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

• 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
• 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

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

项目概要/摘要： 异常纹状体回路与常见神经发育疾病的发病机制有关， 自闭症谱系障碍、抽动障碍、注意力缺陷/多动障碍和强迫症 disorder.这些障碍的运动、认知和社会障碍特征通常会干扰患者的健康。 个人参与日常生活活动的能力。尽管基底神经节缺陷 连接可以驱动这些行为障碍，正常和不正常的遗传和分子起源， 病理性神经回路仍然知之甚少，从而限制了治疗的合理发展。 Sox 8是一种转录因子，其缺失导致纹状体直接途径生长受损。Sox 8突变小鼠 尽管该基因不表达，但在皮质延髓和皮质脊髓投射中似乎也有缺陷， 在这些皮层神经元中。鉴于这两条轴突通路在内囊内紧密相连 因此，在早期发育过程中，Sox 8突变体中存在的解剖缺陷表明， 引导下行皮质投射的直接通路。这个应用的中心假设是 是直接通路轴突率先形成内囊并引导下行皮质延髓 以及穿过间脑和中脑的皮质脊髓轴突。 为了检验这一假设，将使用Sox 8 KO小鼠作为工具，以1）询问以下发育要求： 引导下行离皮质轴突适当生长的直接途径; 2）阐明 他们所遵循的，是一种引导他们的方法。利用Sox 8-EGFP（直接途径）和Fezf 2-TdTomato （离皮质途径）BAC转基因报告子在整个发育过程中追踪这些途径，Aim 1将 重点是确定他们的发展轨迹，并确定他们的相互依存关系， 正确的编队目标2中的拟议实验将侧重于建立体外试验，以确定 直接和离皮质途径轴突成束和生长的分子调节剂。这些试验将 用于评估候选因子Tenm 2介导在Sox 8突变体中观察到的轴突缺陷。 成功完成本申请中概述的目标将增加我们对纹状体如何 缺陷可能影响其他主要轴突束的适当形成，从而导致 神经发育障碍