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Neural Circuits for Stress-Impaired Extinction Learning

Award Number: R01MH117852
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/16/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Neural Circuits for Stress-Impaired Extinction Learning - PROJECT SUMMARY Clinical disorders of fear and anxiety, including trauma- and stressor-related disorders, represent an enormous public health burden. Unfortunately, cognitive-behavioral therapies, such as exposure therapy, that are aimed at reducing pathological fear are vulnerable to relapse. This is particularly problematic for patients under high levels of stress, which undermines exposure-based therapies by impairing extinction learning and promoting fear relapse. Despite years of work elucidating the neural circuitry for extinction, the neural mechanisms responsible for stress-induced extinction impairments remain poorly understood. In previous work on this project, we established that stress recruits bottom-up neuromodulatory circuits that inhibit the medial prefrontal cortex (mPFC), a brain area that is critical for extinction learning. We have now shown that that noradrenergic neurons in the locus coeruleus (LC) are critical for stress-induced extinction impairments, such as the immediate shock deficit. Critically, chemogenetic activation of noradrenergic LC neurons induces basolateral amygdala (BLA) hyperexcitability, which in turn drives feed-forward inhibition of the mPFC. Preliminary data indicate that stress-sensitive corticotropin-releasing factor (CRF) neurons in the central nucleus of the amygdala (CEA) drive extinction learning deficits. Based on this, we propose a novel hypothesis that CEA-CRF+ neurons drive LC-NE projections to the BLA, which results in both BLA hyperexcitability and impaired extinction learning. We propose three specific aims to test this hypothesis using a combination of in vivo electrophysiology, calcium imaging, and intersectional opt0genetic manipulations in male and female rats. The first specific aim examines whether CEA-CRF+ projections to the LC are necessary and sufficient for stress- induced increases in BLA hyperexcitability and extinction learning deficits. The second specific aim examines explores whether noradrenergic modulation of parvalbumin (PV) interneurons in the BLA regulates stress- induced hyperexcitability and extinction deficits. Lastly, the third specific aim examines whether the BLA is critical for transducing stress-induced activation of CEA-CRF+ and LC➙BLA circuits to undermine mPFC activity and extinction learning. The outcomes of these aims will advance a novel circuit mechanism for stress- induced extinction impairments. Understanding this mechanism will facilitate the development of novel pharmacotherapeutic approaches that optimally engage mPFC circuits to promote extinction learning under stress.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $722,520 )
2026	2026	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Mental Health Research Grants	000	9	1/22/2026	NON-COMPETING CONTINUATION	$722,520
														Subtotal = $722,520

Issue Date FY: 2025 ( Subtotal = $722,520 )
2025	2025	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Mental Health Research Grants	002	8	4/8/2025	NON-COMPETING CONTINUATION	$614,142
2025	2025	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Mental Health Research Grants	003	8	9/17/2025	NON-COMPETING CONTINUATION	$108,378
2025	2024	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Mental Health Research Grants	001	6	2/25/2025	COMPETING CONTINUATION	$0
2025	2022	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Mental Health Research Grants	000	5	2/25/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $722,520

Issue Date FY: 2024 ( Subtotal = $722,520 )
2024	2024	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Mental Health Research Grants	000	6	5/29/2024	COMPETING CONTINUATION	$695,828
2024	2024	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Mental Health Research Grants	002	7	8/8/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$722,519
2024	2024	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Mental Health Research Grants	001	6	8/7/2024	COMPETING CONTINUATION	-$695,827
														Subtotal = $722,520

Issue Date FY: 2022 ( Subtotal = $461,693 )
2022	2022	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Mental Health Research Grants	000	5	3/23/2022	NON-COMPETING CONTINUATION	$461,693
														Subtotal = $461,693

Issue Date FY: 2021 ( Subtotal = $504,264 )
2021	2021	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Mental Health Research Grants	000	4	2/26/2021	NON-COMPETING CONTINUATION	$504,264
														Subtotal = $504,264

Issue Date FY: 2020 ( Subtotal = $504,264 )
2020	2020	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Mental Health Research Grants	001	3	7/29/2020	SUPPLEMENT FOR EXPANSION	$42,571
2020	2020	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Mental Health Research Grants	000	3	3/24/2020	NON-COMPETING CONTINUATION	$461,693
														Subtotal = $504,264

Issue Date FY: 2019 ( Subtotal = $461,693 )
2019	2019	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Mental Health Research Grants	000	2	3/8/2019	NON-COMPETING CONTINUATION	$461,693
														Subtotal = $461,693

Issue Date FY: 2018 ( Subtotal = $485,993 )
2018	2018	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Mental Health Research Grants	000	1	6/11/2018	NEW	$485,993
														Subtotal = $485,993

Grand Total All Awards = $4,585,467

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Neural Circuits for Stress-Impaired Extinction Learning

Award Number: R01MH117852

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/16/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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