Molecular Mechanisms Controlling Formation of Basal Ganglia Circuitry

描述（由申请人提供）：基底神经节包括主要参与控制有目的运动和适当行为的核团的集合。纹状体代表基底神经节的主要组成部分，其通过处理皮质输入起作用，随后通过两个不同的通路调节输出核（脚内核和黑质）中的活动。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。据信，这两种途径之间的平衡输出是正常大脑功能所必需的。事实上，已知该回路的功能障碍是在神经退行性疾病、帕金森病和亨廷顿病中观察到的异常运动的基础。此外，该回路的故障也与神经发育障碍图雷特综合征和强迫症（OCD）有关。目前，对纹状体输出通路形成的分子机制知之甚少。我们的命运作图数据表明，LIM同源域转录因子Islet 1主要在直接纹状体输出通路的祖细胞中表达。本提案将研究Islet 1在直接纹状体输出通路的正确形成中的需求。在具体目标1中，我们将确定这种转录因子在纹状体祖细胞中的作用。具体目标2将确定在网状丘脑和齿状回的正确形成中对Islet 1的需求，以及它们在纹状体输出通路的正确形成中的后续作用。最后，我们的初步数据表明，在直接纹状体输出通路的形成中，Islet 1下游的丛蛋白D1-Sema 3E信号传导。因此，具体目标3将解决丛蛋白D1和Sema 3E在纹状体输出通路形成中的作用。阐明基底神经节电路形成的机制可能会导致更好地了解某些基底神经节疾病的神经元改变，以及为这些疾病提供更好的治疗方法。 公共卫生相关性：端脑是大脑中与认知和自主运动最相关的区域。具体来说，大脑皮层通过基底神经节控制这些过程，基底神经节为所需的任务优化和选择适当的皮层程序。基底神经节的主要组成部分，纹状体（或尾壳核）处理皮质输入，随后通过两条输出通路调节基底神经节的输出核。直接通路将纹状体单突触连接到输出核团，而间接通路是多突触回路。据信，直接和间接纹状体输出通路之间的平衡输出对于正常的脑功能至关重要。事实上，这些纹状体通路的功能障碍发生在许多神经退行性疾病中，例如帕金森病和亨廷顿舞蹈病，导致异常运动，在某些情况下导致痴呆。此外，某些神经发育障碍，如图雷特综合征和强迫症（OCD）已被认为是由纹状体回路的功能障碍和/或发育改变引起的。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。这一提议将阐明控制直接和间接途径形成的分子机制，特别是LIM同源结构域蛋白Islet 1及其下游效应分子如丛蛋白D1在这些重要的基底神经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.