AFFERENT CONTROL OF DOPAMINERGIC NEURONS

多巴胺能神经元的传入控制

• 批准号: 6240287
• 负责人: James M Tepper
• 金额: $ 2.51万
• 依托单位: RUTGERS THE STATE UNIV OF NJ NEWARK
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6240287
• 关键词: GABA receptor; afferent nerve; axon; corpus striatum; dopamine; electrodes; electron microscopy; electrophysiology; immunocytochemistry; laboratory rat; light microscopy; neuroanatomy; neurons; substantia nigra; synapses

Dysfunctioning of the midbrain dopamine system has been suggest as an important etiologic factor in schizophrenia and related psychoses and a number of motor disorders. Although much progress has been made in recent years towards understanding the intrinsic cellular mechanisms that control dopamine neuronal activity and the release of dopamine in the brain, progress towards understanding the afferent control of dopamine neuron activity has been slower in coming. In particular, the inputs that modulate the firing rate and pattern of dopaminergic neurons in vivo remain unclear. That the firing patterns of dopaminergic neurons are controlled principally by afferent input is demonstrated by the fact that in vivo, these neurons exhibit firing patterns that range along a continuum from pacemaker-like firing through random firing to bursty firing, but in vitro, only the pacemaker pattern is observed. Based on neuroanatomical evidence, the most important afferents to substantia nigra neurons are likely to be GABAergic and glutamatergic. The densest and best-studied GABAergic inputs to dopaminergic neurons are thought to originate in the neostriatum and globus pallidus, while the most prominent excitatory inputs arise from the subthalamic and pedunculopontine nuclei, and the frontal cortex. However, it is not possible to elicit bursting activity in dopaminergic neurons by stimulation of any of these sites, and the most common response of dopaminergic neurons to simulation of the subthalamic or pedunculopontine nuclei or frontal cortex is inhibition. The experiments in this application for a competitive renewal are designed to t est various aspects of the general hypothesis that there exists an important GABAergic pathway to dopaminergic neurons originating from the local axon collaterals of non-dopaminergic substantia nigra pars reticulate projection neurons. A corollary of this hypothesis is the idea that many of the most excitatory important inputs to dopaminergic neurons that control the rate and pattern of spontaneous activity are "filtered" through these pars reticulate neurons. These ideas will be tested with a variety of electrophysiological and neuroanatomical methods including in vivo and in vitro intracellular recording and intracellular labeling of substantia nigra dopaminergic and non-dopaminergic neurons in vivo extracellular recording from identified substantia nigra dopaminergic and non- dopaminergic neurons, sequential light and electron microscopy of double labeling of anterograde tracers or intracellular biocytin labeling and dopaminergic neurons, and intracellular labeling coupled with immunocytochemical identification of the postsynaptic targets.

中脑多巴胺系统的功能障碍被认为是 精神分裂症及相关精神病重要病因及治疗 运动障碍的数量。 尽管近年来取得了很大进展， 多年来对理解内在的细胞机制，控制 多巴胺神经元活动和大脑中多巴胺的释放， 多巴胺神经元传入控制的研究进展 来的活动比较慢。 特别是， 调节体内多巴胺能神经元的放电频率和模式 不清楚 多巴胺能神经元的放电模式是由 主要通过传入输入的事实证明，在体内， 这些神经元表现出的放电模式沿着一个连续体， 从随机放电到突发放电的起搏器样放电，但在体外， 仅观察到起搏器模式。 根据神经解剖学证据，最重要的传入神经 黑质神经元可能是GABA能和谷氨酸能的。 的 多巴胺能神经元的GABA能输入是 认为起源于新纹状体和苍白球，而大多数 显著的兴奋性输入来自底丘脑和脑桥脚 核和额叶皮层。 但是，不可能引出 多巴胺能神经元的爆发活动，通过刺激任何这些 地点，和最常见的反应，多巴胺能神经元的模拟 丘脑底核或脑桥脚核或额叶皮层的神经元 抑制作用 在此应用程序中的竞争性更新的实验设计 为了检验普遍假设的各个方面， 多巴胺能神经元的重要GABA能通路， 非多巴胺能黑质网状部的局部轴突侧支 投射神经元 这一假设的一个推论是， 多巴胺能神经元最重要的兴奋性输入， 控制自发活动的速率和模式是“过滤”通过 这些部分网状神经元。 这些想法将通过各种各样的 电生理学和神经解剖学方法，包括体内和 物质的体外细胞内记录和细胞内标记 黑质多巴胺能和非多巴胺能神经元在体内细胞外 记录从确定的黑质多巴胺能和非多巴胺能 多巴胺能神经元，双光子连续光镜和电镜， 顺行示踪剂标记或细胞内生物胞素标记， 多巴胺能神经元和细胞内标记偶联 突触后靶点的免疫细胞化学鉴定。