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Glucocorticoid modulation of contextual processing and its neurocircuitry: Testing a new model of PTSD pathophysiology

Award Number: R01MH113574
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/07/2018
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Glucocorticoid modulation of contextual processing and its neurocircuitry: Testing a new model of PTSD pathophysiology - Project Summary/Abstract Fifty to 90% of Americans are exposed to trauma that can lead to Post-traumatic Stress Disorder (PTSD). Only a few develop PTSD. Identifying the vulnerable and modifying the processes that translate risk into illness could reduce the public health burden of this serious disease. Risk factors and neurobiological mechanism are being identified, but much remains unknown. Emerging models identify relevant genes, environments, brain circuits and behavior, expanding our focus beyond simple fear learning to incorporate more complex neural circuits that modulate responses to threat. Studying these circuits and their functions has generated a novel model of PTSD pathophysiology that focuses on deficits in context processing (CP) and on the hippocampal- prefrontal circuitry that subserves CP functions. This model is supported by growing evidence, explains much of PTSD's phenomenology, and integrates much of its neurobiology. The aim of this project is to further develop and test this model, and explore implications for treatment and, potentially, for prevention. PTSD patients respond fearfully to ambiguous cues (e.g., loud noise) even when in safe contexts (e.g., home backyard). Difficulty linking cues to contexts may be a core problem for them, undermining access to contextual information that should modulate adaptive responses. The hippocampus (Hpc) plays a key role in this process, mediating core CP functions like pattern separation (PS) and pattern completion (PC). PS/PC deficits may underlie CP difficulties in PTSD, contributing to an inability to remember that something once threatening is now safe (extinction recall) or to recognize potential danger when danger signals are contextual (fear renewal). Glucocorticoid (GC) signaling in Hpc can impair CP functions, so evidence of increased GC receptor sensitivity in PTSD is consistent with the CP model. Genetic and developmental factors known to shape GC sensitivity may contribute to PTSD risk through impact on CP functions like PS/PC, perhaps mediated by activity/connectivity within Hpc-prefrontal (PFC) circuits. This project will test the CP model, examining links between CP functions like PS/PC and the Hpc-PFC neural pathways subserving these functions, the role of glucocorticoid signaling in moderating these pathways and functions, and the ability of GCs to improve or undermine CP functions. It will do so by studying 120 healthy subjects performing PS/PC and fear learning tasks in fMRI, under low cortisol, physiological cortisol, and elevated (moderate and high) cortisol levels. “Baseline” levels of GC signaling will be assessed via integrated cortisol secretion (hair cortisol) and GC receptor sensitivity (in vitro lysozyme inhibition). The project will also study 150 PTSD patients in the same paradigm, to determine whether PS/PC processes are core deficits in PTSD, linked to symptom severity and extinction recall/fear renewal deficits via Hpc-PFC dysfunction, and to test the ability of GCs to “rescue” CP deficits in PTSD, via impact on Hpc-PFC pathways.


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 = -$316 )
2026	2022	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Mental Health Research Grants	000	5	12/10/2025	NON-COMPETING CONTINUATION	-$316
														Subtotal = -$316

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Mental Health Research Grants	000	5	7/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Mental Health Research Grants	005	4	11/15/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$700,478
2023	2021	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Mental Health Research Grants	001	4	11/10/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$509,696
2023	2021	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Mental Health Research Grants	008	4	12/30/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,210,489
2023	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Mental Health Research Grants	004	3	11/15/2022	NON-COMPETING CONTINUATION	$700,478
2023	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Mental Health Research Grants	000	3	11/10/2022	NON-COMPETING CONTINUATION	$509,696
2023	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Mental Health Research Grants	007	3	12/30/2022	NON-COMPETING CONTINUATION	-$700,478
2023	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Mental Health Research Grants	003	3	11/15/2022	NON-COMPETING CONTINUATION	-$509,696
2023	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Mental Health Research Grants	006	2	12/30/2022	NON-COMPETING CONTINUATION	-$510,011
2023	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Mental Health Research Grants	002	2	11/15/2022	NON-COMPETING CONTINUATION	$509,696
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $519,880 )
2022	2022	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Mental Health Research Grants	007	5	8/2/2022	NON-COMPETING CONTINUATION	$519,880
2022	2021	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Mental Health Research Grants	006	4	1/12/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,210,174
2022	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Mental Health Research Grants	005	3	1/12/2022	NON-COMPETING CONTINUATION	-$700,478
2022	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Mental Health Research Grants	001	3	12/6/2021	NON-COMPETING CONTINUATION	-$700,478
2022	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Mental Health Research Grants	003	3	12/10/2021	NON-COMPETING CONTINUATION	$700,478
2022	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Mental Health Research Grants	004	2	1/12/2022	NON-COMPETING CONTINUATION	-$509,696
2022	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Mental Health Research Grants	000	2	12/6/2021	NON-COMPETING CONTINUATION	-$509,696
2022	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Mental Health Research Grants	002	2	12/10/2021	NON-COMPETING CONTINUATION	$509,696
														Subtotal = $519,880

Issue Date FY: 2021 ( Subtotal = $565,627 )
2021	2021	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Mental Health Research Grants	001	4	9/3/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$565,627
2021	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Mental Health Research Grants	000	3	9/3/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $565,627

Issue Date FY: 2020 ( Subtotal = $700,478 )
2020	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Mental Health Research Grants	000	3	8/1/2020	NON-COMPETING CONTINUATION	$700,478
														Subtotal = $700,478

Issue Date FY: 2019 ( Subtotal = $711,882 )
2019	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Mental Health Research Grants	001	2	8/19/2019	NON-COMPETING CONTINUATION	$711,882
2019	2018	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Mental Health Research Grants	000	1	10/31/2018	NEW	$0
														Subtotal = $711,882

Issue Date FY: 2018 ( Subtotal = $775,808 )
2018	2018	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Mental Health Research Grants	000	1	8/7/2018	NEW	$775,808
														Subtotal = $775,808

Grand Total All Awards = $3,273,359

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Glucocorticoid modulation of contextual processing and its neurocircuitry: Testing a new model of PTSD pathophysiology

Award Number: R01MH113574

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/07/2018

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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