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The impact of stress-induced DNA breaks on chromatin structure, gene activity, and neuron function

Award Number: R01MH130399
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/05/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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The impact of stress-induced DNA breaks on chromatin structure, gene activity, and neuron function - PROJECT SUMMARY: Chronic stress causes molecular adaptations and structural remodeling of neurons within corticolimbic brain areas, including the prefrontal cortex (PFC) and hippocampus (HPC). This is important because the PFC and HPC are integrated in brain circuits that regulate complex behaviors and cognition. Preclinical and clinical studies indicate that synapse loss and reduced connectivity in the PFC and HPC contribute to behavioral and cognitive symptoms in several psychiatric disorders, such as post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). While previous reports have identified candidate genes and pathways, the molecular mechanisms that cause lasting stress-induced changes in gene activity patterns and structural remodeling in neurons remain unknown. In preliminary studies, exposing mice to chronic unpredictable stress (CUS) triggered the formation of DNA double strand breaks (DSBs) within stress-activated neurons in the PFC. Administration of the GABAA receptor agonist, diazepam, diminished both the number of stress-activated neurons and the levels of DSBs, suggesting that stress-induced DSBs are generated by activity-dependent mechanisms. Accumulating evidence indicates that neuronal activity induces the topoisomerase, topoisomerase II (Top2B) to generate DSBs and promote the transcription of an important subset of genes that mediate experience-driven synaptic changes, including early response genes (ERGs), such as Fos, Npas4, Egr1, and Arc. These results suggest that experience-dependent DSB formation could regulate stress-induced gene activity patterns and subsequent remodeling of neurons. Yet the sites of stress-induced DSBs in PFC and HPC neurons have not been mapped and how DSBs affect stress-related gene activity patterns has not been explored. Interestingly, preliminary studies revealed that recurrent and ectopic induction of Top2B-mediated DSBs in cultured neurons is sufficient to recapitulate chronic stress-induced gene expression profiles for various neuronal activity-responsive genes, including ERGs and Bdnf. Preliminary chromosome conformation capture (3C)-based experiments (3C and 4C-seq) further suggest that DSBs regulate gene activity patterns by altering chromatin topology. These observations have led to the hypothesis that recurrent DSB formation during chronic stress alters chromatin architecture at associated genes, which in turn, stabilizes stress-related gene activity patterns that trigger neuronal remodeling and synapse loss in the PFC and HPC. To test this hypothesis, the proposed studies will map genome-wide sites of CUS-induced DSBs and utilize conditional deletion of Top2b to define how DSBs affect stress-dependent changes in transcription and neuronal structure and function in PFC and HPC projection neurons. Additionally, 3C-based methods (HiChIP) will be employed to assess how DSBs affect stress-dependent changes to chromatin architecture. Together, these efforts will provide novel insights into the mechanisms driving stress-induced neuronal adaptations, and may uncover new therapeutic strategies for psychiatric disorders, such as PTSD and MDD.


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 = $789,126 )
2026	2026	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Mental Health Research Grants	000	4	12/23/2025	NON-COMPETING CONTINUATION	$789,126
														Subtotal = $789,126

Issue Date FY: 2025 ( Subtotal = $789,126 )
2025	2025	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Mental Health Research Grants	001	3	9/19/2025	NON-COMPETING CONTINUATION	$118,368
2025	2025	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Mental Health Research Grants	000	3	12/20/2024	NON-COMPETING CONTINUATION	$670,758
														Subtotal = $789,126

Issue Date FY: 2024 ( Subtotal = $789,126 )
2024	2024	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Mental Health Research Grants	001	2	7/30/2024	NON-COMPETING CONTINUATION	$78,913
2024	2024	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Mental Health Research Grants	000	2	1/4/2024	NON-COMPETING CONTINUATION	$710,213
														Subtotal = $789,126

Issue Date FY: 2023 ( Subtotal = $799,766 )
2023	2023	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Mental Health Research Grants	000	1	4/5/2023	NEW	$799,766
														Subtotal = $799,766

Grand Total All Awards = $3,167,144

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The impact of stress-induced DNA breaks on chromatin structure, gene activity, and neuron function

Award Number: R01MH130399

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/05/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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