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ResearchIn-Press PreviewClinical ResearchNeuroscience Open Access | 10.1172/JCI179881

Prefrontal correlates of fear generalization during endocannabinoid depletion

Luis E. Rosas-Vidal,1 Saptarnab Naskar,1 Leah M. Mayo,2 Irene Perini,3 Rameen Masroor,1 Megan Altemus,4 Liorimar Ramos-Medina,1 S. Danyal Zaidi,1 Hilda Engelbrektsson,3 Puja Jagasia,4 Markus Heilig,3 and Sachin Patel1

1Stephen M. Stahl Center for Psychiatric Neuroscience, Department of Psychia, Northwestern University, Feinberg School of Medicine, Chicago, United States of America

2Hotchkiss Brain Institute and Mathison Centre for Mental Health Research an, Cumming School of Medicine, University of Calgary, Calgary, Canada

3Department of Biomedical and Clinical Sciences, Linköping University, Center for Social and Affective Neuroscience, Linköping, Sweden

4Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Rosas-Vidal, L. in: JCI | PubMed | Google Scholar

1Stephen M. Stahl Center for Psychiatric Neuroscience, Department of Psychia, Northwestern University, Feinberg School of Medicine, Chicago, United States of America

2Hotchkiss Brain Institute and Mathison Centre for Mental Health Research an, Cumming School of Medicine, University of Calgary, Calgary, Canada

3Department of Biomedical and Clinical Sciences, Linköping University, Center for Social and Affective Neuroscience, Linköping, Sweden

4Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Naskar, S. in: JCI | PubMed | Google Scholar

1Stephen M. Stahl Center for Psychiatric Neuroscience, Department of Psychia, Northwestern University, Feinberg School of Medicine, Chicago, United States of America

2Hotchkiss Brain Institute and Mathison Centre for Mental Health Research an, Cumming School of Medicine, University of Calgary, Calgary, Canada

3Department of Biomedical and Clinical Sciences, Linköping University, Center for Social and Affective Neuroscience, Linköping, Sweden

4Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Mayo, L. in: JCI | PubMed | Google Scholar

1Stephen M. Stahl Center for Psychiatric Neuroscience, Department of Psychia, Northwestern University, Feinberg School of Medicine, Chicago, United States of America

2Hotchkiss Brain Institute and Mathison Centre for Mental Health Research an, Cumming School of Medicine, University of Calgary, Calgary, Canada

3Department of Biomedical and Clinical Sciences, Linköping University, Center for Social and Affective Neuroscience, Linköping, Sweden

4Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Perini, I. in: JCI | PubMed | Google Scholar |

1Stephen M. Stahl Center for Psychiatric Neuroscience, Department of Psychia, Northwestern University, Feinberg School of Medicine, Chicago, United States of America

2Hotchkiss Brain Institute and Mathison Centre for Mental Health Research an, Cumming School of Medicine, University of Calgary, Calgary, Canada

3Department of Biomedical and Clinical Sciences, Linköping University, Center for Social and Affective Neuroscience, Linköping, Sweden

4Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Masroor, R. in: JCI | PubMed | Google Scholar

1Stephen M. Stahl Center for Psychiatric Neuroscience, Department of Psychia, Northwestern University, Feinberg School of Medicine, Chicago, United States of America

2Hotchkiss Brain Institute and Mathison Centre for Mental Health Research an, Cumming School of Medicine, University of Calgary, Calgary, Canada

3Department of Biomedical and Clinical Sciences, Linköping University, Center for Social and Affective Neuroscience, Linköping, Sweden

4Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Altemus, M. in: JCI | PubMed | Google Scholar

1Stephen M. Stahl Center for Psychiatric Neuroscience, Department of Psychia, Northwestern University, Feinberg School of Medicine, Chicago, United States of America

2Hotchkiss Brain Institute and Mathison Centre for Mental Health Research an, Cumming School of Medicine, University of Calgary, Calgary, Canada

3Department of Biomedical and Clinical Sciences, Linköping University, Center for Social and Affective Neuroscience, Linköping, Sweden

4Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Ramos-Medina, L. in: JCI | PubMed | Google Scholar

1Stephen M. Stahl Center for Psychiatric Neuroscience, Department of Psychia, Northwestern University, Feinberg School of Medicine, Chicago, United States of America

2Hotchkiss Brain Institute and Mathison Centre for Mental Health Research an, Cumming School of Medicine, University of Calgary, Calgary, Canada

3Department of Biomedical and Clinical Sciences, Linköping University, Center for Social and Affective Neuroscience, Linköping, Sweden

4Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Zaidi, S. in: JCI | PubMed | Google Scholar

1Stephen M. Stahl Center for Psychiatric Neuroscience, Department of Psychia, Northwestern University, Feinberg School of Medicine, Chicago, United States of America

2Hotchkiss Brain Institute and Mathison Centre for Mental Health Research an, Cumming School of Medicine, University of Calgary, Calgary, Canada

3Department of Biomedical and Clinical Sciences, Linköping University, Center for Social and Affective Neuroscience, Linköping, Sweden

4Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Engelbrektsson, H. in: JCI | PubMed | Google Scholar

1Stephen M. Stahl Center for Psychiatric Neuroscience, Department of Psychia, Northwestern University, Feinberg School of Medicine, Chicago, United States of America

2Hotchkiss Brain Institute and Mathison Centre for Mental Health Research an, Cumming School of Medicine, University of Calgary, Calgary, Canada

3Department of Biomedical and Clinical Sciences, Linköping University, Center for Social and Affective Neuroscience, Linköping, Sweden

4Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Jagasia, P. in: JCI | PubMed | Google Scholar

1Stephen M. Stahl Center for Psychiatric Neuroscience, Department of Psychia, Northwestern University, Feinberg School of Medicine, Chicago, United States of America

2Hotchkiss Brain Institute and Mathison Centre for Mental Health Research an, Cumming School of Medicine, University of Calgary, Calgary, Canada

3Department of Biomedical and Clinical Sciences, Linköping University, Center for Social and Affective Neuroscience, Linköping, Sweden

4Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Heilig, M. in: JCI | PubMed | Google Scholar |

1Stephen M. Stahl Center for Psychiatric Neuroscience, Department of Psychia, Northwestern University, Feinberg School of Medicine, Chicago, United States of America

2Hotchkiss Brain Institute and Mathison Centre for Mental Health Research an, Cumming School of Medicine, University of Calgary, Calgary, Canada

3Department of Biomedical and Clinical Sciences, Linköping University, Center for Social and Affective Neuroscience, Linköping, Sweden

4Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Patel, S. in: JCI | PubMed | Google Scholar

Published March 27, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI179881.
Copyright © 2025, Rosas-Vidal et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 27, 2025 - Version history
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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 from a childhood maltreatment-exposed and non-exposed mixed population combined with human and rodent fear conditioning models. Here we show that 2-AG levels are inversely associated with fear generalization at the behavioral level in both mice and humans. In mice, 2-AG depletion increases the proportion of neurons, and the similarity between neuronal representations, of threat-predictive and neutral stimuli within prelimbic prefrontal cortex neuronal ensembles. In humans, increased dorsolateral prefrontal cortical-amygdala resting state connectivity is 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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  • Version 1 (March 27, 2025): In-Press Preview
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