Mapping Striatal Dopamine Domains

描述(申请人提供)：多巴胺是中枢神经系统中一种极其重要的神经递质。它有助于运动控制、基于奖励的学习、情绪和焦虑的调节，以及其他几种大脑功能。中枢多巴胺系统的病理显然与帕金森氏症、肌张力障碍、精神分裂症、注意力缺陷多动障碍和药物滥用有关。因此，针对多巴胺系统的药物具有广泛的治疗应用和非法用途。因此，了解脑多巴胺本身的活性和多巴胺靶向药物的作用机制具有非常重要的意义。最近，PI的实验室收集了大量证据，证明了一种以前未知的多巴胺现象。我们的发现来自于大鼠大脑的伏安记录，表明两个关键的多巴胺终端区，背侧纹状体(运动功能的关键)和伏隔核的核心(腹侧纹状体的一个物质滥用的关键区域)，是由空间离散的运动域拼凑而成的。我们将这些区域命名为快域和慢域，因为前者的多巴胺释放和摄取速度明显快于后者。到目前为止，我们所检查的药物的作用也同样具有明显的领域依赖性。到目前为止，我们已经研究了这些结构域的动力学和药理学性质。我们的下一个目标是探索它们的解剖学：我们希望知道这些结构域的大小和分布，它们在动物个体之间的一致性，以及它们与已建立的纹状体结构的解剖和神经化学生物标记物的关系。我们建议通过结合高空间分辨率伏安记录和通过荧光显微镜对记录部位进行详细的免疫组织化学分析来实现这一目标。

DESCRIPTION (provided by applicant): Dopamine is an immensely important neurotransmitter in the central nervous system. It contributes to motor control, reward-based learning, the regulation of mood and anxiety, and several other brain functions. Pathology of the central dopamine systems is clearly implicated in Parkinson's disease, dystonia, schizophrenia, attention deficit hyperactivity disorder, and substance abuse. Consequently, drugs that target dopamine systems have wide-ranging therapeutic applications and illicit uses. So, understanding brain dopamine activity per se and the mechanisms of action of dopamine-targeting drugs is immensely significant. Recently, the PI's laboratory has amassed a substantial body of evidence of a previously unknown dopamine phenomenon. Our findings, derived from voltammetric recordings in the rat brain, show that two key dopamine terminal fields, the dorsal striatum (key to motor function) and the core of the nucleus accumbens (a region of the ventral striatum key to substance abuse), are organized as a patchwork of spatially discrete kinetic domains. We have named these the fast and slow domains because the rates of dopamine release and uptake are significantly faster in the former compared to the latter domains. The actions of the drugs we have examined to date are likewise significantly domain-dependent. Thus far, we have investigated the kinetic and pharmacological properties of the domains. Our next objective is to explore their anatomy: we wish to know the size and distribution of the domains, their consistency between individual animals, and their relationship to established anatomical and neurochemical biomarkers of striatal structure. We propose to achieve this objective by combining high spatial resolution voltammetric recording with detailed immunohistochemical analysis of the recording sites by means of fluorescence microscopy.