Collette Thomas
BME PhD Proposal Presentation

Date: 2026-08-25
Time: 2:00pm-4:00pm
Location / Meeting Link: Krone Engineered Biosystems Building: Children's Healthcare of Atlanta Seminar Room and https://emory.zoom.us/j/98374704369

Committee Members:
Annabelle Singer; Garrett Stanley; Ming-Fai Fong; Joseph Manns; David Weinshenker


Title: Investigating How the APOE4 Allele Alters Parvalbumin Interneuron Activity and Sharp Wave Ripples During Spatial Reversal Learning 

Abstract:
Project Summary and Abstract: Identifying earlier neural circuit changes occurring before cognition is lost is critical for developing early detection and intervention measures before extensive and irreversible neurodegeneration occurs. However, less is known about the neural mechanisms that make the brain vulnerable before symptom onset. Research on Alzheimer’s Disease (AD) is commonly studied after the onset of symptoms, by which point substantial neurodegeneration has already occurred, which limits the effectiveness of current therapeutic interventions. Thus, identifying early circuit-level changes that occur before clinical symptom onset is critical for developing earlier biomarkers and therapeutic strategies. Though APOE4, a variant of the APOE gene, has been identified as the strongest genetic risk factor for AD, previous studies have mainly been done in vitro, in anesthetized animals, or postmortem. Thus, we shift our focus to identifying early circuit-level changes in an APOE genetic risk model of AD in behaving animals. PV interneurons, which are particularly vulnerable in AD, play an essential role in learning and memory and regulate hippocampal SWRs, high-frequency oscillations that occur during quiet wakefulness and sleep, and are required for spatial learning and memory and memory consolidation. Previous work has identified that SWR activity is impaired in APOE4-expressing mice. Additionally, work done in our lab identified a decrease in PV interneurons’ firing rate on approach to reward zones in a spatial navigation task in WT mice and proved that this decrease is necessary for learning reward locations in a novel environment. However, whether there are deficits in PV interneurons in APOE4-expressing mice and whether this contributes to deficits in SWRs has not been investigated. Therefore, this proposal aims to investigate PV interneurons’ neural activity in APOE4-KI expressing mice in the hippocampus, one of the earliest regions affected by AD, to further understand their functional role and their link to neural correlates of memory during spatial reversal learning, defined as learning new reward locations after previously learned ones change within the same environment. We will test the hypothesis that APOE4-KI mice show impaired spatial reversal learning that is correlated with a deficit in goal-related PV activity decreases when compared to APOE3-KI mice, and that this PV interneuron deficit plays a causal role in the associated SWR disruption. We will test this hypothesis by measuring firing rates of PV interneurons in APOE4-KI and APOE3-KI mice (Aim 1) and by using optogenetic manipulation to determine the causal effect of PV interneuron activity on SWRs in APOE4-KI and APOE3-KI (Aim 2). These results will identify early hippocampal circuit dysfunction associated with APOE4 genetic risk long before clinical onset, offering a new perspective on the impact of the APOE4 allele on neural circuits, creating novel prospects for early diagnostic biomarkers and circuit-based therapeutic interventions.