Abstract

The relationship between brainwide functional decline and accumulation of pathological protein aggregates in Alzheimer’s disease (AD) is complex and not well understood. A set of highly interconnected cortical regions known as the Default Mode Network (DMN) exhibits selective vulnerability to both functional decline and amyloid beta (Aβ) plaques in early AD. One possibility is that early Aβ accumulation in the DMN drives vulnerability. However, it is unknown whether there is something intrinsic to neuronal projections within the DMN that biases these circuits towards dysfunction. In this dissertation, I describe the development of a multisite in vivo electrophysiology pipeline for chronic single unit recording in freely behaving mice and subsequent experiments using this pipeline in a mouse model of Alzheimer’s Disease with global cortical Aβ burden (APP/PS1) in order to directly test this hypothesis. Specifically, I track the interactions of a population of neurons within a DMN region and two additional populations that comprise monosynaptic targets, one within and the other outside the DMN. In addition, I show recordings from single neurons in CA1 and examine hippocampal sharp-wave ripple triggered interactions between in-DMN and out-DMN cortical circuits. I examine the statistics of local activity as well as inter-regional communication in a region, genotype, and brain-state dependent manner. Our data reveal dysfunction restricted to within-DMN projecting circuits. In contrast, communication along neuronal projections that originate in the DMN but target non-DMN populations are equivalent in APP/PS1 and control mice. Circuit dysfunction is found to be most evident in non-rapid eye movement (NREM) sleep, on the timescale of hours as well as within sharp-wave ripples, a stereotyped hippocampal event that contributes to memory consolidation in the cortex. Our results indicate that neighboring cells in the DMN exhibit differential intrinsic vulnerability to amyloid injury dependent on their projection targets.

Committee Chair

Keith Hengen

Committee Members

Charles Zorumski; Erik Herzog; Erik Musiek; Eva Dyer

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

5-8-2025

Language

English (en)

Author's ORCID

https://orcid.org/0000-0001-7724-1855

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