MUSCARINIC AND DOPAMINERGIC CONTROL OF STRIATAL NEURONS

纹状体神经元的毒蕈碱和多巴胺能控制

• 批准号: 2267271
• 负责人: DALTON JAMES SURMEIER
• 金额: $ 7.47万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-08-01 至 1995-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2267271
• 关键词: acetylcholine; axon; calcium channel; cholinergic receptors; corpus striatum; dopamine; dopamine receptor; electrical conductance; electrical potential; electrophysiology; fluorescence; guanine nucleotide binding protein; immunocytochemistry; ion transport; juvenile animal; laboratory rat; mature animal; neurons; neurotransmitter metabolism; potassium channel; rhodium; second messengers; tissue /cell culture; voltage /patch clamp

Parkinson's disease afflicts 1 in every 1000 adults, rising exponentially in incidence after the age of fifty. The symptoms of this debilitating psycho-motor illness are thought to result from a functional imbalance between cholinergic and dopaminergic systems of the neostriatum. The treatment of this disease has been hampered by the absence of a clear picture of the neuromodulatory actions of these systems in the neostriatum. Electrophysiological studies in other excitable cells have demonstrated that acetylcholine (ACh) and dopamine (DA) exert their effects on electrical excitability primarily by altering the properties of voltage-dependent ionic conductances. These alterations are reflected in the integration of synaptic input, action potential shape and spike patterning. Previous studies of neostriatal neurons have not been able to provide a similar level of understanding because of their reliance upon techniques that cannot definitively characterize ionic conductances or the molecular mechanisms mediating their modulation. In this project, recently developed whole-cell and patch voltage-clamp techniques that overcome these shortcomings will be used to characterize the effects of ACh and DA on the ionic conductances of identified neostriatal neurons dissociated from adult and juvenile rats. It is the central thesis of this proposal that ACh and DA exert their principal effects on neostriatal function by modulating ionic conductances and that the interaction between these transmitters occurs at the level of the molecular events mediating this modulation in individual neostriatal neurons. The proposed experiments test this hypothesis in mature neostriatal neurons with techniques capable of measuring single or multi-channel ionic currents while controlling the biologically relevant variables: transmembrane voltage and the biochemical composition of the intra- and extra-cellular environment. Specifically, the proposal has three aims pertinent to a test of this hypothesis: (1) to characterize the effects of ACh and DA on the biophysical properties of potassium and calcium conductances in morphologically and immunocytochemically identified postnatal rat neostriatal neurons. Phenotypic identification of studied neurons will focus upon axonal projections using retrograde tracing and transmitter immunocytochemistry; (2) to characterize the role of different receptor subtypes, GTP-binding proteins and second messenger systems in mediating the modulatory effects of ACh and DA; and (3) to characterize the nature of the interaction between cholinergic and dopaminergic signalling pathways in the modulation of ionic conductances. An understanding of the actions of ACh and DA on the electrical excitability of neostriatal neurons should be of significance to the development of effective therapies for Parkinson's disease. The actions of these modulators are also of relevance to the clinical management of Huntington's disease and the psycho-motor side-effects of neuroleptic treatment of schizophrenia.

帕金森氏病在每1000名成年人中受苦1，成倍增加 五十岁以后发病。 这种衰弱的症状 人们认为心理运动疾病是由于功能失衡而引起的 在新纹状体的胆碱能和多巴胺能系统之间。 这 由于没有明确的治疗，这种疾病的治疗受到了阻碍 这些系统在 新纹状体。 其他激发细胞中的电生理研究具有 证明乙酰胆碱（ACH）和多巴胺（DA）发挥 主要通过改变的特性，对电兴奋性的影响 电压依赖性离子电导。 这些改变反映在 突触输入，动作电位形状和尖峰的整合 图案。 对新纹状体神经元的先前研究未能 提供类似的理解水平，因为它们依赖 无法明确表征离子电导的技术或 分子机制介导其调节。 在这个项目中， 最近开发了全细胞和补丁电压钳技术 克服这些缺点将用于表征 ACH和DA在鉴定的新纹状体神经元的离子电导 与成年和少年大鼠分离。 这是 ACH和DA对新纹状体作用的主要影响 通过调节离子电导和之间的功能 这些发射器发生在介导的分子事件水平上 该调节在单个新纹状体神经元中。 提议 实验在成熟的新纹状体神经元中检验了这一假设 能够测量单通道或多通道离子电流的技术 在控制生物学相关的变量时：跨膜 电压和细胞外的生化组成 环境。 具体而言，该提案的三个目标与 该假设的检验：（1）表征ACH和DA对 钾和钙电导的生物物理特性 形态学和免疫细胞化学上鉴定出的产后大鼠 新纹状体神经元。 研究神经元的表型鉴定将 使用逆行跟踪和发射器专注于轴突投影 免疫细胞化学； （2）表征不同受体的作用 介导的子类型，GTP结合蛋白和第二个允许系统 ACH和DA的调节作用； （3）特征自然 胆碱能和多巴胺能信号之间的相互作用 离子电导调节的途径。 对 ACH和DA对新纹状体的电兴奋性的作用 神经元应该对有效的发展具有重要意义 帕金森氏病的疗法。 这些调节器的动作是 也与亨廷顿氏病的临床管理有关 精神分裂症的神经摄取治疗的心理运动副作用。

项目成果

Dopaminergic regulation of striatal efferent pathways.

纹状体传出通路的多巴胺能调节。

• DOI: 10.1016/0959-4388(94)90142-2
• 发表时间: 1994
• 期刊: Current opinion in neurobiology
• 影响因子: 5.7
• 作者: Surmeier,DJ;Kitai,ST
• 通讯作者: Kitai,ST

Estradiol reduces calcium currents in rat neostriatal neurons via a membrane receptor.

雌二醇通过膜受体减少大鼠新纹状体神经元的钙电流。

• DOI: 10.1523/jneurosci.16-02-00595.1996
• 发表时间: 1996
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience.
• 作者: Mermelstein,PG;Becker,JB;Surmeier,DJ
• 通讯作者: Surmeier,DJ

Voltage-dependent facilitation of calcium channels in rat neostriatal neurons.

• DOI: 10.1152/jn.1996.76.4.2290
• 发表时间: 1996-10
• 期刊: Journal of neurophysiology
• 影响因子: 2.5
• 作者: Wen Jie Song;D. Surmeier