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.

在丘脑核 - 美国（STN）对于帕金森氏病（PD）的症状表达至关重要。 GABA能突触输入 来自外部球pallidusand和谷氨酸能突触的输入，来自皮质和丘脑至关重要 对于正常和病理模式，以促进性的方式。将通过以下来检验的主要假设 研究是，PD中多巴胺的丧失导致STN内的突触传播异常 （部分）是病理射击模式的基础。该假设将使用电生理学检验 记录脑切片中的STN神经元，相关的光和电子显微镜和2光子成像。 多巴胺的影响将通过比较突触传播和整合的评估 多巴胺受体激动剂/拮抗剂的存在和不存在，2）在正常和多巴胺中 动物。 该项目有三个特定的目标。特定目的I：测量短期可塑性和影响 Gabaergic和Glutamatorgic intaptictics被启用及其调制，由多巴胺受体激动剂和 对手。特定AIM2：确定底下的前和/或后突触活动模式 GABA能和STN中谷氨酸能突触传播的可塑性。特定目标3：比较 GABA能和谷氨酸能突触的操作和影响 PD的心理模型。 知识生成的条件将进一步了解我们的病理学因素 Stnand中的活动有助于改善症状和间隔的理性发展 通过修饰STN活性，PD的进展破裂。 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。该项目将检验假设 这种病理性的态度是通过对PD中Stnnerve细胞的异常输入来驱动的。通过阐明 活性的基础机制，这项研究将指导疗法的合理发展 这可以缓解症状并打断施加归一化的归一化的进展。