Unravelling the Metabolic Basis of Aberrant Neuroimmune Interactions in MS-Associated Cognitive Decline

About the project

About the Project Summary Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that results in significant long-term disability. While research has historically focused on motor and sensory deficits, cognitive impairment is now recognized as a critical and debilitating aspect of the disease, affecting over half of all patients. These cognitive deficits can manifest early and have significant clinical consequences during the progressive stages of MS, yet the underlying mechanisms remain poorly understood. Within the CNS, neurons orchestrate complex brain functions, but their health is inextricably linked to the surrounding glial cells, particularly the CNS resident immune cells known as microglia. Our lab's recent work has uncovered specific metabolic perturbations that sustain aberrant microglial activation compromising neuronal fitness, leading to cell loss. However, the precise metabolic drivers that disrupt these neuron-microglia interactions within the context of MS-associated cognitive decline have not yet been identified. This project will directly address this knowledge gap by elucidating the metabolic and molecular dynamics of this pathological neuroimmune crosstalk. Project Aims: Aim 1: Identify specific microglial phenotypes associated with the vulnerability of distinct neuronal subpopulations in brain regions critical for cognition. Aim 2: Uncover the key metabolic determinants that drive pathological immune responses and contribute to neuronal frailty. Aim 3: Determine whether targeted therapeutic interference of perturbed metabolic pathways in microglia and/or neurons can restore cognitive function in a preclinical model of MS. Experimental Strategy : This project will employ a multi-modal strategy, integrating transcriptomic studies of brain regions from both MS mouse models and human tissue. Further mechanistic insights will be gained using in vitro 2D co-culture systems of primary mouse cells and, importantly, human induced pluripotent stem cell (iPSC)-derived neurons and microglia. Functional outcomes of targeting the identified metabolic drivers will be assessed in vivo through a battery of behavioural-cognitive tests and electrophysiological recordings in a mouse model of MS. Impact : By integrating neuroimmunometabolism and cognitive neuroscience, this project will define novel mechanisms of cognitive decline in MS. Our aim is to uncover new therapeutic targets and to open promising avenues to preserve or restore cognitive function for those living with this chronic disease. How to Apply; If you are interested in this project, please go to the University pages and apply via the online portal; PhD https://www.postgraduate.study.cam.ac.uk/courses/directory/cvcnpdpcn/apply Research MPhil https://www.postgraduate.study.cam.ac.uk/courses/directory/cvcnmpmds/apply

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