Molecular Mechanisms Controlling Formation of Basal Ganglia Circuitry

描述（由申请人提供）：基底神经节包括一系列核，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，基底神经节的功能是处理皮层输入，随后通过两种不同的途径调节输出核（髓核内核和黑质）的活动。直接通路单突触连接纹状体和输出核，而间接通路通过苍白球和丘底核影响输出核。人们认为，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，这种神经回路的功能障碍是神经退行性疾病、帕金森氏症和亨廷顿氏症中观察到的异常运动的基础。此外，该回路的功能障碍也与神经发育障碍妥瑞氏综合征和强迫症（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通路的祖细胞中表达。本研究将探讨Islet1在纹状体直接输出通路正确形成过程中的必要性。在特异性目标1中，我们将确定该转录因子在纹状体祖细胞本身中的作用。具体目标2将确定Islet1在网状丘脑和无序带正确形成中的需求，以及它们在纹状体输出通路正确形成中的后续作用。最后，我们的初步数据表明PlexinD1-Sema3E信号在Islet1的下游参与直接纹状体输出通路的形成。因此，Specific Aim 3将探讨PlexinD1和Sema3E在纹状体输出通路形成中的作用。阐明基底神经节回路形成的机制可能有助于更好地理解某些基底神经节疾病的神经元改变，并为开发更好的治疗方法提供机会。

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.