PROJECT SUMMARY Neuroinflammation is a shared feature of obesity and dementia, but the processes that initiate and perpetuate glial reactivity are not well understood,. Several recent studies, including from our lab, have outlined signaling cascades linking peripheral and central inflammation in obesity in males, but vulnerability to obesity-induced metabolic pathology is sexually dimorphic, and susceptibility to neuroinflammation follows similar patterns. Adult females exhibit stronger innate immunity, and evidence from clinical and experimental studies suggests that this dimorphism involves sex differences in activation of complement. However, current understanding of tissue- specific complement activation remains rudimentary due to the scarcity of approaches for cell type-specific manipulation. To this end, we generated transgenic mice with inducible, cell type-specific deletion of the endogenous complement inhibitor Crry, and will use this model to distinguish between target cells and 'bystander' populations in the adult brain. After determining whether selective activation of complement is sufficient for neuroinflammation, we will examine the role of sexually dimorphic complement activation as a mechanism for differential vulnerability to synaptic and behavioral dysfunction on obesogenic diets. These themes will be addressed using state-of-the-art methodology, including newly developed strategies for high-throughput morphometric analysis of glial cells in cleared brains and region-specific manipulation of glial gene expression.