Project 2: Coordinate Gene Expression in Limbic Thalamus and Cortex(pgs.221-238)

抑郁性疾病是人类发病率的主要来源，具有巨大的经济和社会影响，其特征是边缘回路功能障碍，但其背后的回路缺陷的性质以及它们是否有发育障碍的连接基础尚不清楚。这项研究计划的总体目标是在人类中识别那些特定于两个边缘回路的基因，与匹配的对照组和精神分裂症患者的大脑相比，这两个边缘回路是由丘脑的主要前核到后扣带皮质(Brodmann‘s Area 23)和丘脑内侧核到前扣带皮质(Brodmann’s Area 24)的投射所定义的。我们将使用Affymetrix基因芯片阵列进行全球基因图谱分析，并使用一系列更高分辨率的技术来定位已知和新基因的细胞表达，这些基因是皮质区域和丘脑核的同源对所特有或显示出不同表达模式的。这些研究有望阐明决定大脑皮层特定区域与丘脑特定核团的相互联系的因素，以及这些因素在以特定丘脑核团的皮质目标功能改变为特征的临床条件下是如何受到干扰的。结合关于信使核糖核酸水平、突变表型、蛋白质定位、蛋白质水平和蛋白质相互作用的更多数据，这些信息应该有助于我们获得更好的 了解这些生物系统，开发改进的诊断测试，确定新的治疗靶点，并可能导致双相情感障碍和严重抑郁障碍的新治疗策略。

Depressive illness, which is a major source of human morbidity with enormous economic and social impact, is characterized by dysfunction of limbic circuitry, but the nature of circuitry defects that underlie this and whether they have their basis in developmentally disturbed connectivity are unknown. The overall aim of this research proposal is to identify, in humans, those genes that are specific to two limbic circuits defined by projections of the principal anterior nucleus of the thalamus to posterior cingulate cortex (Brodmann's area 23) and of the mediodorsal nucleus of the thalamus to anterior cingulate cortex (Brodmann's area 24) in brains from patients who had suffered from major depressive illness and bipolar disorder, compared with brains of matched controls and schizophrenics. We will use Affymetrix GeneChip arrays for global gene profiling and a series of higher resolution techniques for locating the cellular expression of known and novel genes that are either specific to or show different patterns of expression between the cognate pairs of cortical areas and thalamic nuclei. These studies are expected to shed light on the factors that determine the interconnectedness of specific areas of the cerebral cortex with specific nuclei of the thalamus and how these factors are disturbed in clinical conditions characterized by altered function of the cortical targets of specific thalamic nuclei. Together with additional data on mRNA levels, mutant phenotypes, protein localization, protein levels and protein interactions, the information should help us gain a better understanding of these biological systems, develop improved diagnostic tests, identify new therapeutic targets, and potentially lead to novel treatment strategies for bipolar and major depressive disorders.