CNS DA NEURONS--CELLULAR BASIS OF PATTERNED ACTIVITY

中脑端脑多巴胺功能状态的改变 含有多巴胺（DA）的神经元与多种疾病的病因有关。 病理和医源性疾病，包括精神分裂症， 迟发性运动障碍 这些神经元参与了 临床相关性导致了许多基础研究， 更好地了解其所涉及的因素 在细胞水平上的调节。 一个潜在的重要领域， 在很大程度上尚未探索涉及神经元的作用， 放电模式作为调节神经元活动的手段， 多巴胺能系统在脑中的表达。 在我们的申请中提出的研究试图探索离子和 表现出的活动模式的不同群体的细胞基础， 大鼠中脑DA能神经元的变化。 我们的初步研究将 专注于模式生成的内在机制。 实验将 进行鉴定和表征几个电压和配体门控 离子电导，由于它们能够被激活， 在峰间期，可能参与调节 神经元放电模式 单电极电压钳技术 将与几种高选择性的药物联合使用， 用于指定单个电流分量所做贡献的探针 到重复的单次尖峰和爆发放电模式。 第二系列 的实验将集中在外在因素可能有助于 正常模式活动的生成。 第一组 实验中，将使用细胞外单个单位记录技术 探索贡献。由含有兴奋性氨基酸的 传入的放电模式通常观察到的识别DA 体内神经元 兴奋性投射起源于皮层， 脚桥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 包含在传入的主要中脑DA细胞群， 个别传导机制的可能调节剂 在项目的早期阶段。 通过更清楚地 理解内在和外在因素所作贡献的性质， 的模式化电活动的外在机制， 含DA神经元，我们希望进一步了解一个重要的 生理过程，这可能是中央参与调节 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.