Molecular Mechanisms Controlling Formation of Basal Ganglia Circuitry

控制基底神经节回路形成的分子机制

基本信息

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
项目类别：
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

项目摘要

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，并且最近与社交和认知功能有关功能也一样。因此，这些脑核与儿童疾病、多动症、强迫症、抽动秽语症有关综合症和自闭症，表现出一系列行为异常。这些儿童期疾病已推测是由于基底神经节电路的异常发育/功能引起的。纹状体代表主要基底神经节核和纹状体投射神经元 (SPN) 构成主要神经元亚型，基底神经节回路是依赖的。直接通路 (d)SPN 投射到基底神经节的输出核，而间接途径 (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，但人们对控制其的分子遗传机制知之甚少。形成。在上一个资助周期中，我们证明了转录因子Isl1是正常形成所必需的 dSPN。如果没有它，这些神经元会生成但不会存活，因此，输出核的神经支配是严重受损。 Isl1 条件突变体 (cKO) 表现出让人想起 ADHD 的行为异常，因为它们过度活跃并且对精神兴奋剂治疗迟钝。此外，我们在 dSPN 中鉴定出了转录因子 Sox8。我们的数据表明直接通路轴突在 Sox8 纯合突变体中不能正确投射。然而，与 Isl1 cKOs，未观察到 SPN 细胞死亡。有趣的是，Sox8杂合子表现出部分表型减少直接通路轴突神经支配。杂合子和纯合子 Sox8 动物均表现出过度活跃，让人想起 Isl1 cKO，以及认知障碍。该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 Sox8、Bach2 的作用 Arx 与神经元存活/分化和轴突生长有关。我们将通过测试来实现这一目标以下假设：1) Sox8 通过控制 Ebf1 下游的 dSPN 轴突生长的时间来调节成熟，2) Isl1 调节 Foxo/Bach2 介导的 dSPN 发育过程中的生存/分化途径，3) Arx 是 dSPN 发育所需的物质及其在 Arx 突变体中发育的改变导致了某些行为缺陷在这些突变体中观察到。我们的方法将结合小鼠基因突变体的分子和细胞分析表现出 dSPN 连接性的明确改变，并将其与运动和运动方面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为 ADHD、OCD、抽动秽语症以及多动症的人类研究提供信息自闭症和智力障碍。