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Electrophysiological Evaluation of Brain Regions Vulnerable to Alzheimers Disease

Award Number: R01AG064066
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Electrophysiological Evaluation of Brain Regions Vulnerable to Alzheimers Disease - The entorhinal cortex (EC) is long known to be the region affected first in Alzheimer’s disease (AD) with symptoms such as disorientation, confusion and inability to navigate appearing early in life. But more recently, a region in the brainstem- locus coeruleus (LC) was found to have tau accumulation in young healthy adults, making it the first region in the brain with AD pathology. The LC is known to be important for arousal and controls the sleep/wake switch. The neurons of LC project to several regions including EC and hippocampus which are known to be important for spatial memory. Unsurprisingly, one of the earliest symptoms of AD is spatial difficulties and it is possible that early pathology in LC affects sleep leading to spatial memory deficits. With both LC and EC important for memory, we aim to identify which of them is more vulnerable to tau and Aβ pathology. To explore this possibility, we will first inject LC and EC regions of wildtype mouse with pathological tau derived from human AD brains to make them dysfunctional, and evaluate their neuronal function. We will also assess sleep and test memory performance in relevant behavior tasks. To understand how aβ affects tau pathology, we will inject human tau in the APP Knock-In mice which has physiological amounts of APP expressed in them. We will determine if Aβ together with tau worsens the neuronal function of LC and EC neurons and it sleep and memory is impaired further. We will use multi-region silicon probes to simultaneously record activity from LC or medial EC and hippocampal neurons. The MEC and hippocampal neurons are well characterized with properties that can be easily measured using spatial navigation tasks. We will make use of virtual reality head-fixed setup for the animals to navigate in, and allowing us to quickly test animal’s memory in any context and environment. The animals will be tested for object-location memory and context-dependent memory in virtual environment. We will use machine learning algorithms to decode animal’s position in the LC, MEC and HPC neural data and determine if it is affected by tau or Aβ or both. We will also assess sleep parameters and correlate with memory. We hypothesize that tau in LC and EC will make its neurons dysfunctional and directly affect sleep and memory, and this in concert with Aβ will exacerbate neuronal dysfunction leading to increased sleep problems and spatial memory impairment as seen in early AD. With this we aim to identify electrophysiological biomarker of neuronal dysfunction before the onset of behavioral troubles. We will test if increasing the neuronal firing in hypoactive neurons and reducing the firing in hyperactive neurons will restore downstream neuronal dysfunction and reverse sleep problems and cognitive impairment. The proposal brings together diverse fields (neuroscience, pathology and computational neuroscience) applying large-scale recording techniques simultaneously across multiple brain regions to develop analytical and predictive tests to interrogate function in vulnerable brain regions that are dysfunctional in AD.


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 = $0 )
2025	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	002	5	7/10/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	001	5	7/10/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	000	5	7/10/2025	NON-COMPETING CONTINUATION	-$346,588
2025	2024	THE WINIFRED MASTERSON BURKE MEDICAL RESEARCH INSTITUTE, INC	785 MAMARONECK AVE	WHITE PLAINS	NY	10605	WESTCHESTER	USA	Aging Research	003	6	7/11/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$346,588
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $1,352,116 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	001	5	5/8/2024	SUPPLEMENT FOR EXPANSION	$393,785
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	000	5	4/29/2024	NON-COMPETING CONTINUATION	$629,446
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	002	5	8/27/2024	SUPPLEMENT FOR EXPANSION	$328,885
														Subtotal = $1,352,116

Issue Date FY: 2023 ( Subtotal = $629,446 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	000	4	3/23/2023	NON-COMPETING CONTINUATION	$629,446
														Subtotal = $629,446

Issue Date FY: 2022 ( Subtotal = $951,713 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	001	3	8/15/2022	SUPPLEMENT FOR EXPANSION	$326,368
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	000	3	4/29/2022	NON-COMPETING CONTINUATION	$625,345
														Subtotal = $951,713

Issue Date FY: 2021 ( Subtotal = $622,966 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	000	2	4/5/2021	NON-COMPETING CONTINUATION	$622,966
														Subtotal = $622,966

Issue Date FY: 2020 ( Subtotal = $645,926 )
2020	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	000	1	4/9/2020	NEW	$645,926
														Subtotal = $645,926

Grand Total All Awards = $4,202,167

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Electrophysiological Evaluation of Brain Regions Vulnerable to Alzheimers Disease

Award Number: R01AG064066

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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