Defining the Role of Microglia in the Synaptic Rewiring of the Hypothalamus by Early life Adversity

项目总结： 早年的逆境可能会通过调节潜在大脑回路的成熟，深刻地影响一个人患压力相关情绪障碍(包括抑郁症)的风险。我们发现，早期暴露在贫穷的环境中会引发抑郁(快感缺乏症)的核心症状，并伴随着应激敏感神经元连接的改变。具体地说，我们发现在下丘脑室旁核(PVN)，兴奋性突触与促肾上腺皮质激素释放激素(CRH)表达的神经元的数量增加。此外，这些突触变化足以诱导包括CRH在内的关键神经元基因表达的持久表观基因组变化。然而，早期生活中的逆境如何调节与压力相关的大脑回路中突触的发育和持久性的机制仍不清楚。小胶质细胞是大脑的常驻免疫细胞，在发育中的视觉和体感系统中，小胶质细胞已经成为形成突触连接的关键效应者。因此，小胶质细胞在塑造应激相关下丘脑神经元的连接性方面扮演着类似的角色，是有吸引力的候选细胞。目的1验证小胶质细胞调节下丘脑室旁核CRH表达神经元兴奋性突触数量的假说，下丘脑是应激反应的关键区域。目的2验证早期逆境影响小胶质细胞与PVN-CRH神经元及其兴奋性突触相互作用的假说。最终目标将使用假设驱动和数据驱动的方法来确定逆境引发的小胶质细胞功能障碍背后的分子机制。总之，拟议中的实验将首次阐明小胶质细胞在早年遭遇逆境后大脑回路异常成熟中的作用。 K99阶段提供了尖端研究技能方面的培训，包括实时双光子成像和4-D分析，以及转录组的大数据分析。加州大学欧文分校为这种培训提供了理想的环境，拥有世界知名的发育神经生物学、小胶质细胞/神经免疫学和分子生物学专家。此外，UCI提供了一个鼓励合作和合作的智力环境，使候选人能够成长为科学界的一员。结果，PI能够在佐治亚州立大学获得终身教职助理教授的职位，那里的神经科学研究所拥有神经元-神经胶质细胞相互作用、PVN中的神经肽信号、实时双光子成像和行为神经科学方面的专家。在这种良好的环境中，候选人将在终身教职的道路上接受正式的指导，建立密切的研究合作，并建立自己的独立研究计划，研究大脑发育过程中小胶质细胞和神经元的相互作用如何塑造未来的心理健康。

PROJECT SUMMARY: Early-life adversity can profoundly impact an individual’s risk for stress-related emotional disorders including depression, likely by modulating the maturation of the underlying brain circuits. We find that early-life exposure to an impoverished environment provokes core symptoms of depression (anhedonia), accompanied by altered connectivity of stress-sensitive neurons. Specifically, we find an increase in the number of excitatory synapses onto corticotropin-releasing hormone (CRH) expressing neurons in the paraventricular nucleus of the hypothalamus (PVN). Further, these synaptic changes suffice to induce enduring epigenomic changes in the expression of critical neuronal genes including CRH. However, the mechanisms by which early-life adversity modulates synapse development and persistence in stress-related brain circuits remain unknown. Microglia, the brain’s resident immune cells, have emerged as key effectors in the shaping of synaptic connectivity in the developing visual and somatosensory systems. Microglia are thus attractive candidates for playing a similar role in sculpting connectivity of stress-related hypothalamic neurons. Aim 1 will test the hypothesis that microglia regulate excitatory synapse number on CRH-expressing neurons in the PVN, a key stress-responsive brain region. Aim 2 will test the hypothesis that early-life adversity influences the interactions of microglia with PVN-CRH neurons and their excitatory synapses. The final Aim will employ both hypothesis-driven and data-driven approaches to identify molecular mechanisms underlying adversity-provoked microglial dysfunction. Together, the proposed experiments will, for the first time, elucidate the role of microglia in aberrant maturation of brain circuits following early-life adversity. The K99 phase provided training in cutting-edge research skills, including live 2-photon imaging and 4-D analysis, as well as “big-data” analysis of transcriptomics. The University of California-Irvine provided an ideal environment for this training, with world-renowned experts in developmental neurobiology, microglia/neuroimmunology and molecular biology. In addition, UCI provided an intellectual environment that encourages collaboration and cooperation, enabling the candidate’s growth as a member of the scientific community. As a result, the PI was able to attain a tenure-track assistant professor position at Georgia State University, where the Neuroscience Institute boasts faculty members that are experts in neuron-glia interactions, neuropeptide signaling in the PVN, live 2-photon imaging, and behavioral neuroscience. In this excellent environment, the candidate will receive formal mentoring on the tenure-track path, forge close research collaborations, and establish her own independent research program on how microglia-neuron interactions during brain development shape future mental health.