The Thalamostriatal System in Primate

灵长类动物的丘纹状体系统

• 批准号: 7093829
• 负责人: Yoland Smith
• 金额: $ 17.75万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7093829
• 关键词: GABA receptor; Macaca mulatta; Parkinson' s disease; Saimiri; basal ganglia; disease /disorder model; electron microscopy; immunocytochemistry; laboratory rat; neural transmission; neurons; neuropathology; neurophysiology; neurotransmitters; synapses; thalamic nuclei; thalamocortical tract; thalamus

DESCRIPTION (provided by applicant): The proper functioning of CNS neurons relies on complex and highly specific integration of synaptic inputs along their dendritic trees. The striatum is largely made up of two populations of medium sized GABAergic neurons characterized by densely spiny dendrites and differential expression in dopamine receptors immunoreactivity (D1 versus D2). The cerebral cortex and the thalamus are the two main sources of excitatory glutamatergic afferents to striatal medium spiny neurons (MSN). Together, these two afferents contribute more than 30,000 glutamatergic synapses onto individual striatal projection neurons. Midbrain dopaminergic inputs from the substantia nigra pars compacta (SNc) play a critical role in modulating glutamatergic transmission in the striatum. Consequently, lesion of this system results in significant neurochemical, electrophysiological and morphological changes in striatal MSNs in Parkinson's disease. The vesicular glutamate transporters 1 and 2 (vGluT1 and vGluT2) are invaluable tools to label specifically the corticostriatal and thalamostriatal systems, respectively. Although these two striatal inputs have long been established, very little is known about the differential organization of the synaptic microcircuitry of these two pathways in normal and pathological basal ganglia conditions, largely because of the lack of specific markers to differentiate thalamic from cortical afferents in the striatum. For the past 15 years, our laboratory has been at the forefront of research to characterize the organization of synaptic microcircuits in primate basal ganglia. Our work has led to significant advancement in our understanding of the functional anatomy, synaptic connectivity and potential roles of the thalamostriatal system in monkeys. In this project, we propose to use vGluTI and vGluT2 as specific markers of corticostriatal and thalamostriatal terminals to further understand the functional organization and synaptic plasticity of these two pathways in normal monkeys and animal models of Parkinson's disease. Three main hypotheses will be addressed using high resolution electron microscopy immunocytochemistry combined with 3D reconstruction of dendritic spines in normal and MPTP- treated monkeys. Results of these studies will shed light on the substrates that underlie the synaptic mechanisms by which thalamic and cortical glutamatergic afferents control the activity of striatofugal neurons in both normal and pathological basal ganglia conditions.

描述（由申请人提供）：中枢神经系统神经元的正确功能依赖于沿树突树的突触输入的复杂而高度特定的整合。纹状体在很大程度上由两个中等大小的GABA能神经元的种群组成，其特征在于密集的刺树突和多巴胺受体免疫反应性中的差异表达（D1与D2）。脑皮质和丘脑是纹状体培养基神经元（MSN）的兴奋性谷氨酸能传入的两个主要来源。这两个传入共同在单个纹状体投影神经元上贡献了30,000多个谷氨酸能突触。来自黑质Nigra Pars Compacta（SNC）的中脑多巴胺能输入在调节纹状体中的谷氨酸能传播方面起着关键作用。因此，该系统的病变导致帕金森氏病纹状体MSN的明显神经化学，电生理和形态学变化。囊泡谷氨酸转运蛋白1和2（vglut1和vglut2）分别是专门标记皮质纹状体和丘脑纹状体系统的宝贵工具。尽管长期以来已经建立了这两个纹状体输入，但对于正常和病理基底神经节条件下这两种途径的突触微电路的差异组织知之甚少，这在很大程度上是由于缺乏特定的标记来区分纹状体中丘脑与皮质传入的丘脑。在过去的15年中，我们的实验室一直处于研究的最前沿，以表征灵长类动物基底神经节中突触微电路的组织。我们的工作导致了我们对猴子纹状体系统在猴子中功能解剖学，突触连通性和潜在作用的理解的显着发展。在该项目中，我们建议将VGLUTI和VGLUT2用作皮质纹状体和丘脑纹状体末端的特定标记，以进一步了解这两种途径在帕金森氏病的正常猴子和动物模型中的功能组织和突触可塑性。使用高分辨率电子显微镜免疫细胞化学，以及在正常和MPTP处理的猴子中的树突棘的3D重建，将解决三个主要假设。这些研究的结果将阐明丘脑和皮质谷氨酸能传递物控制正常和病理基底神经节条件下纹状体神经元活性的突触机制的基础。