CELLULAR AND MOLECULAR DETERMINANTS OF NEURONAL RHYTHMICITY AND SYNCHRONY

神经节律和同步性的细胞和分子决定因素

• 批准号: 6452799
• 负责人: DALTON JAMES SURMEIER
• 金额: $ 11.11万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6452799
• 关键词: GABA receptor; Parkinson's disease; basal ganglia; biological signal transduction; brain electrical activity; calcium binding protein; calcium channel; disease /disorder model; dopamine; dopamine receptor; dynorphins; enkephalins; in situ hybridization; laboratory rat; lenticular nucleus; membrane potentials; neural conduction; neuropharmacology; polymerase chain reaction; potassium channel; receptor expression; single cell analysis; substance P; subthalamus; voltage gated channel

In human patients with parkinsonism, the motor symptoms (bradykinesia, resting tremor, rigidity) can be relieved by focal lesions of the internal segment of the globus pallidus. Similar results have been obtained in primate models of parkinsonism. In parkinsonism patients and in primate models of parkinsonism, the electrical activity of globus pallidus neurons is abnormal. Unlike neurons from normal animals, an unidentified subpopulation of GP neurons in these animals exhibit synchronous, rhythmic discharge. It has been hypothesized that this abnormal activity is responsible for the motor symptoms in PD and served as the rationale for surgical intervention. This abnormal activity can be attributed to an interaction between the intrinsic properties of GP neurons and altered synaptic input following dopamine depletion. It is our working hypothesis that this altered synaptic input arises either from striatum or from the subthalamic nucleus (STN). To test this hypothesis, a combination of whole-cell voltage clamp, flurometric and single cell RT-PCR techniques will be used to address three specific aims. Specific Aim 1 is to characterize the cellular/molecular determinants controlling the emergence of rhythmic activity in identified GP/EP neurons following dopamine depletion. Our working hypothesis is that elevated enkephalin released and diminished substance P/dynorphin and dopamine release subsequent to dopamine depletion promote burst firing and rhythmicity in GP neurons that do not express parvalbumin. Specific Aim 2 is to characterize the cellular/molecular determinants controlling the emergence of neuronal synchrony in identified GP/EP neurons following dopamine depletion. It is our working hypothesis that disruption of pre- and/or post-synaptic modulation of recurrent collateral GABAergic signaling in the GP leads to the emergence of synchrony. Specific Aim 3 is to characterize the cellular/molecular determinants controlling the expression of rhythmic activity in identified STN neurons following dopamine depletion. Our working hypothesis is that dopamine suppresses rhythmic activity in STN neurons by modulating hyperpolarization activated conductances, voltage- dependent Ca/2+ conductances and the responses to GABAergic input arising from the GP. The successful attainment of these specific aims should provide much needed information about the properties of normal and dopamine-depleted GP/EP/STN neurons. With this information in hand, we should possess not only a better understanding of this critically important, yet under- studied, group of basal ganglia neurons, but we should also be in a position to devise more effective and less invasive treatments for Parkinson's disease than irreversible lesioning.

在人类帕金森病患者中，运动症状（运动迟缓、 静息性震颤、强直）可以通过内部的局灶性病变来缓解 苍白球的一部分。类似的结果已在 帕金森病的灵长类动物模型。在帕金森病患者和灵长类动物中 帕金森病模型，苍白球神经元的电活动 是不正常的。与正常动物的神经元不同，一种身份不明的神经元 这些动物的 GP 神经元亚群表现出同步、有节奏的 释放。据推测，这种异常活动是 造成 PD 运动症状的原因 手术干预。这种异常活动可归因于 GP神经元的内在特性和改变的相互作用之间的相互作用 多巴胺耗尽后的突触输入。这是我们的工作假设 这种改变的突触输入要么来自纹状体，要么来自 丘脑底核（STN）。 为了检验这一假设，结合了全细胞电压钳、 荧光测定和单细胞 RT-PCR 技术将用于解决 三个具体目标。具体目标 1 是表征 控制节律出现的细胞/分子决定因素 多巴胺耗尽后确定的 GP/EP 神经元的活性。我们的 工作假设是脑啡肽释放升高并减少 P物质/强啡肽和多巴胺在多巴胺释放后释放 耗尽会促进 GP 神经元的爆发放电和节律性，而这些神经元不会 表达小清蛋白。具体目标 2 是表征 控制神经元出现的细胞/分子决定因素 多巴胺耗尽后确定的 GP/EP 神经元的同步性。这是 我们的工作假设是突触前和/或突触后的破坏 GP 中循环性 GABA 信号传导的调节导致 同步的出现。具体目标 3 是表征 控制节律表达的细胞/分子决定因素 多巴胺耗尽后确定的 STN 神经元的活性。我们的 工作假设是多巴胺抑制 STN 的节律活动 神经元通过调节超极化激活电导、电压 依赖的 Ca/2+ 电导和对 GABA 能输入的响应 来自全科医生。 这些具体目标的成功实现应该提供很多 需要有关正常和多巴胺耗尽的特性的信息 GP/EP/STN 神经元。有了这些信息，我们不应该拥有 只有更好地理解这一至关重要但尚未充分了解的问题 研究了一组基底神经节神经元，但我们也应该处于一个 能够设计出更有效、侵入性更小的治疗方法 帕金森病是一种不可逆转的病变。