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: 8138698
• 负责人: Mark D Bevan
• 金额: $ 21.02万
• 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 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8138698
• 关键词: Animals; Attenuated; Brain; Cells; Control Animal; Development; Dopamine; Dopamine Agonists; Electric Stimulation; Electron Microscopy; Electrons; Experimental Parkinsonism; Frequencies; Generations; Glutamates; Image; Knowledge; Light; Measures; Mission; Modeling; Modification; Neurons; Parkinson Disease; Pattern; Photons; Primates; Psyche structure; Research; Research Activity; Rodent; Slice; Structure of subthalamic nucleus; Symptoms; Synapses; Synaptic Transmission; Testing; Thalamic Nuclei; Thalamic structure; operation; therapy development

The emergence ofcorrelated, low-frequency (< 30 Hz), rhythmicactivity ofneurons in the subthalamicnucle- us (STN) is critical for the symptomatic expression of Parkinson's disease (PD). GABAergic synaptic inputs from the external globus pallidusand glutamatergicsynaptic inputs from the cortex and thalamus are critical for the normal and pathological patterning ofSTNactivity. The principal hypothesis that will be tested bythis 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 i: Measure the short-term plasticity and impactof GABAergic and glutamatergic synaptictansmission and their modulationby dopamine receptor agonists and antagonists. Specific Aim2: Determine the pre- and/or postynaptic activity patterns that underlielong-term plasticity of GABAergicand glutamatergic synaptic transmission in the STN. Specific Aim 3: Compare the operation and influence of GABAergic and glutamatergic synapses in the STNin control animalsand experi- mental models of PD. The knowledgegenerated bythis project will further our understandingofthe factors underlying pathological activity in the STNand assist the rational development oftherapies that ameliorate the symptoms and inter- rupt 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 STNactivity is driven (in part) by abnormal inputs to STNnerve cells in PD. By elucidating the mechanisms underlyingabnormal activity, this research will guidethe rational development of therapies that ameliorate the symptoms and interrupt the progression ofPDthroughthe normalizationof STNactivity.

丘脑底核神经元相关的低频（<30 Hz）节律活动的出现， us（β）对帕金森病（PD）的症状表现至关重要。GABA能突触输入 来自外部苍白球和来自皮层和丘脑的突触输入是至关重要的 for the normal正常and pathological病理patterns图案ofSTN activity活性.将被测试的主要假设是， 研究表明，PD中多巴胺的丢失导致突触传递异常， (in部分）是病理性放电模式的基础。这一假设将使用电生理学测试 记录脑切片中的神经元，相关的光学和电子显微镜和双光子成像。 多巴胺的影响将通过比较i）突触传递和整合来评估。 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 该项目有三个具体目标。具体目标i：测量短期可塑性和影响 GABA能和多巴胺能突触传递及多巴胺受体激动剂对它们的调节 对手。具体目标2：确定长期睡眠的突触前和/或突触后活动模式 GABA能和多巴胺能突触传递的可塑性具体目标3：比较 在对照动物和实验动物中，STN中GABA能和谷氨酸能突触的操作和影响 PD的心理模型 这个项目所产生的知识将进一步加深我们对病理学基础因素的理解 活动在STN和协助合理发展oftherapies，改善症状和间 通过改变PD的活性来阻断PD的进展。 简单描述：消除丘脑底核神经细胞的病理活动， 帕金森病（PD）症状的显著改善。这个项目将测试这个假设 病理性STN活性（部分）是由PD中STN神经细胞的异常输入驱动的。通过阐明 研究异常活动的机制，将指导治疗方法的合理发展 改善症状并通过正常化STN活性来阻断PD的进展。