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（STN）中神经元相关的低频（< 30 Hz）节律性活动的出现对于帕金森病（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谷氨酸能突触输入对于 STN 活动的正常和病理模式至关重要。这项研究将检验的主要假设是，PD 中多巴胺的缺失会导致 STN 内的突触传递异常，这（部分）是病理性放电模式的基础。这一假设将通过脑切片中 STN 神经元的电生理记录、相关光学和电子显微镜以及 2 光子成像进行测试。多巴胺的影响将通过比较 i) 多巴胺受体激动剂/拮抗剂的存在和不存在以及 2) 正常和多巴胺耗尽的动物中的突触传递和整合来评估。该项目有三个具体目标。具体目标 1：测量 GABA 能和谷氨酸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 2：确定 STN 中 GABA 能和谷氨酸能突触传递长期可塑性的突触前和/或突触后活动模式。具体目标 3：比较对照动物和 PD 实验模型中 STN 中 GABA 能和谷氨酸能突触的运作和影响。该项目产生的知识将进一步我们对 STN 病理活性因素的理解，并有助于合理开发通过改变 STN 活性来改善症状和中断 PD 进展的疗法。外行描述：消除丘脑底核 (STN) 神经细胞的病理活性可显着改善帕金森病 (PD) 的症状。该项目将检验这样的假设：病理性 STN 活动（部分）是由 PD 中 STN 神经细胞的异常输入驱动的。通过阐明异常活性的机制，这项研究将指导合理开发治疗方法，通过 STN 活性正常化来改善症状并阻断 PD 的进展。