Unraveling the Dynamic Role of Purkinje Cell Neurotransmission in Neurodevelopment.

早产引起的神经发育障碍造成了巨大且不断增加的疾病负担， 越来越多地与小脑发病机制有关。小脑的发育与一个关键的 发育期，在此期间，大脑网络的建立支持神经典型的结果。然而，在这方面， 小脑在早期发育中支持网络结构和功能的确切作用是 不太了解。制定干预措施，预防和治疗与以下疾病相关的神经发育障碍 需要全面了解动态电路响应， 功能扰动该提案结合鼠标开发的独特功能 小鼠遗传操作的复杂性，通过一个关键的 发育窗口，同时全面表征所产生的解剖，生理和行为 破坏相关网络。这一提议的核心假设是，小脑的功能首先是 大脑网络的结构建立所必需的，同时随后对持续的功能很重要， 这是神经发育障碍的基础。该提案将利用 由候选人开发的浦肯野细胞神经传递诱导沉默模型。在目标1中， 实验将测试早期与晚期小脑破坏如何影响行为，预测早期沉默将 具有广泛的行为缺陷，而晚期沉默将产生领域特异性功能缺陷。在目标2中， 这些实验旨在研究早期和晚期沉默如何影响大脑的组装和功能。 电路使用解剖和电生理分析。有了这些目标，该提案概述了一个严格的 结合动态遗传扰动，定量解剖和电生理分析， 和跨域行为分析，以更好地了解早期小脑损伤如何有助于 神经发育障碍候选人是一名训练有素的儿科神经科医生，具有广泛的临床经验。 神经发育障碍的诊断和治疗，应用和分析的基础和先进的 成像技术和模式生物行为测定的研究经验。该提案是指导性的 罗伊·西利托博士是小脑神经科学的领导者，他在美国国立卫生研究院的资助、指导 科学的领导力。所有实验将在神经研究所进行，这是一个儿科研究所。 神经病学研究机构，借鉴了得克萨斯州儿童医院的临床卓越和世界一流的 贝勒医学院的神经科学。专业发展和培训计划旨在平衡 候选人的职业生涯作为一个医生科学家专注于预防和治疗 神经发育障碍的儿科人群，特别是利用差距为基础的方法， 包括网络分析和高级统计技术方面的培训。完成所需的 目的是阐明小脑破坏导致神经发育障碍的机制。

Neurodevelopmental disability arising from prematurity poses a large and increasing disease burden and has increasingly been associated with cerebellar pathogenesis. Cerebellar development coincides with a critical developmental period during which establishment of brain networks supports neurotypical outcomes. However, the precise role of the cerebellum in supporting network structure and function through early development is poorly understood. Developing interventions to prevent and treat neurodevelopmental disability associated with associated with prematurity requires a comprehensive understanding of the dynamic circuit response to functional perturbations. This proposal uses unique features of mouse development in combination with the sophistication of mouse genetic manipulations to dynamically alter cerebellar function through a critical developmental window while comprehensively characterizing the resulting anatomic, physiologic, and behavioral disruptions of the associated networks. The central hypothesis of this proposal is that cerebellar function is first required for structural establishment of brain networks while subsequently being important for ongoing function, a dynamic that underlies the spectrum of neurodevelopmental disability. This proposal will take advantage of a model for inducible silencing of Purkinje cell neurotransmission developed by the candidate. In Aim 1, the experiments will test how early vs late cerebellar disruption affects behavior, predicting that early silencing will have pervasive behavioral deficits while late silencing will produce domain specific functional deficits. In Aim 2, the experiments are designed to examine how early vs late silencing affects the assembly and function of brain circuits using anatomic and electrophysiologic analyses. With these aims, the proposal outlines a rigorous approach that combines dynamic genetic perturbations, quantitative anatomic and electrophysiologic analyses, and cross-domain behavioral assays to better understand how early cerebellar insult contributes to neurodevelopmental disability. The candidate is a trained pediatric neurologist with extensive clinical exposure to diagnosis and treatment of neurodevelopmental disorders, application and analysis of basic and advanced imaging techniques, and research experience in model organism behavioral assays. This proposal is mentored by Dr. Roy Sillitoe, a leader in cerebellar neuroscience who has strong track record of NIH funding, mentorship, and scientific leadership. All experiments will be conducted at the Neurologic Research Institute, a pediatric neurology research facility that draws on the clinical excellence of Texas Children’s Hospital and the world-class neuroscience of Baylor College of Medicine. The professional development and training plan is designed to poise the candidate for a career as a physician scientist focused on the prevention and treatment of neurodevelopmental disability in the pediatric population specifically utilizing a gap based approach that incorporates training in network analysis and advanced statistical techniques. The completion of the entailed aims will elucidate the mechanisms by which cerebellar disruptions contribute to neurodevelopmental disability.