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.

在帕金森氏症的人类患者中，运动症状（Bradykinesia， 静止震颤，刚性）可以通过内部病变来缓解 球粒球段。在 帕金森主义的灵长类动物模型。在帕金森氏症患者和灵长类动物中 帕金森主义模型，Globus Pallidus神经元的电活动 是异常的。与普通动物的神经元不同，一个身份不明的 这些动物中GP神经元的亚群表现出同步的节奏 释放。已经假设这种异常活性是 负责PD中的运动症状，并作为理由 手术干预。这种异常活动可以归因于 GP神经元的内在特性与改变的固有特性之间的相互作用 多巴胺消耗后的突触输入。这是我们的工作假设 这种改变的突触输入是由纹状体或 丘脑下核（STN）。 为了检验该假设，全细胞电压夹的组合， flurometric和单细胞RT-PCR技术将用于解决 三个具体目标。特定目的1是表征 控制有节奏的出现的细胞/分子决定因素 多巴胺消耗后鉴定的GP/EP神经元的活性。我们的 工作假设是释放并减少的a夫林升 多巴胺之后的物质P/Dynorphin和多巴胺释放 耗竭促进不释放的GP神经元中的爆发和节奏性 明确的白蛋白。具体目标2是表征 控制神经元出现的细胞/分子决定因素 多巴胺消耗后鉴定出的GP/EP神经元中的同步。这是 我们的工作假设是破坏前和/或突触后的破坏 GP中复发性侧支GABA能信号传导的调节导致 同步的出现。特定目的3是表征 控制有节奏的表达的细胞/分子决定因素 多巴胺消耗后已鉴定出的STN神经元的活性。我们的 工作假设是多巴胺抑制STN的节奏活性 神经元通过调节超极化激活电导，电压 - 依赖性CA/2+电导以及对GABA能输入的响应 来自GP。 这些特定目标的成功实现应提供很多 需要有关正常和多巴胺的特性的所需信息 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不足的理解 研究了一组基底神经神经元，但我们也应该在 为了设计更有效和更少的侵入性治疗的位置 帕金森氏病比不可逆的病变。