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

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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 the multimodal approach which bridges spatial scales from the synapse to the whole-brain. The significance of this proposal lies in deepening our understand how synaptic, circuit and network-level changes are interwoven and how together they shape AD pathogenesis and treatment response.