The Development of Facial Motor Neuron Subtypes in Health and in Congenital Facial Weakness

健康和先天性面部无力的面部运动神经元亚型的发展

• 批准号: 10619232
• 负责人: Gabriela Lizana Carrillo
• 金额: $ 8.61万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-25 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619232
• 关键词: Acute; Address; Adult; American; Behavioral; Biology; Brain; Cause of Death; Cells; Cessation of life; Chronic; Chronic Phase; Clinical; Communicable Diseases; Complement; Complement 1q; Complex; Development; Disease; Electroencephalography; Ensure; Environment; Excitatory Synapse; Face; Faculty; Fetal Development; Genetic; Goals; Health; Human; Human body; Image; Immune response; Immunocompromised Host; Individual; Infection; Infectious Diseases Research; Inflammation; Inflammatory Response; Infrastructure; Inhibitory Synapse; Innate Immune System; Institution; Interdisciplinary Study; Knowledge; Label; Life; Macrophage; Mediating; Mental disorders; Mentors; Microglia; Mission; Molecular; Motor Neurons; Mus; Nerve; Neuroglia; Neuroimmune; Neuroimmunomodulation; Neurologic; Neuronal Injury; Neurons; Neurosciences; Organ; Parasites; Parasitic infection; Pathogenesis; Pathway interactions; Phagocytosis; Pharmaceutical Preparations; Phase; Population; Populations at Risk; Postdoctoral Fellow; Predisposition; Prevalence; Proteins; Publishing; Recording of previous events; Records; Reporting; Research; Research Project Grants; Residencies; Retina; Risk; Risk Factors; Role; Schizophrenia; Seizures; Skeletal Muscle; Surface; Synapses; Testing; Therapeutic; Time; Toxoplasma gondii; Toxoplasmosis; Training; Transgenic Organisms; Translating; Tropism; United States; United States National Institutes of Health; Universities; Work; brain circuitry; chronic infection; complement pathway; experimental study; foodborne illness; glial activation; imaging modality; insight; interdisciplinary collaboration; molecular array; nervous system disorder; neural; neural circuit; neuroimmunology; neurotransmission; novel; novel therapeutics; parasite invasion; pathogen; pre-clinical; presynaptic; prevent; programs; response; success; tenure track; tool; two-photon

PROJECT SUMMARY Aberrant changes in mature neural connections and their function can be induced by infection and inflammation within the brain. The intracellular protozoan parasite, Toxoplasma gondii, is one pathogen that infects the brain, evokes a prolonged inflammatory response and can cause seizures. Persistent infection by this parasite is also associated with behavioral alterations and is a considerable risk factor for developing psychiatric illness, includ- ing schizophrenia. Over 30% of Americans are presently living with an incurable long-term infection of Toxo- plasma gondii, yet, despite its prevalence and implications for serious neurological disorders, we lack sufficient understanding of the effect of life-long parasitic infection on the brain – a major organ of the human body in which the parasite invades cells. This study seeks to elucidate the underlying mechanisms of brain circuitry dysregu- lation in long-term infection in response to this unmet need. Our recent studies have revealed that Toxoplasma gondii brain infection causes changes in inhibitory circuitry (specifically the loss of inhibitory synapses) along with changes in inhibitory neurotransmission, leading to the onset of seizures. Moreover, preliminary studies demonstrating increased expression of classical complement cascade components, elevated microglial activa- tion, and substantial microglial ensheathment of neurons and inhibitory nerve terminals, propose dynamic inter- active roles for the innate immune system and resident-macrophages of the brain in altering functionally mature neural circuits during parasitic infection. In this proposal, we test the hypotheses that molecular components of the innate complement pathway mediate inhibitory synapse loss and seizures, and that microglia remove and phagocytose these synapses following chronic Toxoplasma gondii infection. By capitalizing on multi-scale imag- ing modalities, the aims in this proposal will deliver novel ultrastructural and real-time insight into the impact of chronic parasitic infection on mature neural circuits and will offer a novel mechanism as to how persistent Toxo- plasma gondii infection may contribute to both seizures and psychiatric illness. This study is directly aligned with the NIH's Blueprint Program's mission to expand our understanding of the neuroimmune dynamic interactions that give way to neurological disorders.

项目摘要 感染和炎症可引起成熟神经连接及其功能的异常变化 在大脑中。细胞内的原生动物寄生虫，弓形虫，是一种感染大脑的病原体， 引发长期炎症反应并可能导致癫痫这种寄生虫的持续感染也 与行为改变有关，是发展精神疾病的一个相当大的风险因素，包括- 精神分裂症超过30%的美国人目前患有无法治愈的长期弓形虫感染， 然而，尽管它的流行和严重的神经系统疾病的影响，我们缺乏足够的 了解终身寄生虫感染对大脑的影响-大脑是人体的主要器官， 寄生虫侵入细胞。本研究旨在阐明脑回路失调的潜在机制， 在长期感染的情况下，这一未得到满足的需求。我们最近的研究表明弓形虫 弓形虫脑感染引起抑制回路的变化（特别是抑制性突触的丧失）沿着 伴随着抑制性神经传递的变化，导致癫痫发作。此外，初步研究 表明经典补体级联反应组分表达增加，小胶质细胞活化增加， 和大量的神经元和抑制性神经末梢的小胶质细胞鞘，提出动态的inter-nerve。 先天免疫系统和脑内巨噬细胞在改变功能成熟 寄生虫感染期间的神经回路。在这个建议中，我们测试的假设，分子组成的 先天补体途径介导抑制性突触丧失和癫痫发作，小胶质细胞去除并 慢性弓形虫感染后吞噬这些突触。通过利用多尺度图像- 通过模式，本提案中的目标将提供新的超微结构和实时洞察的影响， 慢性寄生虫感染成熟的神经回路，并将提供一个新的机制，如何持久的弓形虫， 血浆弓形虫感染可能导致癫痫发作和精神疾病。这项研究直接与 NIH蓝图计划的使命是扩展我们对神经免疫动态相互作用的理解， 导致神经系统紊乱