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Epigenetic entrainment of striatal engram-like neurons across the time course of LID development

Award Number: R01NS141959
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/18/2025
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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Epigenetic entrainment of striatal engram-like neurons across the time course of LID development - Project Summary/Abstract Levodopa (L-DOPA)-induced dyskinesia (LID) is a debilitating motor side effect of long-term use of Parkinson disease (PD) medication. Proportionally higher output of the basal ganglia direct pathway compared to the indirect pathway, resulting in hyperkinetic abnormal involuntary movements, is a circuit-level hallmark of LID. Once developed, LID is difficult to mitigate and grows in severity with each successive dose. Our work indicates that a subpopulation of D1 receptor-expressing medium spiny output neurons (D1-MSNs) are transcriptionally altered by the development and stable expression of LID in animal models. This transcriptional profile is reminiscent of that of hippocampal engram cells upon recall of an entrained stimulus. In addition, manipulation of these specific D1-MSNs has been shown to bidirectionally mediate LID expression. THese characteristics suggest that a specific subset of D1-MSNs may serve as engram cells for LID. However, the evolution of cellular and molecular changes that uniquely occur in these engram-like D1-MSNs in response to L- DOPA treatment across the time course of LID development have not been established to date. We have previously observed that epigenetic processes play a key role in the development of LID, though these processes have never been investigated in a cell type-specific manner. The critical next steps are identifying the unique transcriptional, physical, and physiological characteristics of L-DOPA-responsive D1-MSNs upon both acute and chronic L-DOPA exposure and determining the epigenetic mechanisms that may spur this process. The overall goal of the work proposed in this application is to utilize genetic approaches to establish an engram-like population of D1-MSNs utilizing a well-established preclinical model of LID in combination with a novel mouse model, allowing us to specifically target the cells which underlie LID. We will utilize a transcription-to-behavior approach to investigate cellular connectivity at the level of chromatin remodeling, transcription, cellular morphology and physiology, and behavior. Our hypothesis is that LID development is associated with remodeling of L-DOPA-responsive D1-MSNs (Aim 1), mediated by a shift in chromatin availability and corresponding transcriptional networks (Aim 2), that underlies the transition from the acute to chronic LID state. To date, there are no available therapies to halt LID development. The results from this research will indicate targets for LID- mitigating therapies to prolong the usefulness of L-DOPA, the gold standard of PD therapy for over 50 years.


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 = $347,084 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/19/2026	NON-COMPETING CONTINUATION	$347,084
														Subtotal = $347,084

Issue Date FY: 2025 ( Subtotal = $350,036 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/18/2025	NEW	$350,036
														Subtotal = $350,036

Grand Total All Awards = $697,120

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Epigenetic entrainment of striatal engram-like neurons across the time course of LID development

Award Number: R01NS141959

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/18/2025

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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