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: 7236218
• 负责人: Mark D Bevan
• 金额: $ 29.69万
• 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 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7236218
• 关键词: Animals; Attenuated; Brain; Chromosome Pairing; Control Animal; Development; Dopamine; Dopamine Agonists; Electric Stimulation; Electron Microscopy; Electrons; Experimental Models; Experimental Parkinsonism; Fire - disasters; Frequencies; Generations; Globus Pallidus; Glutamates; Image; Knowledge; Light; Measures; Mission; Modeling; Modification; Neurons; Operative Surgical Procedures; Parkinson Disease; Pattern; Photons; Primates; Research; Research Activity; Rodent; Slice; Structure of subthalamic nucleus; Symptoms; Synapses; Synaptic Transmission; Testing; Thalamic Nuclei; Thalamic structure; postsynaptic; therapy development

DESCRIPTION (provided by applicant): The emergence of correlated, low-frequency (< 30 Hz), rhythmic activity of neurons in the subthalamic nucleus (STN) is critical for the symptomatic expression of Parkinson's disease (PD). GABAergic synaptic inputs from the external globus pallidus and glutamatergic synaptic inputs from the cortex and thalamus are critical for the normal and pathological patterning of STN activity. The principal hypothesis that will be tested by this research is that the loss of dopamine in PD leads to abnormal synaptic transmission within the STN, which (in part) underlies the pathological firing pattern. This hypothesis will be tested using electrophysiological recording of STN neurons in brain slices, correlated light and electron microscopy and 2-photon imaging. The influence of dopamine will be assessed by comparison of synaptic transmission and integration in i) the presence and absence of dopamine receptor agonists/antagonists and 2) in normal and dopamine-depleted animals. There are three specific aims of the project. Specific Aim 1: Measure the short-term plasticity and impact of GABAergic and glutamatergic synaptic transmission and their modulation by dopamine receptor agonists and antagonists. Specific Aim 2: Determine the pre- and/or postsynaptic activity patterns that underlie long-term plasticity of GABAergic and glutamatergic synaptic transmission in the STN. Specific Aim 3: Compare the operation and influence of GABAergic and glutamatergic synapses in the STN in control animals and experimental models of PD. The knowledge generated by this project will further our understanding of the factors underlying pathological activity in the STN and assist the rational development of therapies that ameliorate the symptoms and interrupt the progression of PD by modification of STN activity. Lay Description: Abolition of pathological activity of nerve cells in the subthalamic nucleus (STN) leads to a profound improvement in the symptoms of Parkinson's disease (PD). This project will test the hypothesis that pathological STN activity is driven (in part) by abnormal inputs to STN nerve cells in PD. By elucidating the mechanisms underlying abnormal activity, this research will guide the rational development of therapies that ameliorate the symptoms and interrupt the progression of PD through the normalization of STN activity.

描述（由申请人提供）：丘脑底核（subthalamic nucleus，简称PD）中神经元的相关低频（< 30 Hz）节律性活动的出现对于帕金森病（Parkinson's disease，简称PD）的症状表现至关重要。来自外部苍白球的GABA能突触输入和来自皮质和丘脑的GABA能突触输入对于多巴胺活动的正常和病理模式是至关重要的。本研究将检验的主要假设是，PD中多巴胺的丢失导致突触内异常的突触传递，这（部分）是病理性放电模式的基础。这一假设将被测试使用脑切片，相关的光和电子显微镜和2-光子成像的神经元的电生理记录。将通过比较i）存在和不存在多巴胺受体激动剂/拮抗剂和2）正常和多巴胺耗竭动物中的突触传递和整合来评估多巴胺的影响。该项目有三个具体目标。具体目标1：测量GABA能和多巴胺能突触传递的短期可塑性和影响以及多巴胺受体激动剂和拮抗剂对其的调节。具体目标二：确定突触前和/或突触后活动模式，这些模式是突触中GABA能和多巴胺能突触传递的长期可塑性的基础。具体目标3：比较正常动物和实验性PD模型海马GABA能和多巴胺能突触的运作及其影响。该项目所产生的知识将进一步加深我们对帕金森病病理活动因素的理解，并有助于合理开发通过改变帕金森病活动来改善症状和中断PD进展的治疗方法。铺设说明：消除丘脑底核（STN）中神经细胞的病理活动可显着改善帕金森病（PD）的症状。这个项目将测试的假设，即病理性神经元活动是驱动（部分）异常输入到帕金森病的神经细胞。通过阐明异常活动的机制，这项研究将指导合理开发治疗方法，通过正常化的活动来改善症状和中断PD的进展。