MOLECULAR AND GENETIC CORRELATES OF THE ONSET OF SCHIZOPHRENIA

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。精神分裂症（SCZ）是一种破坏性的疾病，扰乱了人类大脑功能的最高秩序。它的许多症状和缺陷似乎是由大规模的前额叶边缘神经网络（PLN）介导的，其中背外侧前额叶皮层（DLPFC），前扣带皮层（ACC），海马（HIPP）和内嗅皮层（EC）是关键组成部分。这个神经系统在青春期后期和成年早期达到功能成熟，这与SCZ的典型发病年龄相吻合。因此，介导PLN成熟的神经发育过程可能直接触发或间接导致疾病的发作。目前，我们对PLN青少年期发展的了解非常有限。因此，我们将使用高磁场结构，扩散张量和磁化传递神经成像系统调查的过程中的青少年期发育的灰质和轴突的连接性内的猴子PLN，这是结构和生理上类似于它的人类同行。然后，我们将利用基因表达谱与激光捕获显微切割相结合，以揭示DLPFC和HIPP的青春期前形态学变化的遗传相关性。我们假设，基因表达的模式将不同的2个区域之间，反映了突触重组过程中，积极发生在青春期前，但不是后者的区域。此外，假设DLPFC和EC的白色物质之间的基因表达模式相似，反映了连接PLN亚区的轴突的同时髓鞘形成。最后，我们将比较我们现有的人类前额叶芯片数据从SCZ和正常对照组的猴子DLPFC的青少年期基因表达谱，以确定基因的差异表达在青少年期的发展和SCZ。然后将使用定量实时逆转录聚合酶链反应来证实这些发现。因此，本提案旨在表征灵长类PLN的形态成熟，定义其遗传相关性，并最终确定可能与SCZ发病相关的基因和分子途径。最终，这些数据可能会激发新的干预策略的概念化，可能是有效的衰减，甚至可能防止SCZ的发作。

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. Schizophrenia (SCZ) is a devastating disease that disturbs the highest order of human brain functions. Many of its symptoms and deficits appear to be mediated by a large-scale prefrontal-limbic neural network (PLN), of which the dorsolateral prefrontal cortex (DLPFC), the anterior cingulate cortex (ACC), the hippocampus (HIPP), and the entorhinal cortex (EC) are key components. This neural system achieves functional maturation during late adolescence and early adulthood, which coincides with the typical age of onset of SCZ. Thus, the neurodevelopmental processes that mediate the maturation of the PLN may directly trigger or indirectly contribute to the onset of illness. At present, our understanding of the periadolescent development of the PLN is very limited. Thus, we will use high magnetic field structural, diffusion tensor, and magnetization transfer neuroimaging to systematically survey the course of periadolescent development of the gray matter and axonal connectivities within the monkey PLN, which is structurally and physiologically similar to its human counterpart. We will then utilize gene expression profiling combined with laser capture microdissection to uncover the genetic correlates of the periadolescent morphological changes of the DLPFC and the HIPP. We postulate that the pattern of gene expression will differ between the 2 regions, reflecing the synaptic reorganization process that is actively taking place during periadolescence in the former but not the latter region. Furthermore, it is hypothesized that the gene expression pattern will be similar between the white matter of the DLPFC and that of the EC, reflecting the concurrent myelination of axons that link subregions of the PLN. Finally, we will compare the periadolescent gene expression profiles of the monkey DLPFC with our existing human prefrontal microarray data obtained from SCZ and normal control subjects in order to identify genes that are differentially expressed both during periadolescent development and in SCZ. Quantitative real-time reverse transcriptase polymerase chain reaction will then be used to confirm these findings. Thus, this proposal seeks to characterize the morphometric maturation of the primate PLN, to define its genetic correlates, and, finally, to identify genes and molecular pathways that may be associated with the onset of SCZ. Ultimately, these data may inspire the conceptualization of novel intervention strategies that may be effective in attenuating or perhaps even preventing the onset of SCZ.