Unraveling the Dynamic Role of Purkinje Cell Neurotransmission in Neurodevelopment.

揭示浦肯野细胞神经传递在神经发育中的动态作用。

• 批准号: 10645079
• 负责人: Jason Singh Gill
• 金额: $ 19.11万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645079
• 关键词: Ablation; Address; Affect; Affective; Age; Anatomy; Animal Behavior; Behavior; Behavioral; Behavioral Assay; Biological Assay; Brain; Brain Injuries; Cell physiology; Cells; Cerebellar Cortex; Cerebellar Diseases; Cerebellar Nuclei; Cerebellum; Childhood; Clinical; Cognitive; Data; Development; Diagnosis; Disease; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; Etiology; Experimental Designs; Exposure to; Family; Funding; Genetic; Genetic Models; Grooming; Human; Image; Imaging Techniques; Immunohistochemistry; Incidence; Inferior; Injury; Instinct; Intervention; Leadership; LoxP-flanked allele; Marble; Mediating; Medicine; Mendelian disorder; Mentors; Mentorship; Modeling; Morbidity - disease rate; Mus; Neurodevelopmental Disability; Neurodevelopmental Disorder; Neurologic; Neurologist; Neurons; Neurophysiology - biologic function; Neurosciences; Nose; Nuclear; Olives - dietary; Outcome; Output; Pathogenesis; Pathology; Pathway Analysis; Patients; Pattern; Pediatric Hospitals; Pediatric Neurology; Personal Satisfaction; Physicians; Physiological; Population; Pregnancy; Prevention; Preventive measure; Property; Public Health; Purkinje Cells; Research; Research Institute; Role; Scientist; Site; Structure; System; Techniques; Testing; Tetracyclines; Texas; Therapeutic; Third Pregnancy Trimester; Training; Transcriptional Activation; United States National Institutes of Health; Work; analytical tool; behavioral outcome; burden of illness; career; cohort; college; critical developmental period; critical period; design; disorder prevention; experience; experimental study; field study; genetic manipulation; genome editing; in vivo; innovation; insight; model organism; motor behavior; motor deficit; mouse development; mouse genetics; network dysfunction; neurodevelopment; neurotransmission; postnatal; premature; prevent; preventive intervention; research facility; response; safety net; social; societal costs; support network; vesicular GABA transporter; water maze

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.

早产引起的神经发育障碍会造成较大且增加的疾病伯恩（Burnen） 越来越多地与小脑发病机理有关。小脑发展与关键 在此期间，大脑网络的建立支持神经型结局。然而， 小脑在通过早期发展支持网络结构和功能中的确切作用是 理解不佳。开发干预措施，以预防和治疗与 与早产相关的需要对动态电路响应的全面理解 功能扰动。该建议使用鼠标开发的独特功能，并结合 小鼠遗传操作的社交化，以通过关键的方式动态改变小脑功能 发展窗口同时全面表征所得的解剖，生理和行为 相关网络的破坏。该提议的中心假设是小脑功能首先 结构建立大脑网络所必需的，而随后对持续功能很重要， 一种动态，是神经发育障碍范围的基础。该建议将利用 候选人开发的Purkinje细胞神经传递的诱导沉默模型。在AIM 1中 实验将测试早期与小脑晚期的破坏会影响行为，预测早期沉默将会 具有普遍的行为定义，而晚期沉默将产生特定的域功能定义。在AIM 2中， 实验旨在检查早期与晚期沉默如何影响大脑的组装和功能 使用解剖学和电生理分析的电路。以这些目的，该提案概述了严格的 结合动态遗传扰动，定量解剖学和电生理分析的方法， 和跨域行为测定法，以更好地了解小脑损伤如何贡献 神经发育残疾。候选人是一名受过训练的儿科神经科医生，具有广泛的临床暴露 为了诊断和治疗神经发育障碍，基本和先进的应用和分析 成像技术和模型生物行为分析的研究经验。该建议被考虑 小脑神经科学领导者Roy Sillitoe博士拥有NIH资助，Mentalship，Mentalship， 和科学领导。所有实验将在儿科神经研究所进行 神经病学研究机构借鉴了德克萨斯儿童医院和世界一流的临床卓越性 贝勒医学院的神经科学。专业发展和培训计划旨在毒化 作为身体科学家职业的候选人，重点是预防和治疗 儿科人群中的神经发育残疾专门利用基于间隙的方法 将培训纳入网络分析和高级统计技术中。完成的完成 目标将阐明小脑干扰导致神经发育障碍的机制。

项目成果

Quantification of Behavioral Deficits in Developing Mice With Dystonic Behaviors.

具有肌张力障碍行为的小鼠的行为缺陷的量化。

• DOI: 10.3389/dyst.2022.10494
• 发表时间: 2022
• 期刊: Dystonia
• 作者: VanDerHeijden,MeikeE;Gill,JasonS;ReyHipolito,AlejandroG;SalazarLeon,LuisE;Sillitoe,RoyV
• 通讯作者: Sillitoe,RoyV