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: 10390465
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390465
• 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; Hyperactivity; 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.

已知基底神经节调节运动功能，并且最近被牵连到社交和认知两个方面。 功能也一样。因此，这些脑核团与儿童期疾病，多动症，强迫症，妥瑞氏症有关。 综合征和自闭症，表现出一系列的行为异常。这些儿童期的疾病 推测是由基底神经节电路发育/功能异常引起的。纹状体代表了大脑中 基底神经节的核和纹状体投射神经元（SPN）包括主要的神经元亚型， 基底神经节回路是依赖性的。直接通路（d）SPN投射到基底神经节的输出核，而直接通路（d）SPN投射到基底神经节的输出核。 间接途径（i）SPN轴突支配中间核，并通过中间核间接影响输出核， 多突触回路这两种途径之间的平衡活动是正常大脑功能的基础。尽管 这些纹状体输出通路的重要性，很少有人知道控制它们的分子遗传机制。 阵在上一个资助周期中，我们发现转录因子Isl 1是正常形成所必需的。 的dspn。在它的缺席，这些神经元产生，但不生存，作为一个结果，神经支配的输出核是 严重受损Isl 1条件突变体（cKO）表现出让人联想到ADHD的行为异常，因为它们 过度活跃，对精神兴奋剂治疗反应迟钝此外，我们确定了转录因子Sox 8在dSPN。 我们的数据表明，直接通路轴突不正确的项目在Sox 8纯合突变体。但不同于 Isl 1 cKO，未观察到SPN细胞死亡。有趣的是，Sox 8杂合子表现出部分表型， 直接通路轴突神经支配。杂合和纯合Sox 8动物都表现出活动过度， 让人联想到Isl 1 cKO以及认知障碍。这项提案的主要目标是了解分子 控制dSPN发育的遗传途径，特别是转录因子Sox 8、Bach 2的作用 和Arx关于神经元存活/分化和轴突生长。我们将通过测试 以下假设：1）Sox 8通过控制Ebf 1下游的dSPN轴突生长的时间来调节Ebf 1下游的dSPN轴突生长。 2）Isl 1调节发育中的dSPN中Foxo/Bach 2介导的存活/分化途径，3）Arx是 dSPN发育所需的蛋白质和它们在Arx突变体中的改变的发育解释了某些行为缺陷 在这些突变体中观察到。我们的方法将联合收割机结合分子和细胞分析遗传小鼠突变 在dSPN连接中表现出明确的改变，并将其与运动和 认知功能该建议中的遗传模型可能会为ADHD，OCD，Tourette's以及其他疾病的人类研究提供信息。 自闭症和智力残疾。

项目成果

Active intermixing of indirect and direct neurons builds the striatal mosaic.

• DOI: 10.1038/s41467-018-07171-4
• 发表时间: 2018-11-09
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Tinterri A;Menardy F;Diana MA;Lokmane L;Keita M;Coulpier F;Lemoine S;Mailhes C;Mathieu B;Merchan-Sala P;Campbell K;Gyory I;Grosschedl R;Popa D;Garel S
• 通讯作者: Garel S

Foxo1 is a downstream effector of Isl1 in direct pathway striatal projection neuron development within the embryonic mouse telencephalon.

• DOI: 10.1016/j.mcn.2017.02.003
• 发表时间: 2017-04
• 期刊: Molecular and cellular neurosciences
• 作者: Waclaw RR;Ehrman LA;Merchan-Sala P;Kohli V;Nardini D;Campbell K
• 通讯作者: Campbell K