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

哺乳动物婴儿出生时处于不成熟状态，在早期生活中面临重大挑战。亲子关系对大脑发育至关重要，并可能产生长期的发展影响，一直持续到成年。啮齿类动物的研究表明，在生命的最初几周内，母婴互动的增加会导致神经元形态的持久变化，从而影响神经网络活动以及情感和认知行为。产妇护理的影响如何影响神经回路在关键的产后时期还没有完全了解。新出现的证据表明，在这一关键时期，小胶质细胞在塑造神经网络方面发挥着重要作用。小胶质细胞是专门的大脑驻留免疫细胞，保护大脑的健康。根据环境刺激，小胶质细胞可以产生炎性细胞因子以对抗感染或产生抗炎细胞因子，并在去除受损组织以促进修复方面具有活性。来自几个实验室的新数据表明，小胶质细胞不仅调节神经元的健康，而且在维持突触，神经元之间的动态连接方面也很重要。有证据表明，神经活动时分泌的神经细胞因子可以启动小胶质细胞中的信号级联，从而调节小胶质细胞的分化和功能：剥离或维持突触。小胶质细胞与神经元相互作用的分子机制仍然难以捉摸。也不知道早期生活经历对小胶质细胞监视重塑神经元突触的功能有什么影响。我们的数据表明，当小鼠幼崽暴露于增强的母亲护理时，小胶质细胞呈现抗炎表型。重要的是，我们还观察到，加强母亲护理的幼崽具有更活跃的小胶质细胞，在修剪下丘脑的相邻神经元突触。这些现象的生理后果是我们希望在这项研究计划中调查的重要问题。下丘脑是一个控制基本生理功能的大脑区域，如进食，血压和产热。因此，我们假设早期的生活经历可能会动员小胶质细胞来塑造下丘脑的神经回路，从而影响动物对代谢应激源的反应（例如，高脂肪饮食，社会和环境压力）和他们成年后的健康。以摄食为读出行为，我们将通过电生理研究、免疫荧光分析结合双光子显微镜在单细胞水平上研究调节摄食的下丘脑神经元。这项研究计划旨在阐明早期生活经验，特别是加强新生儿母亲护理，如何改变小胶质细胞功能，以塑造下丘脑神经回路。影响和意义：关于早期生活经验如何塑造哺乳动物神经回路并影响对代谢应激源的反应的知识可能为改善畜牧业和人类新生儿保育提供有价值的见解。

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.