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

早期生活经历如何改变小胶质细胞塑造下丘脑回路的功能。

• 批准号: RGPIN-2019-03942
• 负责人: Chen, HsiaoHuei
• 金额: $ 2.91万
• 依托单位: University of Ottawa
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=760887
• 关键词: How; early; life; experience; alters

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.

亲子关系对大脑发育至关重要，并具有持续到成年的长期发展影响。啮齿类动物的研究表明，在出生后的最初几周内，母亲与婴儿之间的互动增加会导致神经元形态发生持久的变化，从而影响神经网络的活动以及情感和认知行为。在这个关键时期，小胶质细胞已经成为塑造神经网络的关键角色。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重塑神经元突触的功能有什么影响。我们正在进行的NSERC支持的发现补助金已经证明，加强产后护理（EPC）可以减少焦虑，提高成年后对社会失败的适应力。EPC诱导下丘脑的抗炎基因表达并降低炎性细胞因子的产生。有趣的是，不能分化成抗炎程序的突变小胶质细胞的小鼠对EPC的抗焦虑作用没有反应。这表明EPC通过小胶质细胞来塑造参与焦虑的神经回路。因此，这种遗传小鼠模型提供了一种独特的工具来揭示EPC塑造焦虑神经回路的分子机制。我们发现，EPC影响小胶质细胞的功能，特别是在下丘脑。通过无偏RNAseq分析，我们发现4种细胞外/分泌的神经元蛋白（Ptgds，Prg 4，Itih 2，Bpifa 1）与EPC的焦虑减轻作用有关。蛋白聚糖4（Prg 4）和细胞外基质蛋白酶抑制剂Itih 2是细胞外基质的一部分，而Ptgds和Bpifa 1是分泌因子。本更新提案中详细说明的未来5年的目标是阐明这4种新的细胞和分子候选物如何影响下丘脑功能，以调节EPC的小胶质细胞依赖性抗焦虑作用。影响和意义：了解早期生活经验如何塑造哺乳动物神经回路并影响对压力源的反应，可能为改善人类新生儿保育和畜牧业提供有价值的见解。