How early life experience alters microglia function in shaping hypothalamic circuits.

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Mammalian infants are born in an immature state and face a significant challenge in early life. Parent-child relationships are critical for brain development and can have long-term developmental effects that persist into adulthood. Rodent studies showed that increased maternal-infant interactions during the first few weeks of life produce enduring changes in neuronal morphology that affect neural network activity and emotional and cognitive behaviors. How the effect of maternal care influences neural circuits during the critical postnatal period is not fully understood. Emerging evidence points to an important role for microglia in shaping neural networks during this critical period. Microglia are specialized brain-resident immune cells that guard the health of the brain. Depending on environmental stimuli, microglia can produce inflammatory cytokines to fight infection or produce anti-inflammatory cytokines and are active in removing injured damaged tissue to promote repair. New data from several laboratories show that microglia not only regulate the health of neurons but also are important in maintaining the synapses, the dynamic connections between neurons. Evidence suggests that neuronal cytokine secreted upon neural activity may initiate a cascade of signaling in microglia and thereby modulate microglial differentiation and function: to strip away or to maintain the synapses. The molecular mechanisms whereby microglia cross-talk with neurons remains elusive. It is also not known what the impact of early life experience is on the function of microglia surveillance to remodel neuronal synapses. Our data show that microglia take on an anti-inflammatory phenotype when mouse pups are exposed to enhanced maternal care. Importantly, we also observed that pups with enhanced maternal care have microglia that are more active in trimming adjacent neuronal synapses of the hypothalamus. The physiological consequences of these phenomena are important questions that we would like to investigate in this research program. The hypothalamus is a brain region that controls basic fundamental physiological functions, like feeding, blood pressure and thermogenesis. Thus, we postulate that early life experience may mobilize microglia to shape neural circuits of the hypothalamus and thereby influence the animals’ response to metabolic stressors (e.g., high fat diet, social and environmental stress) and their fitness as adults. Using food intake as a readout behavior, we will investigate the hypothalamic neurons that are regulate food intake at the single cell level by electrophysiological studies, and immunofluorescent analysis combined with 2-photon microscopy. This research program is aimed toward elucidating how early life experience, specifically enhanced neonatal maternal care, alters microglia function to shape hypothalamic neural circuits. Impact & Significance: The knowledge about how early life experience molds mammalian neural circuits and influences the response to metabolic stressors may provide valuable insight to improve animal husbandry and human neonatal childcare.