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.

项目摘要：早期生活广告可能会深刻影响个人患与压力有关的情绪障碍的风险，包括抑郁症，可能是通过调节基础脑电路的成熟。我们发现，早期暴露于贫困环境会引起抑郁症的核心症状（ANHEDONIA），这是通过改变压力敏感神经元的连通性来实现的。具体而言，我们发现在下丘脑（PVN）的脑室核核核心中表达神经元的释放皮质激素的刺激突触数量增加。此外，这些合成变化足以诱导包括CRH在内的关键神经元基因表达的持久表观基因组变化。但是，早期广告调节与压力相关的脑电路的突触发展和持久性的机制尚不清楚。小胶质细胞是大脑的常驻免疫核管，已成为正在发展的视觉和体感系统中突触连通性塑造的关键作用。因此，小胶质细胞是在雕刻与压力相关下丘脑神经元连通性中发挥相似作用的有吸引力的候选者。 AIM 1将检验以下假设：小胶质细胞调节PVN中表达CRH神经元的兴奋性突触数，这是一个关键的应激响应性大脑区域。 AIM 2将检验以下假设：早期广告会影响小胶质细胞与PVN-CRH神经元及其兴奋突触的相互作用。最终目标将采用假设驱动的和数据驱动的方法来识别发动广告发动机的小胶质细胞功能障碍的分子机制。共同提出的实验将首次阐明小胶质细胞在早期广告后脑电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2光子成像和4-D分析，以及对转录组学的“大数据”分析。加利福尼亚大学 - Irvine分校为这项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提供了一种鼓励合作与合作的智力环境，从而使候选人成为科学界成员的成长。结果，PI能够在佐治亚州立大学获得终身制助理教授职位，神经科学研究所在那里拥有神经 - 葡萄球菌相互作用专家的教师，PVN中的神经肽信号传导，实时的2-PHOTON成像和行为神经科学。在这个良好的环境中，候选人将在终身轨道道路上进行正式的心理，锻造紧密的研究合作，并建立自己的独立研究计划，介绍在大脑发育过程中如何影响未来心理健康的小胶质细胞 - 神经元相互作用。