Role of microglial metabolism in perinatal inflammation

Neuroinflammation plays a central role in perinatal brain injury as it impairs oligodendrocyte maturation and myelination and causes neuronal injury. Microglia (MG), brain cells of non-neural origin, orchestrate the inflammatory response to diverse insults but these cells display an enormous plasticity, and can exhibit both beneficial and detrimental functions. Up to date the cellular mechanisms that govern the diverse effector states of MG are poorly understood. Novel insights are highly needed and indispensable in order to prevent the deleterious effects of inflammatory MG and modulate them into a neurosupportive phenotype. To date, the metabolic features of MG in their different activation states have not been investigated. Our goals are i) to resolve the metabolic activities and mitochondrial properties of microglia in diverse activation states using the newest tools; ii) to identify transcriptional mechanisms underlying these different phenotypes; iii) to selectively block key metabolic pathways by genetic or pharmacological tools and assess the consequences on MG effector functions; iv) to investigate the relationship between TLR activation and MG metabolic activities; and v) to manipulate key metabolic pathways in MG in vivo using a novel established mouse model of inflammatory perinatal brain injury. These studies will help to unravel the complex MG phenotypes and to find targets to combat perinatal but also degenerative neurological disorders associated with inappropriate inflammatory reactions.