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Sex differences in CRH signaling in the ovBNST underlie effects of chronic stressors

Award Number: R01MH123544
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/11/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Sex differences in CRH signaling in the ovBNST underlie effects of chronic stressors - Project Summary Chronic exposure to stressful experiences can result in maladaptive affective states that yield behavioral disturbances in rodents and stress-related mood disorders in humans. Over the last decade, the neural circuits underlying these maladaptive effects of stress have become better defined. One region of importance is the bed nucleus of the stria terminalis (BNST), which is a major output pathway connecting the central amygdala to the ventromedial nucleus of the hypothalamus that also receives direct projections from other limbic areas. Therefore, BNST may be an integrative center for limbic information and valence monitoring. Psychological and physiological stressors affect males and females differently. The BNST is a sexually dimorphic structure that may contribute to distinct chronic stress responses in males and females because expression of aromatase and both estrogen receptors (ER)  differs in male and female BNST. Direct activation of neurons within the oval nucleus of the BNST (ovBNST) increases anxiety-associated negative valence behaviors in male rodents, and our preliminary data demonstrates that exposure of C57BL/6J male mice to chronic variable mild stress (CVMS) results in increased corticotropin releasing hormone (CRH/CRF) signaling, increased mEPSC amplitude, altered resting membrane potential, and diminished M-currents in ovBNST neurons. While these data suggest that ovBNST may be a nexus for the effects of chronic stress on affective states, many questions remain unanswered. Our overall hypothesis is that CRH-expressing ovBNST neurons are critical mediators of the chronic stress response and that sexual dimorphism in the BNST underlies the distinct chronic stress responses found in males and females. The proposed specific aims will directly answer these questions and increase our understanding of how ovBNST mediates the maladaptive effects of chronic stress. In Aim 1, we will identify the cell populations that are impacted by chronic stressors (CVMS, chronic nondiscriminatory social defeat stress [CNSDS]) and the neurophysiological consequences in male and female mice. In Aim 2, we will assess how chronic stress affects ER signaling in BNST and whether optogenetic modulation of ER-positive BNST neurons mimics and/or reverses the effects of chronic stress on behavior. In Aim 3, we will determine the necessity and sufficiency of CRH-signaling in ovBNST neurons in mediating the behavioral effects of CVMS and CNSDS.


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 = $0 )
2025	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Mental Health Research Grants	000	5	4/29/2025	NON-COMPETING CONTINUATION	$0
2025	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Mental Health Research Grants	001	5	4/30/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $541,988 )
2024	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Mental Health Research Grants	002	5	8/15/2024	NON-COMPETING CONTINUATION	$40,988
2024	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Mental Health Research Grants	000	5	4/1/2024	NON-COMPETING CONTINUATION	$368,895
2024	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Mental Health Research Grants	001	5	4/3/2024	SUPPLEMENT FOR EXPANSION	$132,105
														Subtotal = $541,988

Issue Date FY: 2023 ( Subtotal = $556,903 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Mental Health Research Grants	001	4	5/23/2023	SUPPLEMENT FOR EXPANSION	$132,105
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Mental Health Research Grants	000	4	3/13/2023	NON-COMPETING CONTINUATION	$424,798
														Subtotal = $556,903

Issue Date FY: 2022 ( Subtotal = $424,798 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Mental Health Research Grants	001	3	6/7/2022	NON-COMPETING CONTINUATION	$42,481
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Mental Health Research Grants	000	3	3/11/2022	NON-COMPETING CONTINUATION	$382,317
														Subtotal = $424,798

Issue Date FY: 2021 ( Subtotal = $431,238 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Mental Health Research Grants	000	2	3/5/2021	NON-COMPETING CONTINUATION	$431,238
														Subtotal = $431,238

Issue Date FY: 2020 ( Subtotal = $465,659 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Mental Health Research Grants	000	1	6/10/2020	NEW	$465,659
														Subtotal = $465,659

Grand Total All Awards = $2,420,586

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Sex differences in CRH signaling in the ovBNST underlie effects of chronic stressors

Award Number: R01MH123544

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/11/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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