Neuron-microglia interactions during neuronal network oscillations: implications for dementia. Medical Studies, PhD (GW4 BioMed MRC DTP)

Supervisory team:
Dr Jonathan Brown, University of Exeter Medical School
Dr Jonathan Witton, University of Bristol
Dr Michael Ashby, University of Bristol
Dr Talitha Kerrigan, University of Exeter

Project description:
Microglia mediate brain inflammation and play a key role in dementias such as Alzheimer’s disease (AD). Recent evidence suggests that microglia are activated by neuronal network activity, which may be beneficial in AD. This project will use electrophysiology and imaging to explore the mechanisms underlying this important neuron-glia interaction.

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.

Network oscillations arise through coordinated patterns of neural activity within the brain. A recent study (Iaccarino et al. 2016) has suggested that induction of gamma frequency network oscillations in the hippocampus and visual cortex is capable of reducing amyloid pathologies (which characterise AD) in various transgenic mouse models of amyloidosis; an outcome that appears to occur via activation of microglia. This highly intriguing finding suggests that deficits in gamma oscillations observed by our group (Booth et al. 2016) in such transgenic mice, may actually play a causative role in AD pathology. To wit, natural physiological gamma frequency oscillations may play a role in regulating the expression of amyloid and/or other protein-based pathologies in the brain. When these are disrupted by dementia-related synaptic and neuronal dysfunction, the gamma-induced neuroimmunological systems which normally regulate these pathologies malfunction. Under these circumstances, according to this thesis, Aβ deposits are allowed to flourish.

Experimental design: 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 transgenic reporter mice to visualise microglia during pharmacologically- and optogenetically-induced gamma oscillations in brain slices. There are several such lines available (e.g. CX3CR1+/GFP mice) lines, which expresses eGFP in microglia. The student will also make use of mouse lines expressing Cre recombinase in a microglia specific manner. Using these mice, we can express fluorescent Ca2+ reporters in microglia to examine Ca2+ dynamics during gamma oscillations. This will allow us to examine the pathways involved in gamma-induced microglial activation. This system will also allow for targeted patch clamp recording of microglia during ongoing network activity to determine the ionic mechanisms underlying this form of activation. We will also use novel pharmacological tools made available by our project collaborators at Eli Lilly which inhibit microglial activation. Finally, the student will use cutting edge in vivo imaging facilities available in both Exeter and Bristol to explore the interplay between visually evoked gamma oscillations, microglial morphology and response to neurotoxic damage (i.e. by Abeta) in an intact system.

Outcome: This project will provide a mechanistic framework underpinning this novel and disease-relevant form of neuron-microglia interaction.

To apply for this project, please complete the application form at https://cardiff.onlinesurveys.ac.uk/gw4-biomed-mrc-dtp-student-2019 by 5pm Friday 23 November 2018.