# Multimodal imaging of prodromal synaptic, circuit, and network-level dysfunction in a murine model of Alzheimer's disease

> **NIH NIH RF1** · YALE UNIVERSITY · 2022 · $2,503,003

## Abstract

PROJECT SUMMARY
Alzheimer's disease (AD) disrupts brain organization, which is evident across spatial scales, from synapse loss
to whole-brain connectivity, and manifests prior to or at the first sign of symptoms. Many neuroimaging modalities
have contributed to our understanding of these changes, yet mechanistic insight into how dysfunction translates
across scales, and species, is lacking. In part, these knowledge gaps exist because imaging modes specialize
within a finite spatial milieu with access to a limited number of contrasts. To close these gaps, we propose a
multimodal approach that leverages the strengths of complementary modes to deepen our understanding of
changes in brain organization and inform the development of early-stage and preventative treatment strategies.
Fully aligned with PAR-22-059, we propose a multimodal approach to interrogate AD-precipitated brain circuit
disturbances and treatment-facilitated recovery. Our approach links excitatory and inhibitory synapse losses
(positron emission tomography, PET), cell-type specific circuit-level dysfunction (wide-field calcium, WF-Ca2+,
imaging) and brain-wide changes in the blood-oxygen-level-dependent (BOLD) functional magnetic resonance
imaging (fMRI) signal in an established murine gene knock-in model of AD. Data will span relevant AD stages
and be powered to address sex as a biological variable. Image collection will coincide with behavior testing.
Our objective is to leverage the combined strength of complementary imaging modes to identify the synaptic
changes that correspond to alterations in circuit and network-level dysfunction in the prodromal and early stages
of AD. These data will provide mechanistic insights into the underlying causes of AD-related changes in brain
functional organization that are evident in clinically accessible contrasts (PET and BOLD-fMRI).
Aim 1. Map excitatory (E) and inhibitory (I) synapse losses. Using three PET tracers, we will map changes in
the density of E, I and all synapses. These data will yield a better understanding of how E/I synapses are lost
during AD pathogenesis and how these local changes in micro-circuits contribute to more global E/I imbalances.
Aim 2. Discover the E/I circuit disruptions that underpin BOLD-fMRI network changes. WF-Ca2+ imaging affords
cell-type specific measures of cortex-wide activity. By co-labeling inhibitory and excitatory neurons, we will
measure E/I cortical circuit-level activity. Through simultaneous WF-Ca2+ and BOLD-fMRI, we will link cell-type
specific E/I activity to brain-wide changes in BOLD-fMRI. Data will be collected from awake unanesthetized mice.
Aim 3. Uncover the imaging correlates of treatment-facilitated recovery. Approaches from Aims 1 and 2 will be
interleaved. Mice will be given one of two treatments to prevent synapse loss and cognitive decline. Synapse
loss (PET), circuit and network function (WF-Ca2+/BOLD-fMRI) will be characterized longitudinally.
The innovation of this work lies in...

## Key facts

- **NIH application ID:** 10562876
- **Project number:** 1RF1NS130069-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Zhengxin Cai
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,503,003
- **Award type:** 1
- **Project period:** 2022-09-19 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10562876

## Citation

> US National Institutes of Health, RePORTER application 10562876, Multimodal imaging of prodromal synaptic, circuit, and network-level dysfunction in a murine model of Alzheimer's disease (1RF1NS130069-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10562876. Licensed CC0.

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