GABA RECEPTORS IN THE THALAMUS

丘脑中的 GABA 受体

• 批准号: 6890299
• 负责人: Yoland Smith
• 金额: $ 19万
• 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 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6890299
• 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

The basal ganglia and thalamus are interconnected through a series of loops that process and convey basal ganglia outflow to either frontal cortical regions via the ventral motor nuclei or back to the striatum via the caudal intralaminar group, namely the centre median (CM) and parafascicular (Pf) nuclei. Although the existence of a thalamostriatal system has long been established, the role of these projections in the functional circuitry of the basal ganglia remains enigmatic. For the first four years of this grant, we focused our interest on the sources and chemical nature of basal ganglia and brainstem synaptic inputs that control the activity of thalamostriatal neurons. Both the internal globus pallidus (GPi) and the substantia nigra pays reticulata (SNr) provide GABAergic afferents to specific regions of CM/Pf. In addition, the pedunculopontine tegmental nucleus (PPN) is the source of highly heterogeneous chemical inputs to CM/Pf, some of them co-localize GABA and acetylcholine. In addition, neurons in CM/Pf, as in most thalamic nuclei, are endowed with intrinsic GABAergic influences from the reticular nucleus and local interneurons. Electrophysiological data show that GABA plays a crucial role in regulating thalamic activity. However, the exact mechanisms by which GABA mediates its effects on thalamic neurons are complex and still matter of speculation. In order to further characterize this issue, we propose to use state-of- the-art immunocytochemical procedures at the electron microscopic level to elucidate the subsynaptic and subcellular localization of GABA-A and GABA-B receptors in the basal ganglia-receiving territories of the ventral motor thalamic nuclei and CM/PF in monkeys. Abnormal increased GABAergic outflow from the basal ganglia to the thalamus is a cardinal feature of Parkinson's disease pathophysiology. Such increased activity likely results in downregulation of postsynaptic GABA receptors in basal ganglia receiving thalamic nuclei. In order to elucidate this issue, another goal of this project is to compare the pattern of subsynaptic localization of GABA-A and GABA-B receptors in CM/Pf and ventral motor nuclei of normal monkeys and animal models of Parkinson's disease. This series of studies should provide a comprehensive analysis of GABA receptors localization at specific synaptic sites in basal ganglia-receiving thalamic nuclei in primates. Such information is critical for the interpretation of functional studies and a better understanding of the pathophysiological changes generated at pallidothalamic and nigrothalamic synapses in Parkinson's disease.

基底神经节和丘脑通过一系列的环路互连，这些环通过腹侧运动核通过腹腔内核的一系列循环传递到额叶皮层区域，或通过腹膜内腔内组回到纹状体，不，即中间（CM）和副心理（pf）核。尽管长期以来已经建立了丘脑纹状体系统的存在，但这些投影在基底神经节的功能电路中的作用仍然神秘。在这笔赠款的头四年中，我们将兴趣集中在控制丘脑神经元活性的基底神经节和脑干突触输入的来源和化学性质上。 Globus pallidus（GPI）和底底尼格拉（Nigra）支付网状（SNR）都为CM/PF的特定区域提供了GABA能传入。另外，pedunculopontine换膜核（PPN）是高度异质化学输入到CM/PF的来源，其中一些是共定位的GABA和乙酰胆碱。此外，与大多数丘脑核一样，CM/PF中的神经元具有网状核和局部神经元的内在GABA能影响。电生理数据表明，GABA在调节丘脑活性中起着至关重要的作用。但是，GABA介导其对丘脑神经元的影响的确切机制是复杂的，仍然存在猜测。为了进一步表征这个问题，我们建议在电子显微镜水平上使用最先进的免疫细胞化学程序，以阐明GABA-A和GABA-B受体在基础丘脑丘脑和CM/CM/CM/cm ff的基础神经节领土上GABA-A和GABA-B受体的亚细胞定位。从基底神经节到丘脑的GABA能流出异常是帕金森氏病病理生理学的主要特征。这种增加的活性可能导致在接受丘脑核的基底神经节中突触后GABA受体的下调。为了阐明这个问题，该项目的另一个目标是比较正常猴子的CM/PF和腹侧运动核和帕金森氏病动物模型中GABA-A和GABA-B受体的次突触定位模式。这一系列的研究应对GABA受体在基底神经节中的特定突触部位的定位进行全面分析。这种信息对于解释功能研究和对帕金森氏病pallidothalamic和nigrothalamic突触产生的病理生理变化的解释至关重要。