Synaptic Transmissions in the Basal Ganglia

基底神经节的突触传递

• 批准号: 7799125
• 负责人: Hitoshi Kita
• 金额: $ 25.29万
• 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/7799125
• 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（由申请人提供）：帕金森氏病（PD）是一种疾病，在这种情况下，多巴胺（DA）在黑质nigra pars compacta中含有神经元的变性会导致运动和认知障碍。 DA-神经元及其传入的丧失会改变基底神经节的神经元活性，这些神经神经节是参与运动和认知控制的大脑区域，并损害其信息处理机制和/或产生不当信号。过去15年来最广泛接受的理论是，帕金森氏症是由于基底神经节中两个主要的神经元途径的失衡所致。这些路径被命名为直接和间接路径。该理论假定基底神经节中的DA止动物导致直接途径中神经元活性的降低和间接途径的增加。越来越明显的是，当PD动物模型中比较平均点火活性的变化时，结果通常不支持这一假设。但是，我们的初步数据以及其他数据强烈建议在PD动物模型中确实改变了直接和间接途径中突触诱导的神经元反应，但是平均发射频率却没有改变。但是，更改的细节仍然未知。我们认为，突触活性改变是与振荡异常以及在帕金森患者和动物中观察到的神经元活性同步相关的异常信息过程的基础，并且这种异常活性会导致PD的发展。 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.拟议的调查结果将为基础神经节中信号流以及DA丢失如何影响神经元活动模式和信息流的损失提供新的了解。该信息对于开发针对参与帕金森主义表现的特定电路的药物至关重要。公共卫生相关性，帕金森氏病（PD）占65岁以上人口的25％，占25％的人口。这项研究是为了揭示基底神经节中突触活动和膜特性改变的细节，并有助于开发有效的手术治疗和PD药物，该PD靶向基底神经节的特定电路，涉及运动和认知控制的大脑区域。