CORTICAL CIRCUITRY RELATED TO NEUROTRANMISSION PROTEINS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。这项研究将前额叶皮层回路与多巴胺神经传递的分子成分联系起来。研究结果将与精神分裂症患者的工作记忆回路有关。工作记忆功能依赖于D1受体激活的最佳水平，并且通过D1受体的过度和不足刺激而受损。我们希望我们的研究结果将导致更好地了解D1受体的复杂调制的工作记忆的机制，并最终更好地了解抗精神病药物的作用。我们将确定终止于含有D1和蛋白磷酸酶-1（PP 1）亚型PP 1（alpha）和PP 1（gamma）1的棘的传入神经的来源。我们已经将神经解剖束示踪剂注射到年轻成年猕猴的大脑中，以标记顶叶、丘脑和后扣带回传入到前额叶皮质，并在前额叶皮质内标记局部水平轴突。我们正在使用适用于电子显微镜的双标记技术来染色标记的轴突和D1，PP 1（alpha）或PP 1（gamma）1。我们正在使用连续切片电子显微镜来确定标记轴突的突触后靶是否包含这些蛋白质。这些蛋白质的分布细分了皮质棘，结果将提示皮质回路的某些方面对工作记忆功能至关重要，并扩展我们对皮质回路可能专门化的机制的理解。我们使用包埋后免疫金标记来检查PP 1靶向蛋白（spinophilin和neurabin）和PP 1（alpha）和PP 1（gamma 1）在脊柱中的分布。我们的数据表明，D1受体有机会在不同的神经元隔室的信号转导蛋白的不同的补充，并建议两个PP 1亚型的功能差异。最后，我们已经使用了单和预嵌入双标签的方法来检查亚细胞定位的组I mGluRs（mGluR 1a和mGluR 5），并确定了一些差异，它们的分布，彼此之间，猴皮质和大鼠皮质之间和皮质和基底神经节之间。该项目的供资于2005年8月结束，目前正处于无费用延长年度。

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. This work relates prefrontal cortical circuitry with the molecular components of dopamine neurotransmission. The results will be related to the circuitry of working memory, which is dysfunctional in schizophrenia. Working memory function depends on an optimal level of D1 receptor activation and is impaired by both over and under stimulation of D1 receptor. It is hoped that our results will lead to a better understanding of the mechanism of the D1 receptor's complex modulation of working memory, and ultimately to a better understanding of antipsychotic drug action. We will identify the source of afferents that terminate onto spines that contain D1 and protein phosphatase-1 (PP1) isoforms PP1(alpha) and PP1(gamma)1. We have injected neuroanatomical tract tracers into the brains of young adult macaque monkeys to label parietal, thalamic and posterior cingulate afferents to prefrontal cortex, and within prefrontal cortex to label local horizontal axons. We are using double-labeling techniques appropriate for electron microscopy to stain the labeled axons and either D1, PP1(alpha) or PP1(gamma)1. We are using serial section electron microscopy to determine if the postsynaptic targets of labeled axons contain these proteins. The distribution of these proteins subdivides cortical spines, and the results will suggest aspects of cortical circuitry that are critical for working memory function and extend our understanding of the mechanisms by which cortical circuitry may be specialized. We have used post-embedding immunogold labeling to examine the distribution of PP1 targeting proteins (spinophilin and neurabin) and PP1(alpha) and PP1(gamma1) in spines. Our date indicates that the D1 receptor has access to different complements of signal transduction proteins in different neuronal compartments and suggests functional differences for the two PP1 isoforms. Finally we have used single and pre-embedding double label methods to examine the subcellular localization of group I mGluRs (mGluR1a and mGluR5) and determined a number of differences in their distribution, both between each other, between monkey cortex and rat cortex and between cortex and basal ganglia. The funding for this project ended in August of 2005 and it is currently in a no cost extension year.