IN VITRO ELECTROPHYSIOLOGY OF MIDBRAIN DOPAMINE SYSTEMS

多巴胺能系统的功能障碍被认为在 几种神经和精神疾病的病因学，例如 帕金森氏症和精神分裂症。然而，这些疾病的模型 到目前为止，他们往往没有考虑到 动态平衡调节在这些系统 被扰乱，这将使系统恢复正常。另一个 调查该系统正常功能的可能方法和 它在疾病中的作用将是详细研究 自动调节调节含有多巴胺的神经元的活动， 并倾向于研究这些过程中的缺陷如何 导致功能失调状态。我们一直在研究这种膜 参与多巴胺神经元活动自我调节的过程 大鼠脑片的体外制备，其中混杂 环境或传入影响可以得到更好的控制。在这 建议，我们计划将这项研究扩展到多巴胺神经元 通过研究五个被认为在其 功能：1)识别多巴胺神经元内的棘波产生区 以及它们的形态关联，并以这种方式使研究 多巴胺神经元对其功能亚室的调节；2) 检测谷氨酸能传入神经对脑电活动的调节作用 多巴胺能神经元的放电模式；3)检测其作用机制。 自身受体刺激及其调控因素 敏感性，目的是为了研究由 多巴胺神经元对自身神经递质的反应；4) 确定对控制多巴胺起作用的重要因素 从树突状细胞库中释放，从而阐明这种释放是否 一种自我调节过程，或像在纹状体中一样，由 谷氨酸能传入过程；5)功能分析 不同的肽能共递质的含义 多巴胺神经元亚群，详细说明它们参与细胞 以及它们的共同释放如何影响自身受体的敏感性和 在已识别的多巴胺神经元亚群中的肽相互作用，这将 通过结合其投影部位的逆行标记进行分类 和细胞内染色。结果对现场的有效性检验。 细胞类别将通过在体内进行平行实验来确定， 如果可行的话。这种功能和形态相结合的分析 因此，单个多巴胺神经元的表达可能促进了 关于精神功能障碍状态的模型。此外，通过 详细研究这些监管流程在以下方面的不同 识别出的多巴胺神经元亚群，可能会衍生出 以这些调节因子为靶点的新的治疗方法 从而避免经常伴随的衰弱的副作用 直接作用药物的使用。

Dysfunctions of dopaminergic systems are thought to play a role in the etiology of several neurological and psychiatric disorders, such as Parkinson's disease and schizophrenia. However, models of these disorders to date have often failed to take into account the large amount of homeostatic regulation that comes into play whenever these systems are perturbed, and which serve to reset the system towards normality. Another possible approach to investigating the normal functions of this system and its role in disease would be to examine in detail the modes of autoregulation that modulate the activity of dopamine-containing neurons, with a predisposition to examining how deficits in these processes could precipitate dysfunctional states. We have been investigating the membrane processes involved in the self-regulation of dopamine neuron activity using the in vitro rat brain slice preparation, in which confounding environmental or afferent influences can be better controlled. In this proposal, we plan to extend this investigation into dopamine neuron regulation by studying five processes believed to play a role in their function: 1) identifying the spike generating zones within dopamine neurons and their morphological correlates, and in this way enable the study of dopamine neuron regulation in terms of its functional subcompartments; 2) testing the involvement of glutamatergic afferents in the regulation of dopamine neuron firing pattern; 3) examining the functional mechanism of autoreceptor stimulation and factors involved in regulating its sensitivity, for the purpose of studying the autonomous control exerted by the dopamine neuron on its responsivity to its own neurotransmitter; 4) determining the important factors which play a role in controlling dopamine release from dendritic stores, and thus elucidating whether this release is an autoregulatory process or is mediated, as it is in the striatum, by glutamatergic afferent processes; and 5) analyzing the functional implications of the different peptidergic cotransmitters contained within subpopulations of dopamine neurons, detailing their involvement in cell firing and how their co-release may influence autoreceptor sensitivity and peptide interactions in identified subsets of dopamine neurons, which will be classified by combining retrograde labelling from their projection sites and intracellular staining. The validity of the results to the in situ cell class will be determined by carrying out parallel experiments in vivo, when feasible. This type of combined functional and morphological analysis of individual dopamine neurons may thus facilitate the development of models concerning states of psychiatric dysfunction. Furthermore, by examining in detail how these regulatory processes differ between identified subpopulations of dopamine neurons, it may be possible to derive new therapeutic approaches by pharmacologically targeting these regulatory sites, and thereby avoid the debilitating side effects often associated with the use of direct-acting drugs.