Thesis

Exploration of sleep-related oscillatory abnormalities in Alzheimer's disease

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Awarding institution
  • University of Strathclyde
Date of award
  • 2024
Thesis identifier
  • T17155
Person Identifier (Local)
  • 202192452
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Qualification Name
Department, School or Faculty
Abstract
  • A hallmark of Alzheimer’s disease (AD) pathology is amyloid plaques which can lead to neuroinflammation, cellular dysfunction and altered neuronal activity. Both AD patients and mouse models exhibit abnormal neural oscillations, including altered hippocampal sharp-wave ripples (SWRs) and cortical sleep spindles. Although these oscillations play a role in memory formation and consolidation, it remains poorly understood how abnormal oscillations relate to novel experiences. We hypothesised that SWRs and sleep spindles are altered in 5xFAD mice, an AD mouse model, in the context of novelty. We performed in vivo electrophysiological recordings in a freely behaving condition to characterize hippocampal SWRs and cortical sleep spindles across the sleep-wake cycle in 5xFAD mice. Although SWRs during non-rapid eye movement (NREM) sleep increased just after exposure to a novel environment or exploration of a novel object in littermate controls, this increase was absent in AD mice. On the other hand, cortical sleep spindles and their co-occurrence with SWRs did not show an experiencedependent increase and were not altered in AD mice, suggesting that thalamocortical functions are spared from amyloid pathology. To examine if the diminished SWRs are associated with abnormal cholinergic tone in the hippocampus, we performed electrophysiology in a freely behaving condition while optically monitoring hippocampal acetylcholine levels across sleepwake cycles. Here we found abnormalities in cholinergic dynamics at state transitions in AD mice, potentially contributing to the diminished SWR rate. Our findings highlight the complexity of AD, revealing that hippocampal SWRs are significantly disrupted by amyloid pathology in the context of novelty, potentially as a result of abnormal cholinergic dynamics, while thalamocortical functions remain unaffected.
Advisor / supervisor
  • Sakata, Shuzo
Resource Type
DOI

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