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

项目总结 感染和炎症可导致成熟神经连接及其功能的异常变化 在大脑里。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， 会引起长期的炎症反应，并可能导致癫痫发作。这种寄生虫的持续感染也是 与行为改变有关，是发展精神疾病的相当大的风险因素，包括- 精神分裂症。超过30%的美国人目前患有无法治愈的弓形虫长期感染- 然而，尽管它的流行率和对严重神经疾病的影响，我们缺乏足够的 了解终身寄生虫感染对大脑的影响--大脑是人体的一个主要器官， 这种寄生虫侵入细胞。本研究旨在阐明脑回路功能障碍的潜在机制。 对这一未得到满足的需求作出反应的长期感染的减少。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改变(特别是抑制突触的丢失) 随着抑制性神经传递的改变，导致癫痫发作。此外，初步研究 显示经典补体级联成分表达增加，小胶质细胞活性增加- 以及神经元和抑制性神经末梢的大量小胶质细胞包膜，提出了动态的相互作用。 脑固有免疫系统和常驻巨噬细胞在改变功能成熟中的积极作用 寄生虫感染期间的神经回路。在这个提议中，我们测试了分子组成的假设 天然补体途径介导抑制性突触丢失和癫痫发作，小胶质细胞去除和 吞噬慢性弓形虫感染后的这些突触。通过利用多尺度图像- 在模式中，本提案中的目标将提供对以下各项影响的新的超微结构和实时洞察 慢性寄生虫感染成熟的神经回路，将提供一种新的机制，说明持续的弓形虫是如何 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 美国国立卫生研究院蓝图计划的使命是扩大我们对神经免疫动态相互作用的理解 这就让位于神经紊乱。

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.