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Mechanisms regulating the formation and repair of neuronal activity-induced DNA breaks and their effects on learning behavior

Award Number: R01MH120132
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Mechanisms regulating the formation and repair of neuronal activity-induced DNA breaks and their effects on learning behavior - Project Summary Experiences have a remarkable influence on animal behavior. At the molecular level, the initiation of new gene transcription in neurons is crucial for the development of experience-driven adaptive behaviors. Moreover, defects in neuronal activity-dependent transcription programs manifest in cognitive deficits and neurological disorders. Understanding how neuronal activity-dependent transcription is orchestrated is therefore significant. A surprising new finding in this regard is that various paradigms of neuronal activity, including exposure to learning behaviors, induce the topoisomerase, topoisomerase IIb (Top2B), to generate DNA double strand breaks (DSBs) at specific loci within the genome of neurons. These activity-induced DSBs are enriched within the promoters of prominent early response genes (ERGs), such as Fos, Npas4, and Egr1, and DSBs facilitate the rapid transcription of these ERGs. These observations describe an intriguing mechanism that governs neuronal activity-dependent transcription. However, precisely how the formation and repair of activity-induced DSBs is controlled, how DSBs stimulate rapid ERG induction, and how defective DSB repair affects activity- dependent transcription and learning behaviors remain obscure. These topics will be the focus of this project. Preliminary data for this project indicate that neuronal stimulation triggers rapid Top2B dephosphorylation and modifies its DNA cleavage activity. Employing high-resolution imaging and biochemical methods, the proposed experiments will unveil the activity-dependent signaling mechanisms that modulate Top2B to generate DSBs at specific genomic loci. A defining feature of genome-wide activity-induced DSBs is that they form at sites co- occupied by CTCF. Chromatin looping by CTCF creates topological barriers to gene enhancer-promoter contacts, and in preliminary studies, knockdown of CTCF elevated ERG levels even in the absence of neuronal stimulation. These results suggest that CTCF constrains ERG expression, and that activity-induced DSBs could be a mechanism to rapidly override CTCF-enforced topological constraints at ERGs. To test this hypothesis, chromosome conformation capture (3C) will be utilized to reveal chromatin interactions at sites of activity-induced DSBs and clarify how DSBs affect these interactions. Additionally, the roles of CTCF in regulating promoter- enhancer coupling at ERGs will be explored following CRISPR-based mutation of specific CTCF sites. Neuronal activity-induced DSBs are repaired through nonhomologous end joining (NHEJ). To assess the role of DSB repair in vivo, previously utilized ChIP-seq strategies were applied to map DSBs formed in response to physiological learning behaviors in the mouse hippocampus. Using this information and by employing similar methods in an NHEJ-deficient mouse model, the proposed experiments will identify genome-wide sites that are vulnerable to DSB accrual in the hippocampus, and study how defective DSB repair affects activity-dependent transcription. Finally, NHEJ-deficient mice will be subjected to appropriate behavioral tasks to test how the repair of activity-induced DSBs impacts learning and memory.


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: 2023 ( Subtotal = $401,150 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	000	5	3/15/2023	NON-COMPETING CONTINUATION	$401,150
														Subtotal = $401,150

Issue Date FY: 2022 ( Subtotal = $401,150 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	000	4	3/23/2022	NON-COMPETING CONTINUATION	$401,150
														Subtotal = $401,150

Issue Date FY: 2021 ( Subtotal = $401,150 )
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	000	3	3/23/2021	NON-COMPETING CONTINUATION	$401,150
														Subtotal = $401,150

Issue Date FY: 2020 ( Subtotal = $401,150 )
2020	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	000	2	3/31/2020	NON-COMPETING CONTINUATION	$401,150
														Subtotal = $401,150

Issue Date FY: 2019 ( Subtotal = $401,150 )
2019	2019	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	000	1	5/22/2019	NEW	$401,150
														Subtotal = $401,150

Grand Total All Awards = $2,005,750

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Mechanisms regulating the formation and repair of neuronal activity-induced DNA breaks and their effects on learning behavior

Award Number: R01MH120132

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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