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

Ozge Gunduz-Cinar; Laura I. Castillo; Maya Xia; Elise Van Leer; Emma T. Brockway; Gabrielle A. Pollack; Farhana Yasmin; Olena Bukalo; Aaron Limoges; Sarvar Oreizi-Esfahani; Veronika Kondev; Rita Báldi; Ao Dong; Judy Harvey-White; Resat Cinar; George Kunos; Yulong Li; Larry S. Zweifel; Sachin Patel; Andrew Holmes

doi:10.1016/j.neuron.2023.06.023

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

Ozge Gunduz-Cinar^*, Laura I. Castillo, Maya Xia, Elise Van Leer, Emma T. Brockway, Gabrielle A. Pollack, Farhana Yasmin, Olena Bukalo, Aaron Limoges, Sarvar Oreizi-Esfahani, Veronika Kondev, Rita Báldi, Ao Dong, Judy Harvey-White, Resat Cinar, George Kunos, Yulong Li, Larry S. Zweifel, Sachin Patel, Andrew Holmes^*

^*Corresponding author for this work

Psychiatry and Behavioral Sciences

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

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.

Original language	English (US)
Pages (from-to)	3053-3067.e10
Journal	Neuron
Volume	111
Issue number	19
DOIs	https://doi.org/10.1016/j.neuron.2023.06.023
State	Published - Oct 4 2023

Funding

We are very grateful to Dr. Josephine M. Egan for providing breeding pairs of Cnr1-floxed mutant mice; to Dr. Eliot Smith for technical advice on the ACD BaseScope procedure; and to Dr. Guohong Cui, Dr. Jie Liu, and Julia Schaffer for valuable discussions. Research supported by the NIAAA Intramural Research Program (A.H.); a NIDA grant, P30 DA048736 (L.S.Z.); and NIMH grants MH107435 and MH119817 (S.P.). O.G.-C. dedicates this work to her father, whom she lost during the course of this study.

Keywords

CRISPR-Cas9
GRAB biosensor
PTSD
amygdala
anxiety
endocannabinoid
extinction
fear
optogenetics
prefrontal cortex

ASJC Scopus subject areas

General Neuroscience

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Gunduz-Cinar, O., Castillo, L. I., Xia, M., Van Leer, E., Brockway, E. T., Pollack, G. A., Yasmin, F., Bukalo, O., Limoges, A., Oreizi-Esfahani, S., Kondev, V., Báldi, R., Dong, A., Harvey-White, J., Cinar, R., Kunos, G., Li, Y., Zweifel, L. S., Patel, S., & Holmes, A. (2023). A cortico-amygdala neural substrate for endocannabinoid modulation of fear extinction. Neuron, 111(19), 3053-3067.e10. https://doi.org/10.1016/j.neuron.2023.06.023

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title = "A cortico-amygdala neural substrate for endocannabinoid modulation of fear extinction",

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{\textquoteright} 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 biosensor, PTSD, amygdala, anxiety, endocannabinoid, extinction, fear, optogenetics, prefrontal cortex",

author = "Ozge Gunduz-Cinar and Castillo, \{Laura I.\} and Maya Xia and \{Van Leer\}, Elise and Brockway, \{Emma T.\} and Pollack, \{Gabrielle A.\} and Farhana Yasmin and Olena Bukalo and Aaron Limoges and Sarvar Oreizi-Esfahani and Veronika Kondev and Rita B{\'a}ldi and Ao Dong and Judy Harvey-White and Resat Cinar and George Kunos and Yulong Li and Zweifel, \{Larry S.\} and Sachin Patel and Andrew Holmes",

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year = "2023",

month = oct,

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doi = "10.1016/j.neuron.2023.06.023",

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Gunduz-Cinar, O, Castillo, LI, Xia, M, Van Leer, E, Brockway, ET, Pollack, GA, Yasmin, F, Bukalo, O, Limoges, A, Oreizi-Esfahani, S, Kondev, V, Báldi, R, Dong, A, Harvey-White, J, Cinar, R, Kunos, G, Li, Y, Zweifel, LS, Patel, S & Holmes, A 2023, 'A cortico-amygdala neural substrate for endocannabinoid modulation of fear extinction', Neuron, vol. 111, no. 19, pp. 3053-3067.e10. https://doi.org/10.1016/j.neuron.2023.06.023

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T1 - A cortico-amygdala neural substrate for endocannabinoid modulation of fear extinction

AU - Gunduz-Cinar, Ozge

AU - Castillo, Laura I.

AU - Xia, Maya

AU - Van Leer, Elise

AU - Brockway, Emma T.

AU - Pollack, Gabrielle A.

AU - Yasmin, Farhana

AU - Bukalo, Olena

AU - Limoges, Aaron

AU - Oreizi-Esfahani, Sarvar

AU - Kondev, Veronika

AU - Báldi, Rita

AU - Dong, Ao

AU - Harvey-White, Judy

AU - Cinar, Resat

AU - Kunos, George

AU - Li, Yulong

AU - Zweifel, Larry S.

AU - Patel, Sachin

AU - Holmes, Andrew

PY - 2023/10/4

Y1 - 2023/10/4

N2 - 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.

AB - 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.

KW - CRISPR-Cas9

KW - GRAB biosensor

KW - PTSD

KW - amygdala

KW - anxiety

KW - endocannabinoid

KW - extinction

KW - fear

KW - optogenetics

KW - prefrontal cortex

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DO - 10.1016/j.neuron.2023.06.023

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SN - 0896-6273

VL - 111

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JO - Neuron

JF - Neuron

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ER -

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

Abstract

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