Molecular Mechanisms Controlling Formation of Basal Ganglia Circuitry

描述(申请人提供)：基底节包括一组核，主要参与控制有目的的运动和适当的行为。纹状体是基底神经节的主要组成部分，它通过处理皮质输入而发挥作用，随后通过两条不同的途径调节输出核(内侧丘脑核和黑质)的活动。直接通路单突触连接纹状体和输出核团，间接通路通过苍白球和丘脑底核影响输出核团。人们认为，这两条通路之间的平衡输出是正常大脑功能所必需的。事实上，众所周知，在神经退行性疾病、帕金森氏症和亨廷顿病中观察到的异常运动是这种回路功能障碍的基础。此外，这个回路的故障也与神经发育障碍多发性抽动症和强迫症(OCD)有关。目前，对纹状体输出通路形成的分子机制知之甚少。我们的命运图谱数据表明，LIM同源结构域转录因子Islet1主要在直接纹状体输出途径的祖细胞中表达。该提案将研究Islet1在直接纹状体输出通路的正确形成中的要求。在特定的目标1中，我们将确定该转录因子在纹状体前体细胞自身中的作用。具体目标2将确定Islet1在网状丘脑和未确定带的正确形成中的需求，以及它们随后在纹状体输出通路的正确形成中的作用。最后，我们的初步数据表明，Islet1下游的PlexinD1-Sema3E信号与直接纹状体输出通路的形成有关。因此，具体目标3将阐述PlexinD1和Sema3E在纹状体输出通路形成中的作用。阐明基底节回路形成的机制可能有助于更好地了解某些基底节疾病的神经元变化，并为开发更好的治疗这些疾病的方法提供机会。 与公共健康相关：端脑代表大脑中与认知和自愿运动最相关的区域。具体地说，大脑皮层通过基底节控制这些过程，基底节为所需的任务提炼和选择适当的皮质程序。纹状体(或尾壳核)是基底节的主要组成部分，负责处理皮质输入，随后通过两条输出通路调节基底节的输出核。直接通路将纹状体单突触连接到输出核团，而间接通路则是一个多突触回路。据认为，直接和间接纹状体输出通路之间的平衡输出对正常的大脑功能至关重要。事实上，这些纹状体通路的故障会发生在一些神经退行性疾病中，如帕金森氏症和亨廷顿舞蹈症，导致异常运动，在某些情况下还会导致痴呆症。此外，某些神经发育障碍，如抽动症和强迫症(OCD)，被认为是纹状体回路功能障碍和/或发育改变的结果。目前，对哺乳动物纹状体的发育，特别是纹状体输出通路的形成知之甚少。这一建议将阐明控制直接和间接通路形成的分子机制，特别是LIM同源结构域蛋白Islet1及其下游效应分子(如PlexinD1)在这些重要基底节连接形成中的作用。

DESCRIPTION (provided by applicant): The basal ganglia comprise a collection of nuclei that are primarily involved in controlling purposeful movements and appropriate behavior. The striatum represents the major component of the basal ganglia which functions by processing cortical inputs and subsequently regulates activity in the output nuclei (the entopeduncular nucleus and substantia nigra) through two distinct pathways. The direct pathway monosynaptically connects the striatum to the output nuclei, while the indirect pathway influences the output nuclei via the globus pallidus and subthalamic nucleus. It is believed that balanced output between these two pathways is required for normal brain function. Indeed, dysfunction of this circuit is known to underlie the abnormal movements observed in the neurodegenerative disorders, Parkinson's and Huntington's disease. Moreover, malfunction of this circuit has also been implicated in the neurodevelopmental disorders Tourette's syndrome and obsessive compulsive disorder (OCD). Currently, little is known about the molecular mechanisms underlying the formation of the striatal output pathways. Our fate mapping data indicates that the LIM homeodomain transcription factor Islet1 is expressed predominantly in the progenitors of the direct striatal output pathway. This proposal will examine the requirement for Islet1 in the correct formation of the direct striatal output pathways. In Specific Aim 1, we will determine the role of this transcription factor in the striatal progenitors, themselves. Specific Aim 2 will determine the requirement for Islet1 in the correct formation of the reticular thalamus and zona incerta as well as their subsequent role in the correct formation of the striatal output pathways. Finally, our preliminary data implicate PlexinD1-Sema3E signaling downstream of Islet1 in the formation of the direct striatal output pathways. Thus, Specific Aim 3 will address the role of PlexinD1 and Sema3E in the formation of the striatal output pathways. Elucidation of the mechanisms underlying the formation of basal ganglia circuitry may lead to a better understanding of the neuronal alterations in certain basal ganglia disorders as well as provide opportunities to develop better treatments for these conditions. PUBLIC HEALTH RELEVANCE: The telencephalon represents the region of the brain most concerned with cognition and voluntary movement. Specifically, the cerebral cortex controls these processes via the basal ganglia, which refine and select appropriate cortical programs for the desired tasks. The major component of the basal ganglia, the striatum (or caudate-putamen) processes cortical inputs and subsequently regulates the output nuclei of the basal ganglia through two output pathways. The direct pathway connects the striatum monosynaptically to the output nuclei while the indirect pathway is a polysynaptic circuit. It is believed that balanced output between the direct and indirect striatal output pathways is crucial for normal brain function. Indeed, malfunction of these striatal pathways occurs in a number of neurodegenerative disorders such as Parkinson's disease and Huntington's chorea, leading to abnormal movements and in some cases dementia. Moreover, certain neurodevelopmental disorders, such as Tourette's syndrome and obsessive compulsive disorder (OCD) have been suggested to result from malfunction and/or altered development of striatal circuitry. At present, little is known about the development of the mammalian striatum and in particular the formation of the striatal output pathways. This proposal will shed light on the molecular mechanisms that control the formation of direct and indirect pathways and specifically the role of the LIM homeodomain protein Islet1 and its down-stream effector molecules such as PlexinD1 in the formation of these important basal ganglia connections.