate avoidance
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An organism’s avoidance of locations or stimuli without previous exposure or knowledge of the exposure outcome through previous experience.
- Learned defensive response generation
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Defensive behaviours, including avoidance, freezing and flight, expressed upon presentation of environmental stimuli that predicts threat as a function of previously formed associations between the stimuli and a negative outcome.
- Stress adaptation
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Dynamic physiological and behavioural responses to stress exposure across time, some of which contribute to allostasis, while others contribute to stress-induced pathological states.
- Stress coping
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An animal’s short-term (usually several minutes) response to stress that is generally assessed by forced swimming or tail suspension, with coping responses noted to be active or passive.
- Stress reactivity
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An animal’s immediate defensive reactions (seconds to minutes) to stress exposure, including avoidance, freezing or flight.
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Cite this article
Loomba, N., Patel, S. Circuit mechanisms governing endocannabinoid modulation of affective behaviour and stress adaptation. Nat. Rev. Neurosci. 26, 677–697 (2025). https://doi.org/10.1038/s41583-025-00961-y
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DOI: https://doi.org/10.1038/s41583-025-00961-y
