Adipose tissue distribution determines microglial regulation of hippocampal plasticity

PROJECT SUMMARY The ‘apple-shaped’ anatomical pattern that accompanies visceral adiposity increases dementia risk in humans, but the 'pear-shaped' distribution that reflects subcutaneous adiposity does not predict cognitive impairment and may be protective. 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 anti-inflammatory cytokines. However, current understanding of tissue-specific anti- inflammatory signaling remains rudimentary due to the scarcity of approaches for selective manipulation. Moreover, regionally heterogeneous responses to dietary obesity in different brain areas remain incompletely characterized, leaving open questions surrounding feedforward neuroimmune control versus immunological feedback. The proposed experiments will generate a comprehensive topographical map of neuroimmune responses to chronic overnutrition and elucidate the role of the anti-inflammatory cytokine interleukin-4 in these effects. We will use light-inducible cre drivers and direct delivery of tamoxifen metabolites to selectively manipulate immune cells in cerebrospinal fluid. These technically innovative approaches will be followed by anatomical mapping of lymphocytes and myeloid cells in cleared tissues, single-cell flow cytometric analysis, or analysis of neuronal function at the behavioral and electrophysiological level. Understanding circuit-specific sexual dimorphisms in obesity could yield fundamental insights into the pathogenesis of neuroinflammation in different microenvironments, and could also identify target structures for noninvasive therapeutic modulation.