Contributions of the striatal direct pathway to the formation of corticofugal axon trajectories

纹状体直接通路对皮质轴突轨迹形成的贡献

基本信息

批准号：
10376754
负责人：
Jacqueline Marie Ehrman
金额：
$ 5.18万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2022-06-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10376754
关键词：
Activities of Daily Living Anatomy Attention deficit hyperactivity disorder Axon Bacterial Artificial Chromosomes Basal Ganglia Behavioral Biological Assay Candidate Disease Gene Cell Nucleus Characteristics Cognition Cognitive Cognitive deficits Collection Corpus striatum structure Corticospinal Tracts Cues Data Defect Development Disease Equilibrium Etiology Exhibits Functional disorder Genes Genetic Globus Pallidus Immunofluorescence Immunologic Impairment In Vitro Individual Integral Membrane Protein Intellectual functioning disability Internal Capsule Knock-out Knockout Mice Mediating Mediator of activation protein Midbrain structure Molecular Motor Movement Mus Muscle fasciculation Mutant Strains Mice Neurodevelopmental Disorder Neurons Obsessive-Compulsive Disorder Output Pathogenesis Pathologic Pathway interactions Patient-Focused Outcomes Phenotype Reporter Role Route SOX8 gene Signal Transduction Social Behavior Social outcome Structure of subthalamic nucleus Substantia nigra structure Synapses Testing Thalamic structure Tic disorder Transgenic Organisms Work autism spectrum disorder axon guidance axonal pathfinding behavioral impairment diencephalon experimental study improved in vitro Assay motor deficit mutant nervous system disorder neural circuit novel programs psychostimulant response social social deficits spatiotemporal therapeutic development therapy development tool transcription factor transcriptome sequencing

项目摘要

Project Summary/Abstract: Abnormal striatal circuitry is implicated in the pathogenesis of common neurodevelopmental conditions including autism spectrum disorder, tic disorder, attention-deficit/hyperactivity disorder, and obsessive-compulsive disorder. The motor, cognitive, and social impairments characteristic of these disorders often interfere with an individual’s ability to participate in activities of daily living. Despite the notion that defects in basal ganglia connectivity can drive these behavioral impairments, the genetic and molecular origins of both normal and pathologic neural circuits remain poorly understood, thereby limiting the rational development of therapeutics. Sox8 is a transcription factor whose loss results in impaired striatal direct pathway outgrowth. Sox8 mutant mice also appear to have defects in corticobulbar and corticospinal projections, despite that this gene is not expressed in these cortical neurons. Given that these two axon pathways form in close proximity within the internal capsule during early development, the anatomical defects present in Sox8 mutants thus suggest a novel role for the direct pathway in the guidance of descending cortical projections. The central hypothesis for this application is that direct pathway axons pioneer the forming internal capsule and guide descending corticobulbar and corticospinal axons through the diencephalon and midbrain. To test this hypothesis, Sox8 KO mice will be used as a tool to 1) interrogate the developmental requirement for the direct pathway in guiding the appropriate outgrowth of descending corticofugal axons and 2) elucidate the mechanism(s) by which it serves to guide them. Utilizing Sox8-EGFP (direct pathway) and Fezf2-TdTomato (corticofugal pathway) BAC transgenic reporters to trace these pathways throughout development, Aim 1 will focus on defining their developmental trajectories and determining their interdependence on one another for their proper formation. The proposed experiments in Aim 2 will focus on establishing in vitro assays to identify molecular regulators of direct and corticofugal pathway axon fasciculation and outgrowth. These assays will be used to evaluate a candidate factor, Tenm2, in mediating the observed axon defects apparent in Sox8 mutants. The successful completion of the aims outlined in this application will increase our understanding of how striatal defects can impact the appropriate formation of other major axon tracts and thereby contribute to the etiology of neurodevelopmental disorders

项目摘要/摘要：在常见神经发育条件的发病机理中暗示了异常的纹状体回路自闭症谱系障碍，抽动障碍，注意力缺陷/多动障碍和强迫症紊乱。这些疾病的运动，认知和社会障碍的特征通常会干扰个人参加日常生活活动的能力。尽管有基础神经节缺陷的观念连通性可以驱动这些行为障碍，正常和病理性的神经元回路仍然很少了解，从而限制了治疗剂的合理发展。 Sox8是转录因子，其损失导致纹状体直接途径的生长受损。 SOX8突变小鼠在皮质骨和皮质脊髓项目中似乎也有缺陷，该基因未表达在这些皮质神经元中。鉴于这两个轴突途径在内部胶囊内近距离形成在早期发育过程中，Sox8突变体中存在的解剖缺陷表明了在下降皮层项目的指导中的直接途径。此应用的中心假设是直接途径轴突先锋形成的内部胶囊和引导降级皮质卵石和皮质脊髓轴突穿过diencephalon和中脑。为了检验该假设，Sox8 KO小鼠将用作工具1）指导降皮层轴突的适当产物的直接途径，2）阐明它可以指导它们的机制。利用Sox8-EGFP（直接途径）和FEZF2-TDTOMATO （皮质法瓜途径）BAC转基因记者在整个开发过程中追踪这些途径，AIM 1 Will 专注于定义其发展轨迹并确定他们的相互依存关系正确的形成。 AIM 2中提出的实验将集中于建立体外测定以识别直接和皮层途径的分子调节剂轴突诱发和生长。这些测定将是用于评估候选因子TENM2，用于介导SOX8突变体中观察到的轴突缺陷。该应用程序中概述的目标的成功完成将增加我们对纹状体的理解缺陷会影响其他主要轴突的适当形成，从而有助于病因神经发育障碍