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Epigenetic Mechanisms of Chronic Stress Action

Award Number: R01MH129306
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/13/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Epigenetic Mechanisms of Chronic Stress Action - PROJECT SUMMARY: This is a revised version of a new R01 grant that characterizes stable epigenetic changes that are induced in mouse limbic brain regions in response to early life stress (ELS) which then increase an individual's susceptibility to subsequent stress for a lifetime. This work has been supported over the past ten years by an NIMH Conte Center, however, that Center has now “sun-setted”—it cannot be renewed—hence, this new proposal to continue this original line of research. Our innovative hypothesis is that ELS induces stable “chromatin scars” that drive long-lived changes in gene expression, which then mediate downstream changes in cell and circuit function and ultimately behavioral responses to chronic stress in adulthood. We concentrate on nucleus accumbens (NAc) based on its central role in brain reward and motivation and on empirical findings of its central role in controlling stress susceptibility. We utilize open-ended, unbiased proteomic and next- generation sequencing approaches to first identify the most robust and significant putative chromatin scars in NAc in a cell-type-specific manner and to then characterize those mechanisms at the molecular, cellular, and behavioral levels. Importantly, we investigate only those mechanisms that are validated in postmortem NAc of depressed humans. One major focus is H3K79me2 (dimethylation of Lys79 of histone H3), the induction of which is the most significant histone modification caused by ELS in NAc of both male and female mice. The methyltransferase (DOT1L) and demethylase (KDM2B) that control H3K79me2 are both induced in NAc by ELS, effects specific to D2-type medium spiny neurons (MSNs). Bidirectional viral-mediated manipulation of DOT1L or KDM2B selectively in D2 NAc MSNs of male and female mice establishes the role played by these enzymes in mediating the ability of ELS to increase stress susceptibility based on rapid behavioral screening assays. We will now extend measures of stress susceptibility to numerous, more sophisticated behavioral procedures with greater translational potential, and test the ability of a DOT1L inhibitor, now in clinical trials for certain cancers, to reverse ELS-induced stress susceptibility upon systemic administration, further promoting the translational potential of the proposed research. As well, we have shown by RNAseq that DOT1L overexpression in D2 MSNs mimics a large portion of gene expression changes induced by ELS in this cell type, while DOT1L knockdown blocks ELS action. We will now map H3K79me2 enrichment genome-wide in D2 MSNs by CUT&RUNseq to identify networks of genes whose altered expression by ELS is mediated by this histone mark. We will also generate more complete open-ended proteomic and transcriptomic datasets and characterize additional putative chromatin scars induced in NAc by ELS. Substantial preliminary data, for example, implicate H3K27me1 as a prominent chromatin scare that predominates in D1 MSNs of male mice only. Together, this work will characterize novel mechanisms that drive a persisting state of enhanced stress susceptibility and offer insight into new ways of reversing such susceptibility in adulthood.


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 = $674,536 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	4	12/9/2025	NON-COMPETING CONTINUATION	$674,536
														Subtotal = $674,536

Issue Date FY: 2025 ( Subtotal = $674,536 )
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	3	11/22/2024	NON-COMPETING CONTINUATION	$573,354
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	001	3	9/18/2025	NON-COMPETING CONTINUATION	$101,182
														Subtotal = $674,536

Issue Date FY: 2024 ( Subtotal = $674,536 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	2	11/15/2023	NON-COMPETING CONTINUATION	$607,082
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	001	2	8/15/2024	NON-COMPETING CONTINUATION	$67,454
														Subtotal = $674,536

Issue Date FY: 2023 ( Subtotal = $674,536 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	1	12/13/2022	NEW	$674,536
														Subtotal = $674,536

Grand Total All Awards = $2,698,144

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Epigenetic Mechanisms of Chronic Stress Action

Award Number: R01MH129306

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/13/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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