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Cortical Alpha-Synuclein in Dementia

Award Number: R01NS129711
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: 02/15/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Cortical Alpha-Synuclein in Dementia - Abstract Lewy-Body dementias, including Parkinson’s disease Dementia and Dementia with Lewy Bodies, are devastating, multi-system diseases and a major cause of dementia worldwide. Patients have characteristic symptoms that suggest dysfunction of the frontal-network, including difficulty with planning, fluctuating attention and impaired flexible learning. The pathology of patients with dementia includes widespread aggregates of the protein alpha-synuclein (𝛼-syn) in the frontal cortex and other extra-nigral regions. Despite this association, the role of 𝛼-syn pathology beyond the dopaminergic system remains unclear. There is a critical need to understand how -syn affects network function to develop treatments for Lewy Body dementias. Our long-term goal is to develop treatments for Lewy Body Dementia by targeting circuit-level dysfunction. Our overall hypothesis is that local -syn aggregation in the cortex disrupts prefrontal circuits, leading to executive dysfunction. Testing this overall hypothesis requires determining the regional effect of 𝛼-syn on cellular activity and neuronal plasticity in isolation from deficits secondary to other major neurotransmitter systems that project to cortex. To accomplish this goal, this proposal uses viral overexpression of -syn localized to the prefrontal cortex. By imaging the activity of individual neurons and the plasticity of dendritic spines, we can learn how cortical cells respond to this enigmatic, disease-associated protein. We propose to use 2-photon transcranial microscopy to determine how neuronal activity (Aim 1) and synaptic plasticity (Aim 2) respond to regional overexpression of -syn over the course of aging. In Aim 3, we will use a rule-learning, reversal and rule- shifting tasks adapted for head-fixed applications to determine how prefrontal-dependent learning and flexibility respond to cortical -syn. In parallel, we will correlate cognitive performance with anatomical plasticity and neuronal activity. Findings from this proposed research will provide targets for future studies to restore cortical function and treat symptoms through circuit-level manipulation. In addition, by comparing outcomes across the three aims, we will be able to connect structural plasticity, neuronal activity and frontal-cognitive behavior to provide broad insights into the prefrontal cortex.


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 = $578,278 )
2026	2026	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/23/2026	NON-COMPETING CONTINUATION	$578,278
														Subtotal = $578,278

Issue Date FY: 2025 ( Subtotal = $506,456 )
2025	2025	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/17/2025	NON-COMPETING CONTINUATION	$506,456
														Subtotal = $506,456

Issue Date FY: 2024 ( Subtotal = $586,246 )
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	5/7/2024	NON-COMPETING CONTINUATION	$58,624
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/1/2024	NON-COMPETING CONTINUATION	$527,622
														Subtotal = $586,246

Issue Date FY: 2023 ( Subtotal = $590,765 )
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/13/2023	NEW	$590,765
														Subtotal = $590,765

Grand Total All Awards = $2,261,745

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Cortical Alpha-Synuclein in Dementia

Award Number: R01NS129711

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: 02/15/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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