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Targeting mesoscale features of dysregulated neuronal activity in a mouse model of amyloidosis

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Title: Targeting mesoscale features of dysregulated neuronal activity in a mouse model of amyloidosis
Authors: Airey, Joe
Item Type: Thesis or dissertation
Abstract: Neuronal network dysfunction is increasingly implicated in the pathological progression of Alzheimer’s Disease (AD), manifesting as destabilized neuronal firing-rates and network hypersynchrony within distributed cortical-hippocampal networks and coinciding with the onset of cognitive decline. Understanding the precise regional and temporal phases of destabilized brain-wide activity during the earliest stages of AD-related pathology could identify vulnerable neuronal circuits and inform targeted bioelectronic interventional strategies aimed at slowing or regulating disease progression. We used widefield calcium imaging to longitudinally track changes in spontaneous and sensory evoked activity across the dorsal cortex of a second-generation mouse model of amyloidosis which models amyloid pathology in diverse cell types. We observed elevated levels of spontaneous calcium mediated neuronal activity in AppNL-G-F mice expressing GCaMP6s in Thy-1-positive excitatory neurons. Elevated activity emerged across posterior-medial cortical networks as early as four months of age. By 6 months of age, further increases in the amplitude of spontaneous activity coincide with a reduction in visually evoked activity. The changes in activity were accompanied by a loss of widespread adaption to a sensory evoked plasticity paradigm, implicating failing homeostatic plasticity processes in the emergence of dysregulated cortical activity. We targeted cortices showing elevated resting state activity with low frequency bioelectronic brain stimulation (Temporal Interference, TI). Repeat bouts of low-frequency TI stimulation reduced elevated resting-state activity within affected cortices of AppNL-G-F mice while sparing sensory evoked activity. Our results highlight the potential of targeted neuromodulatory strategies, informed by knowledge of the underlying neuronal network dysfunction, to reduce early-stage AD pathology in vivo.
Content Version: Open Access
Issue Date: Jul-2023
Date Awarded: Jun-2024
URI: http://hdl.handle.net/10044/1/113392
DOI: https://doi.org/10.25560/113392
Copyright Statement: Creative Commons Attribution NonCommercial ShareAlike Licence
Supervisor: Barnes, Samuel
Sponsor/Funder: Medical Research Council (Great Britain)
UK Dementia Research Institute
Department: Department of Brain Sciences
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Department of Brain Sciences PhD Theses



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