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Neural circuitry of safety, fear and reward cue discrimination

Award Number: R01MH110425
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/02/2018
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Neural circuitry of safety, fear and reward cue discrimination - Project Summary/Abstract Learning when to fear and when not to fear significantly impacts how we interact with our environment. Failure to appropriately regulate fear in situations that should be considered safe can be observed in stress disorders, such as Post-Traumatic Stress Disorder (PTSD). Even in individuals without a stress disorder, arousal is positively correlated with how threatening a safety cue is perceived. Restoring compromised behavioral control over fear under safety/threat conflict appears to rely on the strength of the safety cue as an inhibitor. This effectiveness as an inhibitor is critical to understand as presenting safety cues during exposure therapy could potentially enhance treatment outcomes in reducing maladaptive fear. However, the neural circuits promoting adaptive responding to safety cues that are well discriminated from fear cues are poorly understood. Therefore, identifying the behavioral and neural circuit mechanisms that regulate safety signaling is a critical and unmet medical need. Our extensive experience with safety conditioning paradigms makes us the best qualified to complete the proposed experiments. More specifically, we have the technical ability to articulate the essential neural circuitry for discriminating amongst safety, fear and reward cues, as well as conditioned inhibition of fear and reward. Our prior work has shown separate networks exist within the infralimbic cortex (IL) and basolateral amygdala (BLA) that either respond selectively to safety under threat conflict (safety-specific), or respond to both the safety conflict and reward cue (safety/reward). We propose that safety-specific signaling is encoded within the BLA and IL inputs to the central amygdala (CeA) (Aim 1), while the overlapping safety/reward signal is within the BLA, IL, and prelimbic (PL) inputs to the nucleus accumbens (NAC) (Aim 2). We also propose that the anterior cingulate cortex (ACC) and the retrosplenial cortex (RSC) will participate in the transfer of the fear reducing effects of a learned safety cue to novel contexts since they have been implicated in generalizing memories across contexts and integrating cues with contexts (Aim 3). In the proposed work we will be following individual cells longitudinally across reward cue learning, safety cue discrimination learning, tests for conditioned inhibition, cued fear extinction, and retardation of fear acquisition to determine how individual cells of this circuit generalize across different types of cued safety, cued reward and new contexts. Together, this work will impact the field of safety learning by identifying and teasing apart circuit mechanisms of how a safety cue suppresses fear, how it gains rewarding properties, and how it may regulate fear in unfamiliar contexts, all of which are highly relevant to many psychiatric disorders. In sum, we have a unique and novel translational approach to better understand the neural mechanisms of conditional discrimination that may be negatively affected in many psychiatric disorders.


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: 2025 ( Subtotal = $539,164 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Mental Health Research Grants	001	7	1/7/2025	NON-COMPETING CONTINUATION	$539,164
2025	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Mental Health Research Grants	000	5	12/23/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $539,164

Issue Date FY: 2024 ( Subtotal = $624,927 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Mental Health Research Grants	001	6	7/2/2024	COMPETING CONTINUATION	$62,492
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Mental Health Research Grants	000	6	2/23/2024	COMPETING CONTINUATION	$562,435
														Subtotal = $624,927

Issue Date FY: 2022 ( Subtotal = $396,250 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Mental Health Research Grants	003	5	8/25/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$168,075
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Mental Health Research Grants	001	5	4/6/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$396,250
2022	2021	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Mental Health Research Grants	000	4	4/6/2022	NON-COMPETING CONTINUATION	$0
2022	2021	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Mental Health Research Grants	002	4	8/25/2022	NON-COMPETING CONTINUATION	-$168,075
														Subtotal = $396,250

Issue Date FY: 2021 ( Subtotal = $384,548 )
2021	2021	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Mental Health Research Grants	000	4	2/11/2021	NON-COMPETING CONTINUATION	$384,548
														Subtotal = $384,548

Issue Date FY: 2020 ( Subtotal = $384,605 )
2020	2020	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Mental Health Research Grants	000	3	1/13/2020	NON-COMPETING CONTINUATION	$384,605
														Subtotal = $384,605

Issue Date FY: 2019 ( Subtotal = $384,662 )
2019	2019	PURDUE UNIVERSITY	401 SOUTH GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Mental Health Research Grants	000	2	12/17/2018	NON-COMPETING CONTINUATION	$384,662
														Subtotal = $384,662

Issue Date FY: 2018 ( Subtotal = $384,662 )
2018	2018	PURDUE UNIVERSITY	401 SOUTH GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Mental Health Research Grants	000	1	3/2/2018	NEW	$384,662
														Subtotal = $384,662

Grand Total All Awards = $3,098,818

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Neural circuitry of safety, fear and reward cue discrimination

Award Number: R01MH110425

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/02/2018

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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