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，基底节调节运动功能，最近被认为与社会和认知有关。 功能也是如此。因此，这些大脑核团与儿童障碍、ADHD、强迫症、抽动症有关 综合症和自闭症，表现出一系列行为异常。这些童年时期的障碍一直是 被认为是由于基底节回路的异常发育/功能所致。纹状体代表大脑皮层 基底节核和纹状体投射神经元(SPN)构成主要的神经元亚型，其上的 基底节环路是依赖的。直接通路(D)SPN投射到基底节的输出核团，而 间接通路(I)SPN轴突支配中间核，并通过 多突触回路。这两条通路之间的平衡活动是正常大脑功能的基础。尽管 这些纹状体输出途径的重要性，对控制它们的分子遗传机制知之甚少 队形。在之前的资金周期中，我们证明了转录因子isl1是正常形成所必需的。 DSPN的数量。在没有它的情况下，这些神经元会产生，但不会存活，因此，输出核团的神经支配是 严重受损。ISL1条件突变(CKO)表现出行为异常，使人联想到ADHD 过度活跃，对精神刺激治疗反应迟钝。此外，我们还在dSPN中鉴定了转录因子Sox8。 我们的数据表明，在Sox8纯合子突变体中，直接路径轴突不能正确投射。然而，与 1cKOS，未见SPN细胞死亡。有趣的是，Sox8杂合子表现出部分表型 直接通路轴突神经支配。杂合子和纯合子的Sox8动物都表现出多动， 这让人想起IS11的cKO，以及认知障碍。这项提议的主要目标是理解分子 控制dSPN发育的遗传途径，特别是转录因子Sox8、Bach2的作用 Arx在神经元存活/分化和轴突生长方面的作用。我们将通过测试 以下假设：1)Sox8通过控制时间调控dSPN轴突在EBF1下游的生长 成熟，2)Isl1调节FOXO/Bach2介导的dSPN存活/分化途径，3)Arx IS 在Arx突变体中，dSPN的发育和它们的改变发育所需的蛋白质可以解释某些行为缺陷 在这些突变体中观察到。我们的方法将结合对小鼠遗传突变的分子和细胞分析 表现出dSPN连接性的明确改变，并与运动和运动中的特定行为异常相关 认知功能。这项建议中的遗传模型可能会为ADHD、OCD、Tourette‘s以及 自闭症和智力残疾。