Organization of the Cortical Projection to the Basal Ganglia

描述（申请人提供）：我们以前在大鼠中的工作表明，通过锥体束（PT型）投射到脑干运动前细胞群和脊髓的皮质神经元优先靶向投射到苍白球外段（GPe）的纹状体神经元，而皮质神经元只有端脑内投射（IT型）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。这些研究结果表明，PT-型皮质纹状体神经元可能提供纹状体-GPe神经元的皮质运动命令的信息，需要他们的作用，抑制潜在的冲突运动，而整合的IT型输入从不同的皮层区域可能需要纹状体-GPi/SNr神经元发挥其作用，在启动所需的运动。这些输入的子集的突触易化或非易化可以在运动学习中发挥作用。然而，我们关于两种主要类型的纹状体投射神经元的差分皮质输入的结论是基于纹状体神经元类型的优先但不排他的标记。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，大鼠纹状体投射神经元的三种主要类型中的每一种接受来自一种以上皮层神经元的输入的程度仍然不确定。此外，我们现在也知道我们在大鼠身上的发现是否适用于灵长类动物，因此与人类基底神经节临床相关。在当前提案的目标1中，我们将在大鼠中使用体内细胞内方法来记录单个纹状体投射神经元，然后在生理学会话结束时通过生物胞素填充神经元（随后追踪每个轴突到其目的地）来识别它们的类型。对于每个神经元，我们将使用电生理和LM/EM解剖方法，以表征纹状体GPi/SNr神经元的IT输入和纹状体GPe神经元的PT输入的特异性程度。在目标2和3中，我们将通过葡聚糖胺标记、免疫标记和EM分析确定IT型末端是否优先靶向纹状体-GPi和纹状体-SNr神经元，而PT型末端是否优先靶向猴中的纹状体-GPe神经元。鉴于纹状体的皮层输入在向纹状体提供指导性信号和在运动学习的可塑性中的关键作用，我们的研究将：1）有助于揭示纹状体GPi/SNr和纹状体GPe神经元在运动控制中的互补作用; 2）有助于阐明基底神经节在运动启动和运动序列执行中的作用机制;有助于解释基底神经节在运动学习和运动表现中的作用之间的关系。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，其中一个回路促进期望的运动，另一个回路抑制不必要的运动。这些发现将阐明大脑皮层提供的信息如何使基底神经节在运动控制和学习新的运动程序中发挥作用。这些发现将为亨廷顿病、帕金森病、妥瑞氏综合征和强迫症中纹状体皮质输入异常的作用提供新的见解，从而为治疗这些疾病提出新的治疗方法。

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.