Synaptic Transmissions in the Basal Ganglia

基底神经节的突触传递

• 批准号: 7560009
• 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/7560009
• 关键词: Affect; Age-Years; Anatomy; Animal Model; Animals; Area; Axon; Basal Ganglia; Brain; Cell Nucleus; Chronic; Cognitive; Corpus striatum structure; Data; Development; Dopamine; Drug Delivery Systems; Electrodes; Frequencies; Globus Pallidus; Investigation; Laboratories; Mediating; Membrane; Monkeys; Motor; Names; Neurons; Operative Surgical Procedures; Paralysed; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Physiologic pulse; Physiological; Primates; Principal Investigator; Property; Published Comment; Pyramidal Tracts; Rattus; Reading; Rest; Rodent Model; Signal Transduction; Site; Stimulus; Substantia nigra structure; Synapses; Synaptic Transmission; Testing; Time; aging population; base; caudate nucleus; cognitive control; disability; dopaminergic neuron; implantation; in vivo; information processing; membrane activity; pars compacta; programs; public health relevance; putamen; research study; response; 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(申请人提供)：帕金森病(PD)是一种黑质致密部含有多巴胺(DA)的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缺失改变了参与运动和认知控制的大脑区域基底节的神经元活动，损害了它们的信息处理机制和/或产生了错误的信号。过去15年来最被广泛接受的理论是，帕金森症是由于基底节中两条主要神经通路的不平衡造成的。这些路径被称为直接路径和间接路径。该理论认为，基底神经节中的DA耗竭导致直接通路中神经元活性的降低和间接通路中神经元活性的增加。越来越明显的是，当在帕金森病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，我们和其他人的初步数据强烈表明，在帕金森病动物模型中，直接和间接通路中突触诱导的神经元反应确实发生了改变，但平均放电频率没有改变。然而，这些改动的细节仍不清楚。我们认为，突触活动的改变是帕金森病患者和动物中观察到的与神经元活动的异常振荡和同步有关的异常信息处理的基础，这种异常活动导致帕金森病的发生。因此，拟议的灵长类和啮齿动物帕金森病模型的生理和解剖学研究将检验以下主要假设：DA耗竭降低了直接通路的增益，增加了间接通路的增益，并且增益的变化是由于突触反应、膜特性和纹状体和/或苍白球基底节核团的解剖改变所致。拟议的研究结果将为我们提供对基底节信号流的新理解，以及DA的丢失如何影响神经元的活动模式和信息流。这些信息对于开发针对帕金森症表现中涉及的特定回路的药物至关重要。公共卫生相关性65岁以上的老年人口中，高达25%的人患有帕金森氏病(PD)。这项研究旨在揭示基底节突触活动和膜特性改变的细节，并帮助开发有效的外科治疗方法和药物，以治疗帕金森病，靶向于基底节的特定回路，即参与运动和认知控制的大脑区域。