Organization of the Cortical Projection to the Basal Ganglia

描述(申请人提供)：我们先前在大鼠中的研究表明，通过锥体束向脑干运动前细胞群和脊髓投射的皮质神经元(PT型)优先靶向投射到苍白球外段(GPE)的纹状体神经元，而仅有脑内投射(IT型)的皮质神经元优先靶向投射到苍白球内段(GPI)和/或黑质网状部(SNR)的纹状体神经元。这些发现表明，PT型皮质纹状体神经元可能为纹状GPE神经元提供了抑制潜在冲突运动所需的皮质运动命令信息，而纹状GPI/SNR神经元可能需要整合来自不同皮质区域的IT型输入才能在启动所需运动中发挥作用。这些输入的突触易化或不易化可能在运动学习中发挥作用。然而，我们关于两种主要类型纹状体投射神经元的不同皮质输入的结论是基于对纹状体神经元类型的优先标记，而不是排他性标记。此外，在这些先前的研究中，我们没有区分纹状体-GPI和纹状体-SNR神经元。因此，大鼠的三种主要类型的纹状体投射神经元中的每一种都从不止一种类型的皮质神经元接收输入的程度仍然不确定。此外，我们现在也知道我们在老鼠身上的发现是否适用于灵长类动物，从而在临床上与人类的基底节相关。在当前提议的目标1中，我们将使用大鼠体内的细胞内方法来记录单个纹状体投射神经元，然后在生理学会议结束时通过填充神经元的生物细胞素来确定它们的类型(然后追踪每个神经元的轴突到其目的地)。对于每个神经元，我们将使用电生理和光镜/EM解剖学方法，以表征纹状-GPI/SNR神经元的IT输入和纹状-GPE神经元的PT输入的特异性程度。在目标2和目标3中，我们将通过葡聚糖胺标记、免疫标记和EM分析来确定IT型终末是否优先靶向猕猴纹状体-GPI和纹状-SNR神经元，而PT型终末是否优先靶向纹状-GPE神经元。鉴于纹状体皮质输入在向纹状体提供指导性信号和运动学习的可塑性方面的关键作用，我们的研究将有助于揭示纹状-GPI/SNR和纹状-GPE神经元如何在运动控制中扮演互补角色；2)有助于阐明基础神经节在运动启动和运动序列执行中的作用机制；以及3)有助于解释基础神经节在运动学习和运动表现中的作用之间的关系。公共卫生相关性这项研究将阐明大脑皮层的哪些神经元与基底神经节的两个回路中的每一个进行通信，其中一个促进所需的运动，另一个抑制不想要的运动。这些发现将阐明大脑皮层提供的信息如何使基底节在运动控制和学习新的运动常规方面发挥作用。这些发现将对亨廷顿病、帕金森氏病、抽动症和强迫症中纹状体皮质输入的异常所起的作用提出新的见解，从而为治疗这些疾病提供新的治疗方法。

DESCRIPTION (provided by applicant): Our previous work in rats suggests that cortical neurons projecting to brainstem premotor cell groups and spinal cord via the pyramidal tract (PT-type) preferentially target striatal neurons projecting to the external pallidal segment (GPe), while cortical neurons having only intratelencephalic projections (IT- type) preferentially target striatal neurons projecting to the internal pallidal segment (GPi) and/or the substantia nigra pars reticulata (SNr). These findings suggest that PT-type corticostriatal neurons may provide striato-GPe neurons with information about cortical motor commands needed for their role in suppressing potentially conflicting movements, while integration of IT-type input from diverse cortical areas may be required for striato-GPi/SNr neurons to play their role in initiating desired movement. Synaptic facilitation or disfacilitation of subsets of these inputs could play a role in motor learning. Our conclusions about differential cortical inputs to the two main types of striatal projection neurons are, however, based on preferential but not exclusive labeling of striatal neuron types. Moreover, we did not distinguish between striato-GPi and striato-SNr neurons in these prior studies. Thus, the extent to which each of the three main types of striatal projection neurons in rats receive input from more than one type of cortical neuron remains uncertain. Additionally, we also do now know if our findings for rats are true for primates, and thus clinically relevant to the human basal ganglia. In Aim 1 of the current proposal, we will use in vivo intracellular methods in rats to record from individual striatal projection neurons and then at the end of the physiology session identify their type by biocytin-filling the neuron (and later tracing the axon of each to its destination). For each neuron we will use electrophysiological and LM/EM anatomical methods, so as to characterize the extent of the specificity of the IT input for striato-GPi/SNr neurons and the PT input for striato-GPe neurons. In Aims 2 and 3, we will determine by dextran amine labeling, immunolabeling and EM analysis if IT-type terminals preferentially target striato-GPi and striato-SNr neurons while PT-type terminals preferentially target striato-GPe neurons in monkeys. Given the critical roles of the cortical input to striatum in providing an instructive signal to the striatum and in the plasticity underlying motor learning, our studies will: 1) help reveal how the striato-GPi/SNr and striato-GPe neurons play complementary roles in motor control; 2) help clarify the mechanisms underlying the role of the basal ganglia in movement initiation and in the execution of movement sequences; and 3) help explain the relationship between the role of the basal ganglia in motor learning and in motor performance. PUBLIC HEALTH RELEVANCE This study will clarify which neurons of cerebral cortex communicate with each of the two circuits of the basal ganglia, one of which facilitates desired movements and the other suppresses unwanted movements. The findings will clarify how the information provided by cerebral cortex enables the basal ganglia to play its role in movement control and in the learning of new motor routines. The findings will suggest new insights into the role of abnormalities in the cortical input to striatum in Huntington's disease, Parkinson's disease, Tourette Syndrome, and obsessive-compulsive disorder, and thereby suggest new therapeutic approaches for treating these disorders.