MOLECULAR AND GENETIC CORRELATES OF THE ONSET OF SCHIZOPHRENIA

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。精神分裂症(SCZ)是一种破坏性的疾病，扰乱了人类大脑的最高功能。许多症状和缺陷似乎是由大规模的前额-边缘神经网络(PLN)介导的，其中背外侧前额叶(DLPFC)、前扣带回(ACC)、海马(HIPP)和内嗅觉皮质(EC)是关键组成部分。这种神经系统在青春期晚期和成年期早期达到功能成熟，这与典型的SCZ发病年龄相吻合。因此，调节PLN成熟的神经发育过程可能直接触发或间接促成疾病的发生。目前，我们对PLN的青春期发育情况的了解非常有限。因此，我们将使用强磁场结构、扩散张量和磁化传递神经成像来系统地观察猴PLN在青春期前后灰质和轴突连接的发育过程，它在结构和生理上与人类的PLN相似。然后，我们将利用基因表达谱结合激光捕获显微切割来揭示DLPFC和HIPP青春期周围形态变化的遗传相关性。我们推测，这两个区域的基因表达模式将不同，反映了在青春期前活跃的突触重组过程，而不是后一个区域。此外，假设DLPFC的白质和EC的白质之间的基因表达模式类似，反映了连接PLN亚区的轴突的同时髓鞘形成。最后，我们将把猴子DLPFC的青春期基因表达谱与我们从SCZ和正常对照组获得的现有人类前额叶微阵列数据进行比较，以确定在青春期周围发育期间和SCZ中差异表达的基因。定量实时逆转录聚合酶链式反应将被用来证实这些发现。因此，这一建议试图描述灵长类PLN的形态成熟特征，确定其遗传相关性，并最终确定可能与SCZ发病相关的基因和分子途径。最终，这些数据可能会启发新的干预策略的概念化，这些策略可能在减轻甚至预防SCZ的发病方面有效。

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.