Wednesday, January 15, 2025 1/15/2025

Stress-induced impairments in endogenous neurosteroid signaling in the BLA negatively impacts network and behavioral states

Award Number: R01MH128235
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary The episodic nature of psychiatric disorders suggests that the brain shifts between pathological and healthy brain states. Fear and anxiety have been correlated with changes in oscillations between the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) and abnormalities in these networks have been identified in patients with a range of psychiatric disorders and we propose that these networks may impact emotional processing more broadly. However, we understand very little about the mechanism(s) whereby networks shift between states. 5α-reduced neurosteroids, including allopregnanolone, have been suggested to play a role in affective switching and have been shown to exert robust anxiolytic and antidepressant effects in preclinical models and in clinical trials. In fact, an allopregnanolone analog recently received FDA approval for the treatment of postpartum depression. The current study builds on these findings to investigate the potential role of endogenous neurosteroids in mediating transitions between healthy and unhealthy network and behavioral states. Given that stress has been implicated in numerous psychiatric disorders, we propose to utilize a chronic unpredictable stress (CUS) model to evaluate the impact on mPFC-BLA network function. We propose that stress disrupts network function by impairing local neurosteroid signaling in the BLA (supported by preliminary data) and that increasing the capacity for endogenous neurosteroidogenesis can restore healthy network function. Our proposed mechanism involves the action of neurosteroids on GABAAR δ subunit-containing receptors, expressed at a high density in parvalbumin (PV)-positive neurons in the BLA, which are known to modulate oscillations within and between the mPFC-BLA. Thus, this application will test the hypothesis that deficits in endogenous 5α-reduced neurosteroid signaling in the BLA, via δ-subunit containing GABAARs on PV interneurons, contribute to the stress-induced impairments in network and behavioral states.


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: 2024 ( Subtotal = $516,987 )
2024	2024	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Mental Health Research Grants	000	4	6/14/2024	NON-COMPETING CONTINUATION	$516,987
														Subtotal = $516,987

Issue Date FY: 2023 ( Subtotal = $465,624 )
2023	2023	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Mental Health Research Grants	000	3	6/13/2023	NON-COMPETING CONTINUATION	$465,624
														Subtotal = $465,624

Issue Date FY: 2022 ( Subtotal = $498,891 )
2022	2022	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Mental Health Research Grants	000	2	6/17/2022	NON-COMPETING CONTINUATION	$498,891
														Subtotal = $498,891

Issue Date FY: 2021 ( Subtotal = $525,149 )
2021	2021	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Mental Health Research Grants	000	1	9/20/2021	NEW	$525,149
														Subtotal = $525,149

Grand Total All Awards = $2,006,651

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Stress-induced impairments in endogenous neurosteroid signaling in the BLA negatively impacts network and behavioral states

Award Number: R01MH128235

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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