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

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Parent-child relationships are critical for brain development and 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 maternal care influences neural circuits during the critical postnatal period is not fully understood. Microglia have emerged as key players 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 cytokines 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 remain elusive. It is also not known what impact early life experience has on the function of microglia to remodel neuronal synapses. Our ongoing NSERC-supported Discovery grant has demonstrated that enhanced postnatal care (EPC) reduces anxiety and increases resilience to social defeat in adulthood. EPC induces anti-inflammatory gene expression and lowers inflammatory cytokine production at the hypothalamus. Intriguingly, mice with mutant microglia unable to differentiate to an anti-inflammatory program fail to respond to the anxiolytic effect of EPC. This indicates that EPC works through microglia to shape neural circuits involved in anxiety. Hence, this genetic mouse model offered a unique tool to unveil the molecular mechanisms whereby EPC shapes the neural circuits of anxiety. We found that EPC affects microglia function specifically in the hypothalamus. By unbiased RNAseq profiling, we found 4 extracellular/secreted neuronal proteins (Ptgds, Prg4, Itih2, Bpifa1) implicated in the anxiety-reducing effect of EPC. Proteoglycan 4 (Prg4) and the extracellular matrix protease inhibitor Itih2 are part of the extracellular matrix, whereas Ptgds and Bpifa1 are secreted factors. The goal for the next 5 years, detailed in this renewal proposal, is to elucidate how these 4 novel cellular and molecular candidates affect hypothalamic function to modulate the microglia-dependent anxiolytic effect of EPC. Impact & Significance: Understanding how early life experience molds mammalian neural circuits and influences the response to stressors may provide valuable insight to improve human neonatal childcare and animal husbandry.