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

定义小胶质细胞在早年逆境下丘脑突触重新布线中的作用

基本信息

批准号：
10527373
负责人：
Jessica Lynn Bolton
金额：
$ 24.9万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10527373
关键词：
3-Dimensional Acute Affect Anhedonia Applications Grants Area Attenuated Beds Behavioral Big Data Bioinformatics Brain Brain region California Cells Child Collaborations Communities Complement Computer Analysis Confocal Microscopy Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors Data Data Analyses Development Electron Microscopy Emotional Emotional disorder Environment Excitatory Synapse Exposure to Faculty Functional disorder Future Gene Expression Genes Glucocorticoid Receptor Glucocorticoids Growth Hippocampus Hypothalamic structure Image Immune Individual Intervention Learning Life Experience Mental Depression Mental Health Mental disorders Mentors Microglia Minocycline Molecular Molecular Biology Mus Neuroglia Neurons Neuropeptides Neurosciences Pathway interactions Phase Play Population Positioning Attribute Poverty Reporter Research Research Personnel Resolution Risk Role Shapes Signal Transduction Slice Stress Synapses System Technical Expertise Testing Time Training Universities Visual cognitive function density depressive symptoms developmental neurobiology early life adversity early life exposure epigenomics experience experimental study forging genetic approach hormonal signals improved in vivo member microscopic imaging neonatal mice neuroimmunology paraventricular nucleus pharmacologic postnatal prevent preventive intervention professor programs reconstruction skill acquisition skills somatosensory tenure track transcriptome sequencing transcriptomics two-photon

项目摘要

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.

项目概要：早期生活中的逆境可能会深刻地影响一个人患上与压力有关的情绪障碍（包括抑郁症）的风险，这可能是通过调节潜在大脑回路的成熟来实现的。我们发现，早期生活暴露于贫困环境会引发抑郁症的核心症状（快感缺失），伴随着压力敏感神经元的连接改变。具体来说，我们发现在下丘脑室旁核（PVN）的促肾上腺皮质激素释放激素（CRH）表达神经元的兴奋性突触的数量增加。此外，这些突触变化足以诱导关键神经元基因（包括CRH）表达的持久表观基因组变化。然而，早期生活逆境调节突触发育和与压力相关的大脑回路持续性的机制仍然未知。小胶质细胞，大脑的常驻免疫细胞，已经成为在发育中的视觉和体感系统中塑造突触连接的关键效应器。因此，小胶质细胞在塑造应激相关下丘脑神经元的连接中发挥类似作用的有吸引力的候选者。目的1将检验小胶质细胞调节PVN中CRH表达神经元兴奋性突触数量的假设，PVN是一个关键的应激反应脑区。目的2将验证早期生活逆境影响小胶质细胞与PVN-CRH神经元及其兴奋性突触的相互作用的假设。最终的目标将采用假设驱动和数据驱动的方法来确定潜在的不利因素引起的小胶质细胞功能障碍的分子机制。总之，拟议的实验将首次阐明小胶质细胞在早期生活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的培训，包括实时双光子成像和四维分析，以及转录组学的“大数据”分析。加州大学欧文分校为这次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提供了一个鼓励协作与合作的知识环境，使候选人能够成长为科学界的一员。因此，PI能够在格鲁吉亚州立大学获得终身助理教授的职位，神经科学研究所拥有的教师是神经元-胶质细胞相互作用，PVN中的神经肽信号传导，实时双光子成像和行为神经科学的专家。在这个良好的环境中，候选人将获得终身教职路径的正式指导，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-神经元的相互作用如何塑造未来的心理健康。