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Optogenetic dissection of cellular and circuit mechanisms of network dysfunction and amyloid deposition in mouse models of Alzheimer's disease in vivo

Award Number: RF1AG062234
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Optogenetic dissection of cellular and circuit mechanisms of network dysfunction and amyloid deposition in mouse models of Alzheimer's disease in vivo - SUMMARY A contributing factor to the failure of clinical trials has been the translational limitations of transgenic (TG) overexpression models in which physiological and endogenously-regulated pathogenic interactions are not achieved. In addition, standard behavioral tests may lack sensitivity to identify robust and reproducible behavioral deficits in newly develop knock-in (KI) models. To address or mitigate these limitations, we propose to study the next generation of newly developed KI mouse models of AD without transgene overexpression using the latest machine learning approaches for behavioral phenotyping and chronic wireless EEG/EMG recordings. Specifically, we propose to study knock-in (KI) mice that express humanized Ab under the control of the mouse App locus with or without FAD mutations, including AppAβ/Aβ, AppNL-F/NL-F, and AppNL-G-F/NL-G-F mice using state-of- the-art chronic in vivo electrophysiological recordings and machine learning approaches for behavioral phenotyping. The parent grant heavily focuses on the J20 TG model of AD, because App-KI mice show no prominent cognitive deficits in standard behavioral tests, including the Morris water maze test,10 and because it is unknown if App-KI have robust network abnormalities described in J20 and other TG-APP mouse models and AD patients, including altered gamma oscillations, theta-gamma coupling, epileptiform spikes and seizures.1,3,9,11- 15. The proposed experiments and genotypes expand the focus of our parent grant and will develop tools and procedures that will be directly used by the parent grant to improve behavioral and brain network characterization of TG and KI models of AD. We propose the following aims: Aim 1. Develop and apply machine learning approaches to identify behavioral alterations in late-onset AppAβ/Aβ and early-onset AppNL-F/NL-F and AppNL-G-F/NL- G-F AD mice. Aim 2. Determine electrophysiological phenotypes by chronic wireless EEG/EMG recordings during aging and disease progression in late-onset AppAβ/Aβ and early-onset AppNL-F/NL-F and AppNL-G-F/NL-G-F AD mice. Aim 3. Determine relationships between behavioral alterations and neuronal network dysfunction in late-onset AppAβ/Aβ and early-onset AppNL-F/NL-F and AppNL-G-F/NL-G-F AD mice. In addition, this diversity supplement grant will significantly enhance the research potential of the candidate and further her ability to pursue a research career. The candidate will gain valuable relevant experience with electrophysiological data analysis and mouse behavioral assays during the funding period. These novel in vivo approaches and technical skills will help the candidate to address unexplored questions of AD pathogenesis, thereby creating a technical and conceptual path towards independence. The proposed supplement will provide the conceptual and technological foundation needed to support the production of preliminary data for the candidate’s future F32 grant application.


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 = $0 )
2024	2021	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	000	1	2/20/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	001	1	10/25/2022	SUPPLEMENT FOR EXPANSION	$0
2023	2018	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	000	1	10/25/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $213,379 )
2021	2021	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	000	1	6/29/2021	SUPPLEMENT FOR EXPANSION	$213,379
														Subtotal = $213,379

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	000	1	12/4/2019	NEW	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $3,540,000 )
2018	2018	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	000	1	9/19/2018	NEW	$708,000
2018	2018	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	001	1	9/21/2018	NEW	$2,832,000
														Subtotal = $3,540,000

Grand Total All Awards = $3,753,379

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Optogenetic dissection of cellular and circuit mechanisms of network dysfunction and amyloid deposition in mouse models of Alzheimer's disease in vivo

Award Number: RF1AG062234

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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