AFFERENT CONTROL OF DOPAMINERGIC NEURONS

多巴胺能神经元的传入控制

• 批准号: 6107340
• 负责人: James M Tepper
• 金额: --
• 依托单位: RUTGERS THE STATE UNIV OF NJ NEWARK
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6107340
• 关键词: GABA receptor; afferent nerve; axon; biocytin; 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.

中脑多巴胺系统功能障碍被认为是一种 精神分裂症及相关精神病的重要病因 运动障碍的数量。尽管最近几年取得了很大进展 多年来一直在了解控制 多巴胺神经元的活动和大脑中多巴胺的释放， 了解多巴胺神经元传入控制的研究进展 在未来，活动一直在放缓。具体地说， 调节体内残留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受到控制 主要通过传入输入来证明，在活体内， 这些神经元的放电模式沿着一个连续体的范围从 起搏器样的放电通过随机放电到爆发式放电，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能和谷氨酸能神经元。这个 对多巴胺能神经元的GABA能输入是密度最高、研究最深入的 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丘脑底核和桥脑脚 核团和额叶皮质。然而，不可能引出 刺激上述任一种物质引起的多巴胺能神经元的爆发活动 部位以及多巴胺能神经元对模拟的最常见反应 丘脑底核或桥脑脚核或额叶皮质 抑制力。 此应用程序中的竞争续订实验是设计的 测试普遍假设的不同方面，即存在一个 GABA能通路至多巴胺能神经元的重要途径 非多巴胺能黑质网状部的局部轴突侧支 投射神经元。这一假设的推论是，许多人 对多巴胺能神经元最具兴奋性的重要输入 控制自发活动的速度和模式是通过 这些部分构成了神经元的网状结构。这些想法将通过各种不同的方式进行检验 电生理和神经解剖学方法，包括活体和 脑实质的体外细胞内记录和标记 黑质多巴胺能和非多巴胺能神经元在活体细胞外的分布 黑质多巴胺能和非多巴胺能神经元的记录 多巴胺能神经元的序列光和电子显微镜观察 顺行示踪剂或细胞内生物细胞素标记法 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。