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的和不断增加的疾病负担，并已 越来越多的人认为这与小脑发病有关。小脑发育与一种关键的 大脑网络的建立支持神经典型结果的发育期。然而， 通过早期发育，小脑在支持网络结构和功能方面的确切作用是 人们对此知之甚少。制定干预措施以预防和治疗与以下疾病相关的神经发育障碍 与早熟相关需要全面了解动态电路响应 函数摄动。该方案将鼠标开发的独特功能与 通过关键基因操作动态改变小脑功能的小鼠遗传操作的复杂性 发育窗口期，全面描述由此产生的解剖、生理和行为 相关网络的中断。这一建议的中心假设是小脑功能是第一位的 大脑网络结构的建立所需要的，而随后对正在进行的功能是重要的， 神经发育障碍的基础是一种动态。这项提议将利用 候选人开发的浦肯野细胞神经传递的可诱导沉默模型。在目标1中， 实验将测试早期和晚期小脑中断如何影响行为，预测早期沉默将 有普遍的行为缺陷，而迟发的沉默会产生特定领域的功能缺陷。在目标2中， 这些实验旨在研究早期沉默和晚期沉默对大脑的组装和功能的影响。 使用解剖和电生理学分析的电路。有了这些目标，该提案勾勒出了一个严格的 将动态遗传扰动、定量解剖和电生理分析相结合的方法， 以及跨领域的行为分析，以更好地了解早期小脑侮辱是如何对 神经发育障碍。应聘者是一位训练有素的儿科神经科医生，具有广泛的临床经验。 对神经发育障碍的诊断和治疗，基础和高级的应用和分析 成像技术，以及模型生物行为分析方面的研究经验。这项建议是经过指导的 由Roy Sillitoe博士撰写，他是小脑神经科学领域的领军人物，在NIH资助、指导、 和科学领导力。所有实验都将在神经学研究所进行，该研究所是一家儿科 借鉴德克萨斯儿童医院和世界级医院的卓越临床经验的神经学研究设施 贝勒医学院的神经科学。专业发展和培训计划旨在保持平衡 作为一名内科科学家的候选人，他专注于预防和治疗 儿童人群中的神经发育障碍，特别是使用基于GAP的方法 结合网络分析和高级统计技术方面的培训。完成所需的 AIMS将阐明小脑中断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.