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Circadian dysfunction and neurodegenerative disease

Award Number: R01NS082413
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: 03/15/2013
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Circadian dysfunction and neurodegenerative disease - Cognitive function varies greatly throughout the day and night due to an intrinsic molecular clock localized hippocampal cells. In our last project period, we demonstrated that day-night differences in neuronal excitability, long-term potentiation, and memory are regulated by the circadian clock-controlled mechanisms such as kinase activation and ion channel regulation, and that excitability of central clock neurons in the suprachiasmatic nucleus is dysregulated in a mouse model of Alzheimer's disease. However, little is known about the underlying regulation of neuronal excitability by the molecular clock in hippocampus during both physiological and pathological states. Further investigation of the circadian regulation of passive and active membrane properties in excitatory pyramidal cells as well as inhibitory, parvalbumin-expressing interneurons is required to discover novel chronotherapeutic strategies for early intervention of hyper-excitability, cognitive dysfunction, and pathogenesis in Alzheimer's disease. In this competitive renewal request, we will test the novel hypotheses that the cell-autonomous molecular clock drives day-night differences in active and passive membrane properties of pyramidal neurons and PV+ interneurons at opposite times of the day. We predict that these anti-phase relationships promote day-night differences in excitatory-inhibitory balance, synaptic plasticity, and memory, and that disruption of circadian regulation of hippocampal membrane properties could contribute to hyper-excitability of the network and hasten cognitive impairment and pathogenesis. Using conditional transgenic mice, slice electrophysiology, bioluminescence imaging, chemogenetics, and behavioral assays, we will test whether rhythmic transcription and excitability of CA1 pyramidal neurons (Aim 1) and parvalbumin-expressing interneurons (Aim 2) are driven by the molecular clock and necessary for day-night differences in memory and plasticity. Aim 3 will use chemogenetics to determine whether restoration of day- night differences in the depolarization state and intrinsic excitability of CA1 pyramidal neurons is protective against Alzheimer's disease pathology and memory impairment. Altogether, these experiments have the potential to reveal an entirely novel mechanism by which the hippocampal clock regulates day-night differences in plasticity and cognition and could give critical insight into Alzheimer's disease hyperexcitability, memory impairment, and pathogenesis.


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 = -$17,416 )
2024	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	7/17/2024	NON-COMPETING CONTINUATION	-$17,416
														Subtotal = -$17,416

Issue Date FY: 2022 ( Subtotal = $535,369 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	3/2/2022	NON-COMPETING CONTINUATION	$481,831
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	10	3/24/2022	NON-COMPETING CONTINUATION	$53,538
														Subtotal = $535,369

Issue Date FY: 2021 ( Subtotal = $593,432 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	3/17/2021	NON-COMPETING CONTINUATION	$593,432
														Subtotal = $593,432

Issue Date FY: 2020 ( Subtotal = $590,289 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	3/13/2020	NON-COMPETING CONTINUATION	$590,289
														Subtotal = $590,289

Issue Date FY: 2019 ( Subtotal = $602,414 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	7	3/4/2019	NON-COMPETING CONTINUATION	$0
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	2/21/2019	NON-COMPETING CONTINUATION	$602,414
2019	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	12/28/2018	COMPETING CONTINUATION	-$9,308
2019	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/28/2018	NON-COMPETING CONTINUATION	$9,308
														Subtotal = $602,414

Issue Date FY: 2018 ( Subtotal = $640,247 )
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	5/14/2018	COMPETING CONTINUATION	$0
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	006	6	9/17/2018	COMPETING CONTINUATION	$9,217
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	3/15/2018	COMPETING CONTINUATION	$640,247
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	6	6/19/2018	COMPETING CONTINUATION	$91
2018	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/15/2018	NON-COMPETING CONTINUATION	$0
2018	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	5	9/17/2018	NON-COMPETING CONTINUATION	-$9,217
2018	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	5	6/19/2018	NON-COMPETING CONTINUATION	-$91
														Subtotal = $640,247

Issue Date FY: 2017 ( Subtotal = $284,518 )
2017	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/26/2017	NON-COMPETING CONTINUATION	$256,065
2017	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	7/3/2017	NON-COMPETING CONTINUATION	$28,453
2017	2016	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	5/4/2017	SUPPLEMENT FOR EXPANSION	$0
2017	2016	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	7/12/2017	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $284,518

Issue Date FY: 2016 ( Subtotal = $389,125 )
2016	2016	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	8/1/2016	SUPPLEMENT FOR EXPANSION	$100,000
2016	2016	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/15/2016	EXTENSION WITH OR WITHOUT FUNDS	$289,125
														Subtotal = $389,125

Issue Date FY: 2015 ( Subtotal = $292,978 )
2015	2015	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/23/2015	NON-COMPETING CONTINUATION	$292,978
														Subtotal = $292,978

Issue Date FY: 2014 ( Subtotal = $294,655 )
2014	2014	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/27/2014	NON-COMPETING CONTINUATION	$267,869
2014	2014	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/26/2014	NON-COMPETING CONTINUATION	$26,786
														Subtotal = $294,655

Issue Date FY: 2013 ( Subtotal = $331,926 )
2013	2013	UNIVERSITY OF ALABAMA AT BIRMINGHAM	UAB STATION, CBB 990	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/4/2013	NEW	$331,926
														Subtotal = $331,926

Grand Total All Awards = $4,537,537

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Circadian dysfunction and neurodegenerative disease

Award Number: R01NS082413

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: 03/15/2013

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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