Nigrostriatal Dopamine Function

描述（由申请人提供）：众所周知，基底神经节，尤其是该系统的多巴胺能成分，在包括帕金森病和精神分裂症在内的几种神经和精神疾病的病因学和病理生理学中发挥核心作用。然而，最近，中端脑多巴胺能系统也被视为某些类型的学习和记忆，情感反应和感知，以及几种类型的高级认知功能的组成部分。 在体内，多巴胺能神经元以低速率自发放电。这种活动沿着连续的放电模式存在，从一端的规则起搏器样模式到另一端的不规则或随机模式再到缓慢的突发模式。体内多巴胺能神经元通常对行为相关的环境刺激作出反应，其放电率以通常持续几百毫秒的低频爆发的形式增加。多巴胺能信号的时间对于多巴胺能系统在信号刺激特征、奖励显著性或预测错误中的许多功能是至关重要的。虽然很明显，切换到不同的活动模式是由传入活动触发的，传入负责，特别是爆发或爆发启动的机制还不清楚。这是一个竞争性更新的总体目标，通过集中在黑质多巴胺能神经元的传入控制中的GABA能机制，通过体内和体外神经生理学，光学和电子显微镜以及体内微透析研究，扩展了在最后一个Brant周期中所做的观察。 有5个具体目标将检验以下假设：（1）在典型的实验条件下，多巴胺能神经元上的GABA-A受体在体内主要或专门被GABA能输入激活，并且GABA-B受体的激活仅在GABA转运蛋白被过量或高频输入和/或药理学阻断饱和时发生，（2）黑质多巴胺能神经元突触后GABA-B受体大多位于突触周。（3）传入性改变多巴胺能神经元的活动方式，导致纹状体和黑质细胞外多巴胺水平的显著变化，（4）黑质GABA能中间神经元是DA能神经元的传入输入来源;（5）黑质DA能神经元和GABA能神经元对GABA-A受体激动剂的敏感性差异是由于GABA-A亚单位组成和/或GABA-A受体密度的差异。 这些数据应提供答案的黑质多巴胺能神经元的传入控制，这是必不可少的了解基底神经节的正常功能，也可能指向改善药物治疗涉及多巴胺系统的疾病的几个重要问题。

DESCRIPTION (provided by applicant): The basal ganglia, and especially the dopaminergic components of this system, are well known to play a central role in the role in the etiology and pathophysiology of several neurological and psychiatric disorders including Parkinson's disease and schizophrenia. More recently, however, mesotelencephalic dopaminergic systems have also been viewed as integral to certain types of learning and memory, affective responses and perception, and several types of higher cognitive function. In vivo, dopaminergic neurons fire spontaneously at low rates. This activity exists along a continuum of firing pattern from a regular pacemaker-like pattern on one end, to an irregular or random pattern to a slow bursty pattern on the other end. Dopaminergic neurons in vivo typically respond to behaviorally relevant environmental stimuli with an increase in firing rate in the form of a low frequency burst that usually lasts for a few hundred milliseconds. The timing of the dopaminergic signal is crucial for many of the functions ascribed to the dopaminergic system in signaling stimulus characteristics, reward salience or predictive error. Although it is clear that switches to the different patterns of activity are triggered by afferent activity, the afferents responsible and in particular the mechanisms of the burst or burst initiation are not clear. It is the overall goal of this competing renewal to extend observations made in the last Brant cycle by concentrating on GABAergic mechanisms in the afferent control of substantia nigra dopaminergic neurons studied by in vivo and in vitro neurophysiology, light and electron microscopy and in vivo microdialysis. There are 5 specific aims that will test the following hypotheses: (1) GABA-A receptors on dopaminergic neurons re predominantly or exclusively activated by GABAergic inputs in vivo under typical experimental conditions and activation of GABA-B receptors only occurs when the GABA transporter is saturated by excessive or high frequency Input and/or pharmacological blockade, (2) Most postsynaptic GABA-B receptors on substantia nigra dopaminergic neurons are located perisynaptically, (3) Afferent induced alterations in the pattern of activity of DAergic neurons lead to significant changes in extracellular levels of DA in striatum and substantia nigra, (4) Nigral GABAergic interneurons ore a source of afferent input to DAergic neurons, and (5) The difference in sensitivity to GABA-A receptor agonists between DAergic and GABAergic neurons in substantia nigra is due to a differential GABA-A subunit composition and/or a difference in the density of GABA-A receptors. These data should provide answers to several important questions about the afferent control of nigral dopaminergic neurons which are essential for understanding the normal function of the basal ganglia and which may also point the way toward improved pharmacotherapies for disorders involving the dopamine system.