Synaptic Transmissions in the Basal Ganglia

基底神经节的突触传递

• 批准号: 7466854
• 负责人: Hitoshi Kita
• 金额: $ 25.55万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7466854
• 关键词: Affect; Age-Years; Anatomy; Animal Model; Animals; Area; Basal Ganglia; Brain; Cell Nucleus; Cognitive; Computer information processing; Condition; Corpus striatum structure; Data; Development; Dopamine; Dopamine Agonists; Drug Delivery Systems; Effectiveness; Figs - dietary; Fire - disasters; Frequencies; Globus Pallidus; Hand; In Vitro; Injection of therapeutic agent; Interneurons; Investigation; Levodopa; Light; Membrane; Methods; Microscopic; Monkeys; Motor; Motor Cortex; Names; Neostriatum; Neurons; Numbers; Operative Surgical Procedures; Output; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Physiological; Physiology; Primates; Property; Public Health; Rattus; Rodent; Rodent Model; Signal Transduction; Site; Staging; Staining method; Stains; Structure of subthalamic nucleus; Substantia nigra structure; Synapses; Synaptic Transmission; Testing; Time; aging population; awake; base; cell type; cognitive control; disability; dopaminergic neuron; frontal lobe; membrane activity; pars compacta; research study; response; restoration; theories

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a condition in which degeneration of dopamine (DA) containing neurons in the substantia nigra pars compacta leads to motor and cognitive disability. The loss of DA-neurons and their afferents alters neuronal activity of basal ganglia, which are brain areas involved in motor and cognitive control, and impair their information processing mechanism and/or generate improper signals. The most widely accepted theory from the last 15 years is that parkinsonism is due to the imbalance of the two major neuronal pathways in the basal ganglia. The pathways are named as the direct and indirect pathways. The theory assumes that a DA-depletion in the basal ganglia results in a decrease of neuronal activity in the direct pathway and an increase in the indirect pathway. It has become increasingly apparent that when changes in the average firing activity are compared in animal models of PD, the results often do not support this assumption. However, our preliminary data and those of others have strongly suggested that synaptically induced neuronal responses in the direct and indirect pathways were indeed altered in animal models of PD, but the mean firing frequencies were not. However, details of the alterations are still unknown. We believe that the altered synaptic activity is the basis for the abnormal information processes that are associated with abnormal oscillations and synchronization of neuronal activity observed in parkinsonian patients and animals and that this abnormal activity leads to a development of PD. Thus, the proposed physiological and anatomical investigations in primate and rodent model of PD will test the main hypothesis that DA- depletion decreases the gain of the direct and increases the gain of indirect pathways and that the changes of the gains are due to altered synaptic responses, membrane properties, and anatomy of the basal ganglia nuclei the striatum and/or pallidum. The results of proposed investigations will provide new understanding of the flow of signals in the basal ganglia and how the loss of DA affects the neuronal activity patterns and information flow. This information is essential for developing drugs that target specific circuitry involved in the manifestation of parkinsonisms. PUBLIC HEALTH RELEVANCE A large number of people, up to 25% of aging population over 65 years of age, suffer from Parkinson's disease (PD). This study is to reveal the details of the altered synaptic activity and membrane properties in the basal ganglia and aid developing effective surgical treatments and drugs for PD that target specific circuitry of the basal ganglia, the brain areas involved in motor and cognitive control.

描述（由申请人提供）：帕金森病（PD）是一种黑质背侧部含多巴胺（DA）神经元变性导致运动和认知障碍的疾病。DA神经元及其传入神经元的丧失改变了基底神经节的神经元活动，基底神经节是参与运动和认知控制的脑区，并损害其信息处理机制和/或产生不正确的信号。在过去的15年里，最被广泛接受的理论是帕金森病是由于基底神经节中两个主要神经元通路的不平衡。这些途径被称为直接途径和间接途径。该理论假设基底神经节中的DA耗尽导致直接途径中的神经元活性降低和间接途径中的神经元活性增加。越来越明显的是，当在PD动物模型中比较平均放电活动的变化时，结果往往不支持这一假设。然而，我们的初步数据和其他人强烈建议，突触诱导的神经元反应的直接和间接途径确实改变了PD的动物模型，但平均放电频率没有。然而，修改的细节仍然未知。我们认为，突触活动的改变是异常信息处理的基础，这些异常信息处理与在帕金森病患者和动物中观察到的神经元活动的异常振荡和同步有关，并且这种异常活动导致PD的发展。因此，拟在灵长类和啮齿类动物PD模型中进行的生理学和解剖学研究将检验主要假设，即DA-耗竭降低了直接途径的增益，增加了间接途径的增益，并且增益的变化是由于改变了突触反应、膜特性以及基底神经节核纹状体和/或苍白球的解剖结构。这些研究结果将为基底神经节中的信号流以及DA的丢失如何影响神经元的活动模式和信息流提供新的认识。这些信息对于开发针对帕金森症表现中涉及的特定电路的药物至关重要。公共卫生相关性大量的人，高达65岁以上老龄人口的25%，患有帕金森病（PD）。这项研究旨在揭示基底神经节中突触活动和膜特性改变的细节，并帮助开发针对基底神经节特定回路的有效手术治疗和药物，基底神经节是参与运动和认知控制的大脑区域。