REGIONAL VARIATION IN D1 SIGNALING PROTEIN LOCALIZATION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 前额叶皮层（PFC），杏仁核（NAc）和杏仁核形成了一个皮质边缘回路，参与正常认知，精神分裂症，焦虑和恐惧状态，奖励途径和药物滥用。 多巴胺作用于D1受体家族，对这些大脑区域的个体和集体功能至关重要。 对这些受体的细胞作用的研究发现，它们在一个区域内的作用以及这些大脑区域之间的变化是可变的。 这里提出的工作的目标是研究这种变异性的结构基础。 D1家族由两个独立的受体D1和D5组成，它们无法通过药理学区分。 突触前和突触后位点这些受体可用性的区域差异将改变D1激动剂在这些位点的作用。 这两种受体都与复杂的信号转导系统偶联。 这些系统的组件的定位受到严格控制，并且这种定位对于功能至关重要。 本工作包括三个目的：1）确定D1和D5在PFC、NAc和杏仁核中的定位以及共定位。 2)确定D1受体信号转导通路的三个组分在PFC、NAc和杏仁核中的定位以及任何共定位。 3)将D1和D5的定位与它们的信号转导蛋白联系起来。 出于几个原因，我们使用恒河猴模型进行这些研究。 皮质边缘回路的一个关键组成部分，PFC，在灵长类动物和啮齿类动物之间显示出显著的差异。 特别是，背外侧区域，感兴趣的认知和精神分裂症，在大鼠中没有明确的同源性。 多巴胺能投射到PFC的组织在大鼠和灵长类动物中是不同的。 此外，现在有证据表明，单胺神经递质的作用，如血清素和多巴胺，在啮齿动物和猴子之间存在差异，即使在相对同源的区域，如杏仁核。 因此，为了产生能够说明人类疾病的结果，最好使用非人类灵长类动物模型进行这些实验。 这些研究的结果将阐明D1受体作用的相互矛盾的生理学研究，并促进我们对多巴胺能药物对这些重要脑区的作用的理解。 这一信息预计将增加与皮质边缘回路有关的疾病，包括精神分裂症，药物滥用和焦虑症，包括创伤后应激障碍的药物治疗的合理发展。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The prefrontal cortex (PFC), nucleus accumbens (NAc) and amygdala form a corticolimbic circuit that is involved in normal cognition, schizophrenia, anxiety and fear states, reward pathways and drug abuse. Dopamine, acting at the D1 family of receptors is critical to the individual and collective function of these brain regions. Studies of the cellular actions of these receptors have found variability in their effects within a region as well as variation between these brain regions. The goal of the work proposed here is to study the structural basis for this variability. The D1 family is comprised of two separate receptors, D1 and D5, which can not be distinguished by pharmacology. Regional differences in the availability of these receptors at pre- and postsynaptic sites would alter the action of D1 agonists at these sites. Both of these receptors are coupled to complex signal transduction systems. The localization of the components of these systems is tightly controlled and this localization is critical to function. This work is comprised of three aims: 1) Determine the localization of D1 and D5 in PFC, NAc and amygdala as well as any colocalization. 2) Determine the localization of three components of the D1 receptor signal transduction pathway in PFC, NAc and amygdala, as well as any colocalization. 3) Relate the localization of D1 and D5 to their signal transduction proteins. We use a rhesus monkey model for these studies for several reasons. A key component of the corticolimbic circuit, the PFC, shows significnant differences between primates and rodents. In particular, the dorsolateral region, of interest with regard to cognition and schizophrenia, has no clear homology in rat. The dopaminergic projections to PFC are organized differently in rats and primates. Furthermore, there is now evidence that the actions of monoamine neurotransmitters, such as serotonin and dopamine, vary between rodent and monkey, even in regions that are relatively homologus, such as the amygdala. Therefore, in order to produce results that can speak to the human illnesses in question, it is best to use a non-human primate model for these experiments. The results of these studies will shed light on conflicting physiological studies of D1 receptor action and advance our understanding of the effect dopaminergic drugs have on these important brain regions. This information is expected to add in the rational development of pharmacotherapies for the disorders associated with the corticolimbic circuit, including schizophrenia, substance abuse and anxiety disorders, including PTSD.