ArticleThe Journal of clinical investigation2025
Prefrontal correlates of fear generalization during endocannabinoid depletion.
Article in The Journal of clinical investigation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- The efficacy of elevating anandamide via inhibition of fatty acid amide hydrolase (FAAH) combined with internet-delivered cognitive behavioral therapy in the treatment of post-traumatic stress disorder: a randomized, placebo-controlled clinical trial.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Trial
- Cannabinoid modulation of central amygdala population dynamics during threat investigation.Nature communications · 2026Article
- Relationships among peri-traumatic circulating endocannabinoids and long-term, negative outcomes following traumatic injury.Psychopharmacology · 2026Article
- Circuit mechanisms governing endocannabinoid modulation of affective behaviour and stress adaptation.Nature reviews. Neuroscience · 2025Review
- Endocannabinoids Block Headache and Anxiety Comorbidity via Two-Pronged Anterior Insular Projections.Research (Washington, D.C.) · 2025Article
- Endocannabinoid and neuroplasticity-related changes as susceptibility factors in a rat model of posttraumatic stress disorder.Neurobiology of stress · 2024Article
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Abstract
Maladaptive fear generalization is one of the hallmarks of trauma-related disorders. The endocannabinoid 2-arachidonoylglycerol (2-AG) is crucial for modulating anxiety, fear, and stress adaptation, but its role in balancing fear discrimination versus generalization is not known. To address this, we used a combination of plasma endocannabinoid measurement and neuroimaging in a childhood maltreatment-exposed and -nonexposed mixed population, combined with human and rodent fear-conditioning models. Here we show that 2-AG levels were inversely associated with fear generalization at the behavioral level in both mice and humans. In mice, 2-AG depletion increased the proportion of neurons that respond to, and the similarity of neuronal representations for, both threat-predictive and neutral stimuli within prelimbic prefrontal cortex neuronal ensembles. In humans, increased dorsolateral prefrontal cortical-amygdala resting-state connectivity was inversely correlated with fear generalization. These data provide convergent cross-species evidence that 2-AG is a key regulator of fear generalization and further support the notion that 2-AG deficiency could represent a trauma-related disorder-susceptibility endophenotype.
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