OLFACTORY NEURODEVELOPMENTAL PATHOLOGY IN SCHIZOPHRENIA

越来越多的临床和尸检研究证据表明精神分裂症的病理生理学中存在神经发育异常。 虽然在CNS的几乎所有部分中，神经元的出生、迁移、分化和连接在很大程度上都在妊娠结束时完成，但嗅上皮和嗅球的独特之处在于它们在整个生命过程中经历连续的再生和神经再支配。 因此，他们提供了一个机会，调查正在进行的神经元和连接的发展，即使在晚年的细胞和分子事件。此外，细胞结构异常提示异常发展已被描述在嗅觉皮质，虽然研究结果仍然存在争议。 检查嗅觉系统在精神分裂症中的重要性进一步强调了这种疾病中存在的气味检测，识别和记忆的明显障碍。拟议的研究将描述精神分裂症患者和匹配对照组中人类嗅上皮、嗅球和初级嗅皮质的神经发育过程。 我们的总体假设是，分子，细胞和连接神经发育的异常模式在精神分裂症的嗅觉区域是显而易见的。 在嗅觉上皮（目的1）中，将使用细胞类型特异性抗体的免疫组织化学和计算机辅助显微镜来确定嗅觉受体神经元谱系中分化细胞类型的相对比例和形态特征，以及它们对嗅觉受体神经元谱系中分化细胞类型的相对比例和形态特征，以及它们对嗅觉受体神经元细胞骨架和神经营养因子介导的信号转导重要的多肽的表达。 在嗅球中（目标2），在免疫标记突触素、酪氨酸羟化酶、钙视网膜蛋白、钙结合蛋白D28 k、NCAM和GAP- 43后，将定量肾小球的细胞、树突和轴突组成。 在目标3中，我们将对梨状皮质和内嗅皮质进行定量细胞结构分析。 将确定化学上不同的神经元群体的相对密度，并使用空间点模式分析评估神经元的空间排列。

Growing evidence from clinical and postmortem research implicates abnormal neurodevelopment in the pathophysiology of schizophrenia. While neuron birth, migration, differentiation, and connectivity are largely completed by the end of gestation in almost all parts of the CNS, the olfactory epithelium and olfactory bulb are unique in that they undergo continuous regeneration and reinnervation throughout life. Thus, they offer an opportunity to investigate cellular and molecular events of ongoing neuronal and connectional development, even in late life. In addition, cytoarchitectural abnormalities suggestive of abnormal development have been described in olfactory cortices, although findings remain controversial. The importance of examining the olfactory system in schizophrenia is further underscored by the marked impairments in odor detection, identification, and memory that are present in the disorder. The proposed research will characterize neurodevelopmental processes in human olfactory epithelium, olfactory bulb, and primary olfactory cortices in well-characterized individuals with schizophrenia and matched controls. Our overarching hypothesis is that abnormal patterns of molecular, cellular and connectional neurodevelopment are evident in olfactory regions in schizophrenia. In the olfactory epithelium (Aim 1), immunohistochemistry with cell-type-specific antibodies and computer-assisted microscopy will be used to determine the relative proportions and morphologic characteristics of differentiating cell types in the olfactory receptor neuron lineage, as well as their expression of polypeptides that are important for the neuronal cytoskeleton and for neurotrophin mediated signal transduction. In the olfactory bulb (Aim 2), the cellular, dendritic, and axonal composition of the glomerulus will be quantified after immunolabeling for synaptophysin, tyrosine hydroxylase, calretinin, calbindin D28k, NCAMs and GAP- 43. In Aim 3, we will perform a quantitative cytoarchitectural analysis of piriform and entorhinal cortices. The relative densities of immunohistochemically distinct populations of neurons will be determined and the spatial arrangement of neurons will be assessed using spatial point pattern analyses.