Synaptic Transmission, Plasticity and Integration in the Subthalamic Nucleus

丘脑底核的突触传递、可塑性和整合

• 批准号: 8422560
• 负责人: Mark D Bevan
• 金额: $ 38.63万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8422560
• 关键词: Action Potentials; Acute; Animals; Basal Ganglia; Biochemical; Bradykinesia; Brain region; Cell physiology; Characteristics; Chemosensitization; Chronic; Development; Dopamine; Down-Regulation; Electrical Stimulation of the Brain; Endocytosis; Exhibits; Exocytosis; Experimental Models; Experimental Parkinsonism; Frequencies; Functional disorder; Genetic Transcription; Globus Pallidus; Glutamate Receptor; Glutamates; Health; Hyperactive behavior; Laser Scanning Microscopy; Lesion; Measures; Mediating; Molecular; Motor; Movement; N-Methyl-D-Aspartate Receptors; Nature; Neurons; Output; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Pattern; Pharmaceutical Preparations; Photons; Process; Property; Protein Kinase; Rodent; Signal Transduction; Source; Structure of subthalamic nucleus; Substantia nigra structure; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Therapeutic; Therapeutic Intervention; Translations; Viral Vector; base; dopaminergic neuron; improved; neuronal patterning; optogenetics; prevent; synaptic function; trafficking; transmission process

DESCRIPTION (provided by applicant): The debilitating motor symptoms of akinesia, bradykinesia and rigidity in Parkinson's disease (PD) are intimately related to changes in the frequency and pattern of neuronal activity in the reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN) and associated cortico-basal ganglia-thalamocortical networks. In idiopathic and experimental PD the GPe and STN exhibit hypo- and hyperactivity, respectively, and abnormal synchronous, rhythmic, burst firing. Following acute loss of substantia nigra dopamine neurons in experimental models of PD abnormal STN activity emerges slowly and intensifies gradually until it reaches a stable maximum after 2-3 weeks. This process suggests that adaptive changes in cellular and network properties contribute to the development of parkinsonian STN activity. Because the GPe potently regulates the frequency and synchronization of STN activity and can generate rebound burst firing in the STN, GPe-STN transmission was compared in control and 6-hydroxydopamine-lesioned rodents using electrophysiological, molecular and anatomical approaches. These studies revealed that 2-3 weeks after loss of dopamine the GPe-STN projection had strengthened considerably through proliferation of synaptic connections. This alteration could therefore be a major contributor to the emergence of abnormal GPe-STN activity in PD. Here we propose to study the timecourse, nature, underlying mechanisms and functional consequences of alterations in GPe-STN transmission that follow the loss of dopamine. We propose to apply cellular physiology to measure GPe-STN synaptic function and dysfunction; anatomical approaches to define the structural and molecular bases of GPe-STN synaptic plasticity; 2-photon laser scanning microscopy and optogenetics to define the sources of Ca2+ that trigger synaptic plasticity; viral vector, molecular and biochemical approaches to define the underlying molecular mechanisms and enable us to manipulate GPe-STN transmission. We propose 4 Specific Aims: Aim 1. Determine the timecourse and nature of alterations in GPe-STN synaptic transmission in experimental PD. We hypothesize that alterations in GPe-STN transmission are correlated with the development of parkinsonian STN activity; Aim 2. Determine the triggers leading to potentiation of GPe-STN synaptic transmission in experimental PD. We hypothesize that hyperactivation of STN glutamate receptors and/or Cav channels leads to the potentiation of GPe-STN synaptic transmission in experimental PD; Aim 3. Determine the cellular and molecular mechanisms underlying the potentiation of GPe-STN synaptic transmission. We hypothesize that hyperactivation of STN glutamate receptors and/or hyperactivity of STN neurons leads to an increase in intracellular Ca2+, which activates signaling cascades that mediate synaptic potentiation and proliferation; Aim 4. Determine the impact of chronic dopamine depletion on action potential-dependent inhibition of STN neurons. We hypothesize that the autonomous activity of GPe-STN neurons is not altered by dopamine depletion and that GPe-STN inhibition is increased through potentiation of GPe-STN connectivity. PUBLIC HEALTH RELEVANCE: In Parkinson's disease a small brain region called the subthalamic nucleus exhibits a characteristic, abnormal pattern of activity, which if corrected by medication or deep brain electrical stimulation greatly improves movement. The emergence of this abnormal pattern of activity is associated with alterations to the inputs of the subthalamic nucleus. We propose to study the mechanisms underlying these alterations and to determine whether they can be prevented for therapeutic benefit.

描述（由申请人提供）：帕金森氏病（PD）中脱智毒，心理肌症和僵化的运动症状与相互连接的Gabaergic Globus pallidus（GPE）和谷胱甘肽亚thalamic nutagic-Bthalamic and Cators（STRAMIC NUCTERUS（Stort）的频率和模式的变化密切相关，并与神经元活动的频率和模式变化密切相关。神经节 - 丘脑皮层网络。在特发性和实验性PD中，GPE和STN分别表现出多动症和多动症，并异常同步，有节奏，爆发。在PD异常的STN活性实验模型中急性丧失质体的底菌质多巴胺神经元会缓慢出现，并逐渐增强，直到2-3周后达到稳定的最大值。该过程表明，细胞和网络特性的自适应变化有助于帕金森氏症STN活性的发展。由于GPE有效地调节了STN活性的频率和同步，并可以在STN中产生反弹爆发，因此使用电生理，分子和解剖学方法比较了对照和6-羟基多巴胺的啮齿动物的GPE-STN传播。这些研究表明，多巴胺丧失后2-3周，GPE-STN投影通过突触连接的增殖大大增强。因此，这种改变可能是PD中GPE-STN活性异常的主要原因。在这里，我们建议研究遵循多巴胺丧失的GPE-STN传播改变的时间，性质，潜在机制和功能后果。我们建议应用细胞生理学来测量GPE-STN突触功能和功能障碍。解剖方法来定义GPE-STN突触可塑性的结构和分子碱基； 2光子激光扫描显微镜和光遗传学，以定义触发突触可塑性的Ca2+来源；病毒载体，分子和生化方法来定义潜在的分子机制，并使我们能够操纵GPE-STN传播。我们提出了4个具体目标：目标1。确定实验性PD中GPE-STN突触传播改变的时间和性质。我们假设GPE-STN传播的变化与帕金森氏症STN活动的发展相关。 AIM 2。确定触发器导致实验性PD中GPE-STN突触传播的增强。我们假设STN谷氨酸受体和/或CAV通道的过度激活导致实验性PD中GPE-STN突触传播的增强。目标3。确定GPE-STN突触传播增强的基础的细胞和分子机制。我们假设STN谷氨酸受体的过度激活和/或STN神经元的过度活化导致细胞内Ca2+的增加，这激活了介导突触增强和增殖的信号级联。目标4。确定慢性多巴胺耗竭对STN神经元的作用势依赖性抑制的影响。我们假设多巴胺消耗不会改变GPE-STN神经元的自主活性，并且通过增强GPE-STN连接性，GPE-STN抑制作用增加。 公共卫生相关性：在帕金森氏病中，一个称为丘脑下核的小脑区域表现出一种特征性的，异常的活性模式，如果通过药物或深层大脑电刺激纠正，则可以大大改善运动。这种活性异常模式的出现与丘脑下核的输入的改变有关。我们建议研究这些改变的基础机制，并确定是否可以为治疗益处进行预防。