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）：相关，低频（<30 Hz）的出现，丘脑下核（STN）中神经元的节奏活性对于帕金森氏病（PD）的症状表达至关重要。来自外部球粒和谷氨酸的GABA能突触输入来自皮质和丘脑的谷氨酸能突触输入对于STN活性的正常和病理学构图至关重要。这项研究将检验的主要假设是，PD中多巴胺的丧失导致STN内的突触传播异常，这（部分）是病理发射模式的基础。该假设将使用脑切片中的STN神经元的电生理记录，相关的光和电子显微镜和2光子成像进行测试。多巴胺的影响将通过比较突触传播和整合I）在正常和多巴胺动物中的存在和不存在，以及2）多巴胺受体受体激动剂/拮抗剂的影响。该项目有三个特定的目标。具体目标1：测量GABA能和谷氨酸能突触传播的短期可塑性和影响，以及多巴胺受体激动剂和拮抗剂的调节。具体目标2：确定STN中GABA能和谷氨酸能突触传播的长期可塑性构成的突触前和/或突触后活性模式。具体目标3：比较对照动物中STN和PD实验模型中GABA能和谷氨酸能突触的操作和影响。该项目产生的知识将进一步了解STN中病理活性的因素，并有助于通过修饰STN活性来改善症状并中断PD的疗法的合理发展。铺面描述：废除丘脑下核（STN）中神经细胞的病理活性导致帕金森氏病（PD）的症状有了深远的改善。该项目将检验以下假设：病理学STN活性是由PD中STN神经细胞异常输入驱动的。通过阐明活性异常的机制，这项研究将指导疗法的合理发展，从而改善症状并通过STN活性的归一化来减轻PD的发展。