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Sex- and hormone-dependent differences in memory vulnerability to acute traumatic stress

Award Number: R01MH139931
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Sex- and hormone-dependent differences in memory vulnerability to acute traumatic stress - Project Summary/Abstract This proposal focuses on the fundamental sex differences in the vulnerability to acute traumatic stress (ATS) and the role of the sex hormone estrogen, and signaling via sex-specific hippocampal receptors, in the enduring memory problems that follow ATS. It is now recognized that acute traumatic events (e.g., mass shooting, earthquakes) may provoke enduring disturbances of hippocampus-dependent memory, and that these problems are more common in women. We leverage robust preliminary data to probe why males, and females at different phases of the estrous cycle, differ in their vulnerabilities to ATS, what these differences are and the mechanisms that drive them. This information will provide important targets for promoting resilience to ATS. We find ATS causes memory disturbances in male (♂) and proestrous female (♀) but not estrous ♀ mice, and the deficits are long-lasting only in proestrous ♀. ♂ and ♀ differ in numerous measures, including in levels of hippocampal estrogens: ♂ and proestrous ♀, both vulnerable to ATS, have high levels of hippocampal estrogen compared with estrous ♀. Estrogen acts via several receptors (ERs) and its enduring effects are thought to result from interactions of ERα or Erβ with the chromatin. Leveraging robust preliminary data we will (1) Test whether ATS-induced memory disturbances require ERα in ♂ and, in contrast, Erβ in ♀ (Aim 1). (2) establish if sex- and Estrogen-level dependent vulnerability to ATS in ♂ and proestrous ♀ mice is a result of sex and hormone-dependent hippocampal chromatin states, which elicit distinct transcriptional programs upon exposure to ATS (Aim 2). (3) use focal conditional ER deletions to test whether the unique vulnerability of proestrous ♀ to persistent ATS-induced memory disturbances results from activation of distinct transcriptional targets of ERβ in ♀ hippocampus. Together, the expected discoveries will illuminate the mechanisms for the fundamental sex differences in vulnerability to enduring trauma-induced memory disturbances and will offer targets for mitigation.


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 = $802,256 )
2026	2026	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Mental Health Research Grants	000	1	7/30/2026	NEW	$802,256
														Subtotal = $802,256

Grand Total All Awards = $802,256

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Sex- and hormone-dependent differences in memory vulnerability to acute traumatic stress

Award Number: R01MH139931

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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