Molecular Mechanisms Controlling Formation of Basal Ganglia Circuitry

控制基底神经节回路形成的分子机制

• 批准号: 9918974
• 负责人: KENNETH J CAMPBELL
• 金额: $ 57.88万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918974
• 关键词: Anatomy; Animals; Attention deficit hyperactivity disorder; Axon; BACH2 gene; Basal Ganglia; Behavior; Behavioral; Brain; Brain Diseases; Brain region; Candidate Disease Gene; Cell Death; Cell Nucleus; Childhood; Cognition; Cognitive; Cognitive deficits; Corpus striatum structure; Data; Defect; Development; Disease; Embryo; Exhibits; FOXO1A gene; Funding; Gene Expression Profile; Genes; Genetic; Genetic Models; Gilles de la Tourette syndrome; Globus Pallidus; Goals; Heterozygote; Human; Huntington Disease; Hyperactive behavior; Impaired cognition; Intellectual functioning disability; Mediating; Molecular; Molecular Genetics; Motor; Movement; Mus; Mutant Strains Mice; Neurons; Output; Parkinson Disease; Pathway interactions; Phenotype; Play; Prosencephalon; Publishing; Regulatory T-Lymphocyte; Reporting; Role; SOX8 gene; Social Functioning; Substantia nigra structure; Telencephalon; Testing; Transgenic Organisms; Ventricular; autism spectrum disorder; axon growth; cell type; cognitive function; conditional mutant; genetic analysis; locomotor deficit; loss of function; mutant; nerve supply; neuron development; neuron loss; neuronal survival; neuropsychiatric disorder; novel; novel marker; oligodendrocyte lineage; postnatal; premature; progenitor; psychostimulant; restoration; single-cell RNA sequencing; social; transcription factor; transcriptome

The basal ganglia are known to regulate motor function and have recently been implicated in both social and cognitive functions as well. As a result, these brain nuclei have been implicated in childhood disorders, ADHD, OCD, Tourette's syndrome and autism, which display a spectrum of behavioral abnormalities. These childhood disorders have been proposed to result from abnormal development/function of basal ganglia circuitry. The striatum represents the major nucleus of the basal ganglia and the striatal projection neurons (SPNs) comprise the major neuronal subtype on which the basal ganglia circuit is dependent. The direct pathway (d)SPNs project to the output nuclei of the basal ganglia, while the indirect pathway (i)SPN axons innervate an intermediate nucleus and indirectly influencing the output nuclei though a polysynaptic circuit. Balanced activity between these two pathways is fundamental for normal brain function. Despite the importance of these striatal output pathways, little is known about the molecular genetic mechanisms controlling their formation. In the previous funding cycle, we showed that the transcription factor Isl1 is required for the normal formation of dSPNs. In its absence, these neurons are generated but do not survive and as a result, innervation of the output nuclei is severely compromised. Isl1 conditional mutants (cKOs) exhibit behavioral abnormalities reminiscent of ADHD as they are hyperactive and blunted to psychostimulant treatment. Moreover, we identified the transcription factor Sox8 in dSPNs. Our data indicate that the direct pathway axons do not project properly in Sox8 homozygous mutants. However, unlike the Isl1 cKOs, no SPN cell death was observed. Interestingly, Sox8 heterozygotes showed a partial phenotype with reduced direct pathway axonal innervation. Both the heterozygous and homozygous Sox8 animals exhibited hyperactivity, reminiscent of Isl1 cKOs, as well as, cognitive impairments. The main goal of this proposal is to understand the molecular genetic pathways controlling the development of dSPNs and specifically the roles of the transcription factors Sox8, Bach2 and Arx with respect to neuronal survival/differentiation and axon outgrowth. We will achieve this by testing the following hypotheses: 1) Sox8 regulates dSPN axon outgrowth downstream of Ebf1 by controlling the timing of maturation, 2) Isl1 regulates a Foxo/Bach2-mediated survival/differentiation pathway in developing dSPNs and 3) Arx is required for development of dSPNs and their altered development in Arx mutants accounts for certain behavioral defects observed in these mutants. Our approach will combine molecular and cellular analysis of genetic mouse mutants exhibiting defined alterations in dSPN connectivity and correlate this with specific behavioral abnormalities in motor and cognitive function. The genetic models in this proposal may inform human studies of ADHD, OCD, Tourette's as well as autism and intellectual disabilities.

众所周知，基底神经节可以调节运动功能，最近与社会和认知有关 功能也是如此。结果，这些脑核与儿童疾病有关 综合症和自闭症，表现出一系列行为异常。这些童年疾病一直 提议是由于基底神经节回路异常的发育/功能所致。纹状体代表专业 基底神经节和纹状体投射神经元（SPN）的核包括主要神经元亚型 基底神经节电路取决于。直接途径（D）SPNS向基底神经节的输出核项目项目，而 间接途径（i）SPN轴突支配中间核并间接影响输出核A通过A 多突触电路。这两种途径之间的平衡活动对于正常的大脑功能是基础。尽管有 这些纹状体输出途径的重要性，对控制其的分子遗传机制知之甚少 形成。在上一个融资周期中，我们表明正常形成需要转录因子ISL1 DSPN。在没有的情况下，这些神经元是生成但无法生存的，因此，输出核的神经是 严重妥协。 ISL1条件突变体（CKO）表现出行为异常，让人联想到ADHD。 过度活跃，对精神刺激治疗感到钝化。此外，我们确定了DSPN中的转录因子SOX8。 我们的数据表明，直接途径轴突在SOX8纯合突变体中无法正确投射。但是，与 ISL1 CKO，未观察到SPN细胞死亡。有趣的是，Sox8杂合子显示出部分表型，降低 直接途径轴突神经。杂合和纯合SOX8动物都表现出多动症， 让人联想到ISL1 CKO以及认知障碍。该提议的主要目标是了解分子 控制DSPN的发展，特别是转录因子Sox8，Bach2的作用的遗传途径 和ARX相对于神经元存活/分化和轴突生长。我们将通过测试 以下假设：1）SOX8通过控制EBF1下游的DSPN轴突的生长 成熟，2）ISL1调节发育中的DSPN中的FOXO/BACH2介导的生存/分化途径，3）ARX IS DSPN的开发及其在ARX突变体中的开发改变所必需的所必需的某些行为缺陷 在这些突变体中观察到。我们的方法将结合遗传小鼠突变体的分子和细胞分析 展示了DSPN连接性的定义变化，并将其与电动机和电动机的特定行为异常相关联 认知功能。该提案中的遗传模型可能会为人类的ADHD，OCD，Tourette的研究提供信息 自闭症和智力残疾。