Nigrostriatal Dopamine Function

描述(由申请人提供)：众所周知，基底节，特别是这个系统的多巴胺能成分，在包括帕金森氏病和精神分裂症在内的几种神经和精神疾病的病因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认为是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所必需的。 在活体中，多巴胺能神经元以较低的频率自发放电。这种活动沿着放电模式的连续体存在，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，再到缓慢的爆发性模式。活体中的多巴胺能神经元通常对行为相关的环境刺激做出反应，放电频率增加，表现为通常持续数百毫秒的低频爆发。多巴胺能信号的时序对多巴胺能系统在信号刺激特性、奖赏突显或预测误差等方面的许多功能至关重要。虽然向不同活动模式的切换显然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。这次竞争性更新的总体目标是通过集中在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黑质多巴胺能神经元传入控制的GABA能机制来扩展在上一次Brant循环中所做的观察。 有5个特定的目标将检验以下假设：(1)在典型的实验条件下，体内多巴胺能神经元上的GABA-A受体主要或完全被GABA能输入激活，而GABA-B受体的激活仅在GABA转运体被过量或高频输入和/或药物阻断饱和时发生；(2)黑质多巴胺能神经元上的大多数突触后GABA-B受体位于突触周围；(3)传入引起纹状体和黑质DA能神经元活动模式的改变，(4)黑质GABA能中间神经元是DA能神经元传入的来源，(5)黑质DA能和GABA能神经元对GABA-A受体激动剂敏感性的差异是由于GABA-A亚单位组成不同和/或GABA-A受体密度不同所致。 这些数据应该为黑质多巴胺能神经元的传入控制提供了几个重要问题的答案，这些问题对于理解基底节的正常功能是必不可少的，也可能为改善涉及多巴胺系统的疾病的药物治疗指明方向。

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.