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Infralimbic circuit control over a sex-dependent switch in threat responding.

Award Number: R01MH123803
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Infralimbic circuit control over a sex-dependent switch in threat responding. - Project Summary Sex differences in the development and prevalence of mental illnesses are widespread, suggesting that the factors that promote disease risk and resilience may be distinct in men and women. The neurobiological mechanisms underlying this possibility are poorly understood, however, because the vast majority of pre-clinical animal research has been conducted in males. In addition, the behavioral outcome measures used to understand learned fear have focused predominantly on freezing behavior. We recently identified an active, escape-like conditioned fear response in rats (“darting”) that occurs almost exclusively in females and is associated with both reduced freezing and an augmented response to the foot shock unconditioned stimulus, suggesting that individual differences in how animals process aversive stimuli could determine their behavioral strategies when faced with a threat. A better understanding of potentially sexually dimorphic mechanisms that drive this behavior could open new avenues for treatment of disorders that are more prevalent in women, like PTSD. Data collected during the first award period suggests that darting cannot be explained by general behavioral differences but instead represents a discrete conditioned response that is context-specific. Our data further implicate activity in the infralimbic cortex (IL) as distinctly related to reduced conditioned freezing only in Darters. Since the IL is typically associated with suppression of freezing through activation of glutamatergic outputs, here we present a model in which darting emerges via disinhibition of IL projection neurons, due to reduced activity in parvalbumin (PV)-expressing GABAergic neurons. We further hypothesize that this disinhibition occurs selectively in Darters due to individual differences in gene expression within PV populations and their responses to contextual input from the ventral hippocampus (vHPC). To test these hypotheses, we will first map the cellular makeup of IL inhibitory populations in behaviorally characterized animals, and then perform FACS-assisted proteomics analyses of PV and glutamatergic neurons in Darters, Non-darters, and Males. We will then use fiber photometry and chemogenetic approaches to record from and manipulate PV populations during fear conditioning. Finally, we will use circuit-focused viral approaches to determine the specific role of vHPC-ILPV neurons in driving conditioned darting. Our work will integrate powerful molecular and genetic tools with multi-faceted behavioral assays, taking advantage of transgenic animals that allow targeted identification and control of PV-expressing neurons. Together, these studies can provide insight into sex-dependent circuit mechanisms underlying individual differences in stress resilience and vulnerability.


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 = $746,265 )
2026	2026	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	001	6	7/29/2026	COMPETING CONTINUATION	$746,862
2026	2024	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	5	11/20/2025	NON-COMPETING CONTINUATION	-$597
														Subtotal = $746,265

Issue Date FY: 2024 ( Subtotal = $434,852 )
2024	2024	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	5	5/29/2024	NON-COMPETING CONTINUATION	$434,852
														Subtotal = $434,852

Issue Date FY: 2023 ( Subtotal = $445,292 )
2023	2023	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	4	6/1/2023	NON-COMPETING CONTINUATION	$445,292
														Subtotal = $445,292

Issue Date FY: 2022 ( Subtotal = $490,159 )
2022	2022	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	3	5/11/2022	NON-COMPETING CONTINUATION	$490,159
														Subtotal = $490,159

Issue Date FY: 2021 ( Subtotal = $445,292 )
2021	2021	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	2	6/9/2021	NON-COMPETING CONTINUATION	$445,292
														Subtotal = $445,292

Issue Date FY: 2020 ( Subtotal = $503,268 )
2020	2020	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	1	7/24/2020	NEW	$503,268
														Subtotal = $503,268

Grand Total All Awards = $3,065,128

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Infralimbic circuit control over a sex-dependent switch in threat responding.

Award Number: R01MH123803

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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