Neuron-microglia interactions during gamma-frequency oscillations

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Background:Dementias such as Alzheimer's disease (AD) are associated with substantial levels of neuroinflammation mediated by the macrophages of the brain, microglia. There is a current and lively debate on whether this inflammatory response is a causative factor in neurodegenerative disease or a compensatory mechanism attempting to repair damage caused by other pathological features. A recent study has suggested that continuous induction of gamma frequency network oscillations in the hippocampus and visual cortex is capable of reducing amyloid pathologies in various transgenic mouse models of progressive amyloidosis; an outcome that appears to occur via activation of microglia. This highly surprising and intriguing finding suggests that deficits in gamma oscillations observed by our group and others in such transgenic mice, may actually play a causative role in pathology. To wit, naturally occurring physiological gamma frequency oscillations may play a role in regulating the expression of A-beta and/or tau pathologies; and when these are disrupted by dementia-related synaptic dysfunction, the gamma-induced neuroimmunological systems which normally regulate these pathologies malfunction. Under these circumstances, according to this thesis, A-beta and/or tau deposits are allowed to flourish. Experimental design: In this project, the student will combine electrophysiological techniques with in vitro and in vivo imaging to establish the cellular mechanisms underlying this form of oscillation driven neuron-microglia interaction. We will use established transgenic microglia reporter mice lines to visualise microglia during ongoing gamma oscillations in brain slices. There are several such lines available including the MacGreen and CX3CR1+/GFP mice lines, both of which expresses eGPF in microglia and the latter of which is available in Bristol. The student will also make use of mouse lines expressing Cre recombinase in a microglia specific manner. Using the Cre-Lox system, we can use these mice to express florescent Ca2+ reporters in microglia to examine Ca2+ dynamics in microglia during gamma frequency oscillations. These systems will allow us to examine the neurotransmitter and biochemical pathways involved in gamma-induced microglial activation. The student will also apply cutting edge in vivo imaging facilities available in both Exeter and Bristol to explore the interplay between visually evoked gamma oscillations and microglial morphology in an intact system. Finally, the student will combine the in vitro and in vivo approaches outlined here to investigate the dynamics of neuron-microglia interactions in response to dementia related pathology, such as beta amyloid. Outcome:This project will provide a mechanistic framework underpinning this novel and disease-relevant form of neuron-microglia interaction.