CNS DA NEURONS--CELLULAR BASIS OF PATTERNED ACTIVITY

中脑多巴胺功能状态的改变 含有(DA)的神经元与多种疾病的病因学有关 病理和医源性疾病，包括精神分裂症和 迟发性运动障碍。这些神经元在神经功能紊乱中的作用 临床相关性导致了一些针对以下方面的基础研究 更好地了解他们的工作中涉及的因素 在细胞水平上的调控。一个潜在的重要领域是 在很大程度上仍未被探索与神经元的作用有关 放电模式作为调节神经元活动的手段，因此 多巴胺能系统在脑内的表达。 在我们的申请中提出的研究试图探索离子和 不同类型活动模式的细胞基础 大鼠中脑内含DA的神经元。我们的初步研究将 关注模式生成的内在机制。实验将是 用于识别和表征几个电压和配体门控 离子电导，它凭借其被激活的能力 在间歇期，很可能参与调节 神经元放电模式。单电极电压钳技术 将与几种高度选择性的药剂一起使用 用于指定单个当前组件所做贡献的探测 到重复的单峰和爆发式发射模式。第二季 实验的重点将放在可能有助于 生成正常的图案化活动。在第一组 实验中，将使用细胞外单单元记录技术 来探索他们的贡献。由含有兴奋性氨基酸的 在已识别的DA中典型观察到的放电模式的传入 活体中的神经元。兴奋性投射起源于大脑皮层和 桥脑脚被盖将是这些实验的重点。 最后，我们将研究其他神经活性物质的作用。 包含在主要的中脑DA细胞群的传入中 单个电导机制的可能调节器 在项目的早期阶段具有鲜明的特点。通过更清楚地 理解内部和内部贡献的性质 图案化电子活动的外部机制 含DA的神经元，我们希望对一个重要的 一种生理过程，可能集中参与调节 这些神经元在正常和病理状态下的表达。

Alterations in the functional state of mesotelencephalic dopamine (DA)-containing neurons have been implicated in the etiology of a variety of pathological and iatrogenic conditions including schizophrenia and tardive dyskinesia. Involvement of these neurons in disorders of clinical relevance has led to a number of basic studies directed at obtaining a better understanding of the factors involved in their regulation at the cellular level. One area of potential importance that has remained largely unexplored pertains to the role of neuronal discharge pattern as a means of modulating neuronal activity and thus expression of dopaminergic systems in brain. The research proposed in our application seeks to explore the ionic and cellular basis of the diverse group of activity patterns exhibited by mesencephalic DA-containing neurons in the rat. Our initial studies will focus on intrinsic mechanisms of pattern generation. Experiments will be performed to identify and characterize several voltage- and ligand-gated ion conductances, which by virtue of their ability to become activated during the interspike interval, are likely to be involved in regulating neuronal discharge pattern. Single electrode voltage clamp techniques will be used in conjunction with several highly selective pharmacological probes to specify the contribution made by individual current components to repetitive single spike and burst firing patterns. The second series of experiments will focus on extrinsic factors likely to contribute to generation of normal patterned activity. In the first group of experiments, extracellular single unit recording techniques will be used to explore the contribution. made by excitatory amino acid-containing afferents to the firing patterns typically observed among identified DA neurons in vivo. Excitatory projections originating in the cortex and pedunculopontine tegmentum will be the focus of these experiments. Finally, we will examine the role of other neuroactive substances contained in afferents to the principle mesencephalic DA cell groups as possible modulators of the individual conductance mechanisms characterized in the earlier phases of the project. By more clearly understanding the nature of the contributions made by intrinsic and extrinsic mechanisms to the patterned electrical activity of DA-containing neurons, we hope to gain further insights into an important physiological process which may be centrally involved in regulating the expression of these neurons in normal and pathological states.