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The Integrated Role of Vasopressin and Oxytocin Receptors in the Modulation of BNST Activity and Fear Processing

Award Number: R01MH113007
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/12/2017
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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The Integrated Role of Vasopressin and Oxytocin Receptors in the Modulation of BNST Activity and Fear Processing - SUMMARY: Anxiety disorders are the most common psychiatric conditions, yet no new anxiolytic drug has been approved for treatment in the last decade. Therefore, there is a significant unmet need to develop new effective pharmacotherapies. In rodent and human studies, the bed nucleus of the stria terminalis (BNST) has emerged as a key brain region translating prolonged exposure to uncertain threats into sustained fear. The BNST is hyperactive in patients suffering from anxiety disorders and post-traumatic stress disorder. Human imaging studies demonstrate an enhanced functional connectivity between the BNST and the central amygdala (CeA) in anxious individuals. In rats, the BNST sends inhibitory projection to the CeA (BNSTàCeA) but there is a significant knowledge gap on how the BNST interacts with the CeA to modulate fear processing. As the CeA and BNST drive fear responses to predictable and unpredictable threats, respectively, increased activity of the BNSTàCeA neurons will favor responses to the unpredictable threats and can precipitate hypervigilance, an important hallmark of anxiety disorders in humans. Therefore, the factors that inhibit this BNSTàCeA output have untapped potential as novel therapeutic targets. Recent findings from the lab show that one such target involves oxytocin receptors (OTR) in the BNST, as OTR activation inhibits BNSTàCeA output and facilitates fear to predictable threats (cued fear). In contrast, our compelling preliminary data indicate that activation of vasopressin 1a receptor (V1aR) in the BNST directly excites Type III/Corticotropin- releasing factor (CRF) neurons, which promote sustained fear responses. Based on this scientific premise, the central hypothesis of this proposal is that by inhibiting and exciting the BNSTàCeA neurons, OTR and V1aR facilitate fear responses to predictable vs. unpredictable threats, respectively. This innovative concept will be investigated using cutting-edge experimental approaches, including chemogenetic and optogenetic manipulations of BNSTàCeA neurons in recently developed transgenic rat models (OTR-Cre, AVP-Cre, CRF- Cre). Rigorously designed behavioral and electrophysiological experiments will test the hypothesis with the following specific aims: 1) Determine the integrated role of V1aR and OTR in modulating activity of BNST neurons, 2) Determine whether predictable vs. unpredictable threats differentially modulate activity of BNSTàCeA neurons via OTR and V1aR, 3) Determine the role of BNSTàCeA neurons in mediating fear responses to predictable vs. unpredictable threats, and the contribution of OTR vs. V1aR. By refining mechanisms underlying the activity of BNSTàCeA neurons, this proposal will have a positive impact on the understanding how an imbalance in processing of predictable vs. unpredictable threats can lead to a hypervigilance and precipitate the onset of anxiety 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 = $459,403 )
2025	2025	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE & SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Mental Health Research Grants	000	9	9/5/2025	NON-COMPETING CONTINUATION	$459,403
														Subtotal = $459,403

Issue Date FY: 2024 ( Subtotal = $459,403 )
2024	2024	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE & SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Mental Health Research Grants	000	8	5/24/2024	NON-COMPETING CONTINUATION	$459,403
2024	2021	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE & SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Mental Health Research Grants	001	5	5/24/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $459,403

Issue Date FY: 2023 ( Subtotal = $490,004 )
2023	2023	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE & SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Mental Health Research Grants	000	7	5/30/2023	NON-COMPETING CONTINUATION	$490,004
														Subtotal = $490,004

Issue Date FY: 2022 ( Subtotal = $491,427 )
2022	2022	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE & SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Mental Health Research Grants	001	6	7/27/2022	COMPETING CONTINUATION	$491,427
2022	2021	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE & SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Mental Health Research Grants	000	5	7/26/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $491,427

Issue Date FY: 2021 ( Subtotal = $390,000 )
2021	2021	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Mental Health Research Grants	000	5	2/19/2021	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2020 ( Subtotal = $467,998 )
2020	2020	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Mental Health Research Grants	000	4	3/4/2020	NON-COMPETING CONTINUATION	$390,000
2020	2020	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Mental Health Research Grants	001	4	8/18/2020	SUPPLEMENT FOR EXPANSION	$77,998
														Subtotal = $467,998

Issue Date FY: 2019 ( Subtotal = $390,000 )
2019	2019	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Mental Health Research Grants	000	3	2/22/2019	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2018 ( Subtotal = $390,000 )
2018	2018	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Mental Health Research Grants	001	2	6/15/2018	NON-COMPETING CONTINUATION	$39,000
2018	2018	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Mental Health Research Grants	000	2	2/21/2018	NON-COMPETING CONTINUATION	$351,000
														Subtotal = $390,000

Issue Date FY: 2017 ( Subtotal = $390,000 )
2017	2017	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Mental Health Research Grants	000	1	5/12/2017	NEW	$390,000
														Subtotal = $390,000

Grand Total All Awards = $3,928,235

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The Integrated Role of Vasopressin and Oxytocin Receptors in the Modulation of BNST Activity and Fear Processing

Award Number: R01MH113007

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/12/2017

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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