Saturday, December 21, 2024 12/21/2024

Interrogating Maladaptive Serotonin Raphe-Striatal Plasticity in L-DOPA-Induced Dyskinesia

Award Number: R01NS122226
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT: L-DOPA remains the gold-standard treatment for Parkinson’s disease (PD). Unfortunately, within a decade of commencing L-DOPA, nearly 90% of PD patients develop intractable abnormal involuntary movements known as L- DOPA-induced dyskinesias (LID), severely impacting quality of life. Research implicates serotonin (5-HT) neurons as a source of LID as they can take up L-DOPA, convert it to dopamine (DA), and release DA as an unregulated “false neurotransmitter” leading to a dyskinesogenic phenotype. Although treatments aimed at alleviating LID have emerged, only a minority of patients benefit due to their cost, side effects and/or invasiveness. Moreover, we have yet to find a way to prevent LID development, in part due to major gaps in knowledge on how L-DOPA treatment instigates maladaptive 5-HT reorganization and aberrant striatal output. Our research team has recently collected preliminary data using novel approaches that provide exciting new insights into the mechanisms of 5-HT neuroplasticity that will enlighten both basic and clinical science. These convergent findings led us to postulate our Central Hypothesis that maladaptive 5-HT-raphe-striatal neurocircuit plasticity precipitates and maintains LID. The overarching goal for our multi-investigator team is to identify the mechanisms underlying the development of structural and functional maladaptation within the raphe-striatal circuit driving LID, which in turn could lead to novel, optimized targets for intervention. We will fill this knowledge gap through the pursuit of 3 independent, but inter-related Specific Aims. Our 3 Specific Aims will: 1) define the extent to which DA denervation and/or L-DOPA treatment results in anatomical and functional reorganization of the 5-HT raphe- striatal pathway in PD and experimental parkinsonism, 2) use projection-specific chemogenetic modulations to determine the impact of the 5-HT raphe-striatal activity on L-DOPA-induced anti-parkinsonian efficacy and dyskinesia, and 3) establish how regulating DA release from 5-HT raphe-striatal neurons prevents the development of LID and associated maladaptive neuronal changes. The proposed cross-species investigation will establish neuroplasticity within the 5-HT raphe-striatal circuit as a foremost factor in the development and expression of LID and in so doing, identify optimal treatment strategies to improve the quality of life for millions of current and prospective PD patients.


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: 2025 ( Subtotal = $545,253 )
2025	2025	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/20/2024	NON-COMPETING CONTINUATION	$545,253
														Subtotal = $545,253

Issue Date FY: 2024 ( Subtotal = $593,907 )
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/11/2024	NON-COMPETING CONTINUATION	$42,858
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/21/2023	NON-COMPETING CONTINUATION	$551,049
														Subtotal = $593,907

Issue Date FY: 2023 ( Subtotal = $651,165 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/21/2022	NON-COMPETING CONTINUATION	$586,050
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/30/2023	NON-COMPETING CONTINUATION	$65,115
														Subtotal = $651,165

Issue Date FY: 2022 ( Subtotal = $689,984 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/24/2021	NEW	$689,984
														Subtotal = $689,984

Grand Total All Awards = $2,480,309

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Interrogating Maladaptive Serotonin Raphe-Striatal Plasticity in L-DOPA-Induced Dyskinesia

Award Number: R01NS122226

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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