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Microglial control of thalamocortical circuits in Alzheimer's disease

Award Number: K99NS146256
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 02/15/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Microglial control of thalamocortical circuits in Alzheimer's disease - PROJECT SUMMARY / ABSTRACT Alzheimer’s disease (AD) is a neurodegenerative disorder affecting nearly five million Americans. Treatments are limited treatments and provide only modest benefits. Genome-wide association studies have identified TREM2 as one of the top AD risk genes. In particular, the TREM2R47H variant increases disease risk four-fold. How TREM2R47H affects risk for AD is currently unknown, but our preliminary observations in a mouse model indicate that it triggers hypersynchrony of thalamocortical circuits. TREM2 is expressed principally in microglia, and emerging evidence links microglial dysfunction and disrupted synapse remodeling to AD pathogenesis. My central hypothesis is that TREM2R47H causes thalamocortical hypersynchrony in AD mice by disrupting electrical properties of microglia that are essential for synaptic remodeling. To address this hypothesis, I will use a combination of advanced techniques spanning electrophysiology in human iPSC-derived cultures, brain slices and behaving mice, transcriptomics, and behavioral analysis. I will determine how TREM2R47H affects microglial electrical properties and transcriptional states by integrating electrophysiology with single-cell transcriptomics using Patch-seq and transcriptomic analyses in mouse and human iPSC-derived microglia (Aim 1). I will assess how these changes disrupt glutamatergic and GABAergic synaptic function in the thalamocortical system using patch-clamp recordings, circuit-level electrophysiology, and synapse reconstruction to identify synaptic mechanisms underlying thalamocortical hypersynchrony (Aim 2). Finally, I will test whether optogenetic manipulation of microglial membrane voltage can restore synaptic balance, reduce hypersynchrony, and improve behavioral deficits in mouse models of AD, providing critical proof-of- concept for therapeutic strategies (Aim 3). This integrated approach will yield a detailed understanding of how TREM2R47H microglia contribute to AD pathogenesis and identify novel therapeutic targets. This proposal will provide me with mentored training in advanced innovative techniques, including microglial optogenetics, circuit electrophysiology, machine-learning-based behavioral testing, and humanized rodent models of AD, which are essential for investigating microglial control of network dysfunction. Alongside the excellent training environment at Gladstone Institutes, my mentoring and advising teams expertise in defining the mechanisms of AD and network dysfunction driven by microglia, as well as advanced methods for circuit dissection, behavioral analysis, and thalamocortical oscillatory rhythms in cognition. This work will build upon my prior research into the molecular mechanisms of circuit hyperexcitability in neurodegenerative and neurodevelopmental disorders and form the foundation for my independent research program aimed at studying microglial contributions to thalamocortical circuit dysfunction and guiding the development of novel therapeutic strategies for neurodegenerative disorders.


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: 2026 ( Subtotal = $122,850 )
2026	2026	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/5/2026	NEW	$122,850
														Subtotal = $122,850

Grand Total All Awards = $122,850

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Microglial control of thalamocortical circuits in Alzheimer's disease

Award Number: K99NS146256

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 02/15/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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