Nigrostriatal Dopamine Function

黑质纹状体多巴胺功能

基本信息

批准号：
6731973
负责人：
James M Tepper
金额：
$ 33.24万
依托单位：
RUTGERS THE STATE UNIV OF NJ NEWARK
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-02-01 至 2008-03-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：众所周知，基底神经节，特别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着核心作用。然而，最近，中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，以低频爆发的形式增加放电率，通常持续几百毫秒。多巴胺能信号的时机对于多巴胺能系统在信号刺激特征、奖励显着性或预测误差方面的许多功能至关重要。尽管很明显，不同活动模式的切换是由传入活动触发的，但负责的传入，特别是突发或突发启动的机制尚不清楚。这项竞争性更新的总体目标是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的黑质多巴胺能神经元传入控制中的 GABA 能机制来扩展上一个布兰特周期中所做的观察。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 受体主要或完全由体内 GABA 能输入激活，而 GABA-B 受体的激活仅在 GABA 转运蛋白被激活时才会发生。因过度或高频输入和/或药理学阻断而饱和，(2) 黑质多巴胺能神经元上的大多数突触后 GABA-B 受体位于在突触周围，（3）传入诱导的 DA 能神经元活动模式的改变导致纹状体和黑质中 DA 细胞外水平的显着变化，（4）黑质 GABA 能中间神经元是 DA 能神经元传入输入的来源，以及（5 ) 质内DAergic和GABAergic神经元对GABA-A受体激动剂敏感性的差异黑质是由于 GABA-A 亚基组成不同和/或 GABA-A 受体密度差异造成的。这些数据应该为有关黑质多巴胺能神经元传入控制的几个重要问题提供答案，这些问题对于理解基底神经节的正常功能至关重要，并且也可能为改善涉及多巴胺系统的疾病的药物治疗指明道路。