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

Active Cooperative Agreement Awarded Last action

Award ID
U01AG076791
Recipient
Awarding agency
Obligated
$21,497,276

Award facts

Assistance listing
93.866 Aging Research
Completion date 90% complete
Place of performance
Irvine, CA 92697, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
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 ASS 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.

Transactions

Action Obligated Date
Amendment $0
Amendment $2,651,729
Amendment $2,651,729
Amendment $2,591,567
Amendment $0
Amendment $0
Amendment $2,650,917
Amendment $2,650,917
Amendment $2,644,061
Amendment $2,644,061
Original award $3,012,295
Show all 11

Subawards

Subrecipient Amount Awarded
Allen Institute The Allen Institute will perform the following work to support the construction of a comprehensive neuron type atlas in critical neuron types and circuits… $300,000
The University Of Texas Southwestern Medical Center In this grant, my research group will primarily perform the experiments in Aim2, namely using the YFV-17D anterograde transneuronal tracing systems to trace the… $300,000
Allen Institute The Allen Institute will perform the following work to support the construction of a comprehensive neuron type atlas in critical neuron types and circuits… $312,507
The University Of Texas Southwestern Medical Center In this grant, my research group will primarily perform the experiments in Aim2, namely using the YFV-17D anterograde transneuronal tracing systems to trace the… $295,631
The University Of Texas Southwestern Medical Center In this grant, my research group will primarily perform the experiments in Aim2, namely using the YFV-17D anterograde transneuronal tracing systems to trace the… $300,653
Allen Institute Lydia Ng, Ph.D., Co-Investigator, Data and Technology Investigator (15% effort = 1.8 calendar months years 15) will be responsible for the overall… $350,498

Quick answers

Who received award U01AG076791?

U01AG076791 was awarded to University Of California Irvine by National Institute on Aging (National Institutes of Health) on May 15, 2022.

How much is award U01AG076791 worth?

$21,497,276 has been obligated on U01AG076791.

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