Prefrontal correlates of fear generalization during endocannabinoid depletion
Luis E. Rosas-Vidal, … , Markus Heilig, Sachin Patel
Luis E. Rosas-Vidal, … , Markus Heilig, Sachin Patel
Published March 27, 2025
Citation Information: J Clin Invest. 2025;135(11):e179881. https://doi.org/10.1172/JCI179881.
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Research Article Clinical Research Neuroscience

Prefrontal correlates of fear generalization during endocannabinoid depletion

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.

Authors

Luis E. Rosas-Vidal, Saptarnab Naskar, Leah M. Mayo, Irene Perini, Rameen Masroor, Megan Altemus, Liorimar Ramos-Medina, S. Danyal Zaidi, Hilda Engelbrektsson, Puja Jagasia, Markus Heilig, Sachin Patel

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Figure 1

Decreased levels of 2-AG are associated with increased generalization to neutral stimuli and self-reported emotional regulation.

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Decreased levels of 2-AG are associated with increased generalization to...
(A) Experiment schematic. (B) Generalization between CS+ and CS– and (C) difficulties in emotional regulation as a function of baseline peripheral 2-AG levels. Scatter plots: yellow, participants with CM and SUD history; red, participants with CM history; green, participants with SUD history; and gray, participants with no CM or SUD history. (D) Experiment schematic depicting stimuli for differential fear-conditioning and recall test sessions. (E) Percentage of time freezing in response to CS+ and CS–. Arrow, i.p. injection of vehicle or DO34 before recall test. (F) Generalization index for CS– t1 and t2 for vehicle and DO34 groups. (G) Experiment schematic depicting stimuli for partial differential fear-conditioning and recall test sessions. (H) Percentage of time freezing to CS+ and CS–. (I) Generalization index for CS– t1 and t2 for vehicle and DO34 groups. (J) Experiment schematic depicting stimuli for classical fear-conditioning and recall test sessions. (K) Percentage of time freezing to CS+ and NT. (L) Generalization index for NT t1 and t2 for vehicle and DO34 groups. (M) Experiment schematic depicting stimuli for contextual fear-conditioning and recall test sessions. (N) Percentage of time freezing to conditioning context (CtxA) and novel context (NCtx). (O) Generalization index for NCtx relative to freezing to CtxA on conditioning day 2 (CtxC). (P) Experiment schematic depicting stimuli for classical fear-conditioning and recall test sessions. (Q) Sagittal depiction (left) and coronal section (right) showing optic fiber and GRABeCB2.0 expression in PL. The dashed lines correspond to the subdivisions of the medial prefrontal cortex. (R) Average NT response for trials with freezing to tones above 75% (high generalization) and below 25% (low generalization). (S) Peak population NT response for high- and low-generalization trials. Repeated-measures or 2-way ANOVA followed by Šídák’s multiple-comparison test or Student’s t test where appropriate. *P < 0.05, **P < 0.01, ***P < 0.001.