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Resilience, Dysregulation, and Rescue of Basal Ganglia Indirect Pathway Function in Progressive Parkinsonism

Award Number: R01NS041280
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 While the bradykinetic and akinetic symptoms of Parkinson’s disease (PD) are clearly linked to the degeneration of substantia nigra dopaminergic (SN DAergic) neurons1-3, the mechanisms that underlie the emergence and escalation of basal ganglia circuit and motor dysfunction remain poorly defined. Degeneration of SN DAergic neurons long precedes the expression of symptoms in PD4-6. At the point of diagnosis ~50-75% of nigrostriatal DAergic axons and ~30% of SN DAergic neurons no longer express DA cell markers or have been lost7,8, arguing for an extensive prodromal period, masked by compensatory mechanisms9-25. As degeneration proceeds, increasingly dysregulated activity24,26-41 and maladaptive plasticity13-24 within the indirect pathway may progressively degrade basal ganglia computation, leading to motor deficits17,18,26-28,36-40. This circuit pathophysiology has also been suggested as an additional source of bioenergetic stress in SN DAergic neurons that could accelerate their degeneration42-47. Although plausible, these concepts cannot be rigorously studied in acute toxin models that mimic the absence of DA in advanced PD but not the spatiotemporal pattern of DAergic neuron degeneration in patients48,49. To fill this gap, we propose to examine the emergence of parkinsonism and its impact of indirect pathway function in the MitoPark model of PD50. MitoPark mice are generated through genetic deletion of the nuclear encoded mitochondrial transcription factor TFAM in DAergic neurons, which causes mitochondrial dysfunction50-52, a consistent vulnerability of these cells in familial and sporadic forms of PD53-58. These mice recapitulate key aspects of PD, including: 1) progressive SN DAergic neuron degeneration and levodopa-sensitive motor deficits, but within a compressed, experimentally tractable time frame spanning 6- 7 months50,51,59; 2) relative susceptibility of SN DAergic neuron axon terminals in the dorsal striatum in the initial stages of parkinsonism50,52,59-61; 3) relative susceptibility of SN versus ventral tegmental area DAergic neurons50,51,59; 4) circuit plasticity and pathophysiology analogous to that in advanced PD and its models (pilot data). Using in vivo and ex vivo electrophysiological, optogenetic, chemogenetic, 2-photon imaging, electrochemical, immunohistochemical, and behavioral approaches, we propose 3 specific aims: 1) determine the mechanisms responsible for the retention of indirect pathway and motor function in prodromal MitoPark mice; 2) determine the mechanisms underlying progressive indirect pathway and motor dysfunction in symptomatic MitoPark mice; 3) determine whether motor dysfunction and degeneration of SN DAergic neurons can be rescued in symptomatic MitoPark mice by chemogenetically manipulating indirect pathway activity. Through the execution of this research, we will learn why aspects of basal ganglia indirect pathway function are initially resilient to but ultimately dysregulated by degeneration of SN DAergic neurons, and whether chemogenetic indirect pathway manipulation is an effective symptomatic and/or disease-modifying therapy for parkinsonism.


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: 2024 ( Subtotal = $548,208 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	23	4/8/2024	NON-COMPETING CONTINUATION	$548,208
														Subtotal = $548,208

Issue Date FY: 2023 ( Subtotal = $602,602 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	22	5/5/2023	NON-COMPETING CONTINUATION	$565,162
2023	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	11/9/2022	COMPETING CONTINUATION	$37,440
														Subtotal = $602,602

Issue Date FY: 2022 ( Subtotal = $607,102 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	21	4/22/2022	COMPETING CONTINUATION	$0
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	2/21/2022	COMPETING CONTINUATION	$607,102
														Subtotal = $607,102

Issue Date FY: 2010 ( Subtotal = $210,235 )
2010	2010	SHEFFIELD UNIVERSITY	WESTERN BANK	SHEFFIELD				GBR	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	5/7/2010	NON-COMPETING CONTINUATION	$210,235
2010	2010	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60201	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	13	9/29/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2010	2010	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	13	9/9/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$210,235
2010	2010	SHEFFIELD UNIVERSITY	WESTERN BANK	SHEFFIELD				GBR	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	12	9/10/2010	NON-COMPETING CONTINUATION	-$210,235
2010	2010	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60201	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	13	9/14/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $210,235

Issue Date FY: 2009 ( Subtotal = $212,358 )
2009	2009	SHEFFIELD UNIVERSITY	WESTERN BANK	SHEFFIELD				GBR	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	11	7/24/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$212,358
2009	2009	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	10	7/24/2009	NON-COMPETING CONTINUATION	-$296,908
2009	2009	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	4/28/2009	NON-COMPETING CONTINUATION	$296,908
														Subtotal = $212,358

Issue Date FY: 2008 ( Subtotal = $296,908 )
2008	2008	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60201	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	3/20/2008	NON-COMPETING CONTINUATION	$296,908
														Subtotal = $296,908

Issue Date FY: 2007 ( Subtotal = $296,908 )
2007	2007	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60201	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	4/20/2007	NON-COMPETING CONTINUATION	$296,908
														Subtotal = $296,908

Issue Date FY: 2006 ( Subtotal = $304,763 )
2006	2006	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60201	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	5/25/2006	COMPETING CONTINUATION	$304,763
														Subtotal = $304,763

Issue Date FY: 2005 ( Subtotal = $183,514 )
2005	2005	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60201	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	3/28/2005	NON-COMPETING CONTINUATION	$183,514
														Subtotal = $183,514

Issue Date FY: 2004 ( Subtotal = $183,595 )
2004	2004	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60201	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/17/2004	NON-COMPETING CONTINUATION	$183,595
														Subtotal = $183,595

Issue Date FY: 2003 ( Subtotal = $177,500 )
2003	2003	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3		NON-COMPETING CONTINUATION	$31,610
2003	2003	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60201	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/28/2003	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$145,890
														Subtotal = $177,500

Issue Date FY: 2002 ( Subtotal = $177,500 )
2002	2002	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Biological Basis Research in the Neurosciences	000	2	3/29/2002	NON-COMPETING CONTINUATION	$177,500
														Subtotal = $177,500

Issue Date FY: 2001 ( Subtotal = $238,000 )
2001	2001	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/29/2001	NEW	$238,000
														Subtotal = $238,000

Grand Total All Awards = $4,039,193

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Resilience, Dysregulation, and Rescue of Basal Ganglia Indirect Pathway Function in Progressive Parkinsonism

Award Number: R01NS041280

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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