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Cell-type-specific neural circuit connectomes in the mouse models of aging and Alzheimer's disease

Award Number: U01AG076791
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Cell-type-specific neural circuit connectomes in the mouse models of aging and Alzheimer's disease - Project Summary Alzheimer’s disease (AD) is the most common cause of progressive dementia in older adults, but there is no cure for this debilitating condition. We hypothesize that aging and AD-related pathologies cause maladaptive changes within hippocampal formation circuits that serve as connectome hubs for large numbers of critical brain regions, ultimately leading to age- and AD-related cognitive deficits. In response to RFA-AG-22-008, we have assembled a strong multi-investigator team across multiple institutions with complementary expertise in neural circuit mapping, next-generation AD mouse model development, single-cell transcriptomics and epigenomics analysis, and mouse brain common coordinate framework / atlas development. We will leverage the exceptional resources offered by the UCI Center for Neural Circuit Mapping, the MODEL-AD Consortium and the Allen Institute for Brain Science. We propose to perform large-scale, cell-type-specific mapping of hippocampal formation circuits to generate cellular resolution connectome data that combines molecular and anatomical annotations. To capture a more accurate composite of human AD features, we will use three complementary AD mouse models including two next-generation AD mouse models. These include 1) the 5xFAD mouse model with familial mutations, 2) the hAß-KI mouse that expresses human wild-type Aβ sequence from the endogenous mouse App locus to model late-onset AD features, and 3) Trem2 R47H knock-in mice that model the increased risk of the R47H coding variant for late onset AD. We will comprehensively map and characterize hippocampal formation brain circuits, including CA1, the subiculum (SUB) and the entorhinal cortex (EC) that show earliest neurodegeneration across AD mouse models and in human patients. These sub-circuits serve as hubs for neural processing from many other cortical and sub-cortical brain regions. We will use genetically modified transsynaptic neurotropic viruses developed by our team to map brain-wide anterograde and retrograde neural networks. The brain connectomes generated from viral tracing experiments will be enhanced with spatially resolved, single-cell transcriptomics-based molecular annotation using MERFISH (multiplexed error-robust fluorescence in situ hybridization). We will identify molecular candidates that confer vulnerability versus disease resistance as we superimpose spatial transcriptomic data on AD-modulated circuit connectomes. The entire data set will be annotated using the Allen Mouse Brain Common Coordinate Framework to facilitate resource and data sharing. Our work will improve our understanding of brain circuits susceptible to aging and AD towards developing better early diagnostic tools and new treatment strategies for 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 = $2,591,567 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Aging Research	001	4	6/20/2025	NON-COMPETING CONTINUATION	$2,591,567
2025	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Aging Research	000	3	4/29/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,591,567

Issue Date FY: 2024 ( Subtotal = $2,650,917 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Aging Research	000	3	5/21/2024	NON-COMPETING CONTINUATION	$2,650,917
														Subtotal = $2,650,917

Issue Date FY: 2023 ( Subtotal = $2,644,061 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Aging Research	000	2	5/24/2023	NON-COMPETING CONTINUATION	$2,644,061
														Subtotal = $2,644,061

Issue Date FY: 2022 ( Subtotal = $3,012,295 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Aging Research	000	1	5/11/2022	NEW	$3,012,295
														Subtotal = $3,012,295

Grand Total All Awards = $10,898,840

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Cell-type-specific neural circuit connectomes in the mouse models of aging and Alzheimer's disease

Award Number: U01AG076791

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 05/15/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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