A cortico-amygdala neural substrate for endocannabinoid modulation of fear extinction

doi:10.1016/j.neuron.2023.06.023

. 2023 Oct 4;111(19):3053-3067.e10.

doi: 10.1016/j.neuron.2023.06.023. Epub 2023 Jul 21.

A cortico-amygdala neural substrate for endocannabinoid modulation of fear extinction

Ozge Gunduz-Cinar¹, Laura I Castillo², Maya Xia², Elise Van Leer², Emma T Brockway², Gabrielle A Pollack², Farhana Yasmin³, Olena Bukalo², Aaron Limoges², Sarvar Oreizi-Esfahani², Veronika Kondev⁴, Rita Báldi³, Ao Dong⁵, Judy Harvey-White⁶, Resat Cinar⁷, George Kunos⁶, Yulong Li⁵, Larry S Zweifel⁸, Sachin Patel³, Andrew Holmes⁹

Affiliations

¹ Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA. Electronic address: [email protected].
² Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA.
³ Northwestern Center for Psychiatric Neuroscience, Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
⁴ Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232, USA.
⁵ Peking University School of Life Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
⁶ Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA.
⁷ Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA; Section on Fibrotic Disorders, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA.
⁸ Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA; Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
⁹ Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA. Electronic address: [email protected].

PMID: 37480845
PMCID: PMC10592324 (available on 2024-10-04)
DOI: 10.1016/j.neuron.2023.06.023

A cortico-amygdala neural substrate for endocannabinoid modulation of fear extinction

Ozge Gunduz-Cinar et al. Neuron. 2023.

. 2023 Oct 4;111(19):3053-3067.e10.

doi: 10.1016/j.neuron.2023.06.023. Epub 2023 Jul 21.

Authors

Affiliations

¹ Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA. Electronic address: [email protected].
² Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA.
³ Northwestern Center for Psychiatric Neuroscience, Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
⁴ Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232, USA.
⁵ Peking University School of Life Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
⁶ Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA.
⁷ Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA; Section on Fibrotic Disorders, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA.
⁸ Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA; Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
⁹ Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA. Electronic address: [email protected].

PMID: 37480845
PMCID: PMC10592324 (available on 2024-10-04)
DOI: 10.1016/j.neuron.2023.06.023

Abstract

Preclinical and clinical studies implicate endocannabinoids (eCBs) in fear extinction, but the underlying neural circuit basis of these actions is unclear. Here, we employed in vivo optogenetics, eCB biosensor imaging, ex vivo electrophysiology, and CRISPR-Cas9 gene editing in mice to examine whether basolateral amygdala (BLA)-projecting medial prefrontal cortex (mPFC) neurons represent a neural substrate for the effects of eCBs on extinction. We found that photoexcitation of mPFC axons in BLA during extinction mobilizes BLA eCBs. eCB biosensor imaging showed that eCBs exhibit a dynamic stimulus-specific pattern of activity at mPFC^→BLA neurons that tracks extinction learning. Furthermore, using CRISPR-Cas9-mediated gene editing, we demonstrated that extinction memory formation involves eCB activity at cannabinoid CB1 receptors expressed at vmPFC^→BLA synapses. Our findings reveal the temporal characteristics and a neural circuit basis of eCBs' effects on fear extinction and inform efforts to target the eCB system as a therapeutic approach in extinction-deficient neuropsychiatric disorders.

Keywords: CRISPR-Cas9; GRAB(eCB2.0) biosensor; PTSD; amygdala; anxiety; endocannabinoid; extinction; fear; optogenetics; prefrontal cortex.

Published by Elsevier Inc.

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Conflict of interest statement

Declaration of interests S.P. is or has been a scientific consultant for H. Lundbeck A/S and Psy Therapeutics, unrelated to the current work.

Comment in

Endocannabinoids modulate fear extinction controlled by a cortical-amygdala projection.
Adhikari A. Adhikari A. Neuron. 2023 Oct 4;111(19):2948-2950. doi: 10.1016/j.neuron.2023.09.011. Neuron. 2023. PMID: 37797579

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References

1. Craske MG, Stein MB, Eley TC, Milad MR, Holmes A, Rapee RM, and Wittchen HU (2017). Anxiety disorders. Nature reviews. Disease primers 3, 17024. 10.1038/nrdp.2017.24. - DOI - PMC - PubMed
1. Pavlov IP (1927). Conditioned reflexes (Oxford University Press).
1. Hariri AR, and Holmes A (2015). Finding translation in stress research. Nat Neurosci 18, 1347–1352. 10.1038/nn.4111. - DOI - PMC - PubMed
1. Gunduz-Cinar O, Hill MN, McEwen BS, and Holmes A (2013). Amygdala FAAH and anandamide: mediating protection and recovery from stress. Trends Pharmacol Sci 34, 637–644. 10.1016/j.tips.2013.08.008. - DOI - PMC - PubMed
1. Mayo LM, Rabinak CA, Hill MN, and Heilig M (2021). Targeting the Endocannabinoid System in the Treatment of Posttraumatic Stress Disorder: A Promising Case of Preclinical-Clinical Translation? Biol Psychiatry 10.1016/j.biopsych.2021.07.019. - DOI - PMC - PubMed

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[1] Craske MG, Stein MB, Eley TC, Milad MR, Holmes A, Rapee RM, and Wittchen HU (2017). Anxiety disorders. Nature reviews. Disease primers 3, 17024. 10.1038/nrdp.2017.24. - DOI - PMC - PubMed

[2] Craske MG, Stein MB, Eley TC, Milad MR, Holmes A, Rapee RM, and Wittchen HU (2017). Anxiety disorders. Nature reviews. Disease primers 3, 17024. 10.1038/nrdp.2017.24. - DOI - PMC - PubMed

[3] Pavlov IP (1927). Conditioned reflexes (Oxford University Press).

[4] Pavlov IP (1927). Conditioned reflexes (Oxford University Press).

[5] Hariri AR, and Holmes A (2015). Finding translation in stress research. Nat Neurosci 18, 1347–1352. 10.1038/nn.4111. - DOI - PMC - PubMed

[6] Hariri AR, and Holmes A (2015). Finding translation in stress research. Nat Neurosci 18, 1347–1352. 10.1038/nn.4111. - DOI - PMC - PubMed

[7] Gunduz-Cinar O, Hill MN, McEwen BS, and Holmes A (2013). Amygdala FAAH and anandamide: mediating protection and recovery from stress. Trends Pharmacol Sci 34, 637–644. 10.1016/j.tips.2013.08.008. - DOI - PMC - PubMed

[8] Gunduz-Cinar O, Hill MN, McEwen BS, and Holmes A (2013). Amygdala FAAH and anandamide: mediating protection and recovery from stress. Trends Pharmacol Sci 34, 637–644. 10.1016/j.tips.2013.08.008. - DOI - PMC - PubMed

[9] Mayo LM, Rabinak CA, Hill MN, and Heilig M (2021). Targeting the Endocannabinoid System in the Treatment of Posttraumatic Stress Disorder: A Promising Case of Preclinical-Clinical Translation? Biol Psychiatry 10.1016/j.biopsych.2021.07.019. - DOI - PMC - PubMed

[10] Mayo LM, Rabinak CA, Hill MN, and Heilig M (2021). Targeting the Endocannabinoid System in the Treatment of Posttraumatic Stress Disorder: A Promising Case of Preclinical-Clinical Translation? Biol Psychiatry 10.1016/j.biopsych.2021.07.019. - DOI - PMC - PubMed

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A cortico-amygdala neural substrate for endocannabinoid modulation of fear extinction

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A cortico-amygdala neural substrate for endocannabinoid modulation of fear extinction

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