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.

丘脑底核中神经元相关的低频（< 30 Hz）节律性活动的出现 us (STN) 对于帕金森病 (PD) 的症状表现至关重要。 GABA能突触输入 来自外部苍白球和谷氨酸的来自皮质和丘脑的突触输入至关重要 用于 STN 活性的正常和病理模式。将通过此检验的主要假设 研究表明，PD 中多巴胺的缺失会导致 STN 内的突触传递异常，从而导致 （部分）是病理性放电模式的基础。该假设将使用电生理学进行检验 脑切片中 STN 神经元的记录、相关光学和电子显微镜以及 2 光子成像。 多巴胺的影响将通过比较 i) 中的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情况 动物。 该项目有三个具体目标。具体目标一：衡量短期可塑性和影响 GABA能和谷氨酸能突触传递及其多巴胺受体激动剂的调节 对手。具体目标 2：确定长期的突触前和/或突触后活动模式 STN 中 GABA 能和谷氨酸能突触传递的可塑性。具体目标 3：比较 STN 对照动物和实验中 GABA 能和谷氨酸能突触的运作和影响 PD 的心理模型。 该项目产生的知识将进一步加深我们对病理基础因素的理解 STN 的活动并协助合理开发改善症状和间质的疗法 通过改变 STN 活性来中断 PD 的进展。 外行描述：消除丘脑底核（STN）神经细胞的病理活动会导致 帕金森病 (PD) 症状的显着改善。该项目将测试假设 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 异常活动的机制，这项研究将指导疗法的合理开发 通过 STN 活性正常化来改善症状并中断 PD 的进展。