TARGETED NEURONAL DELETIONS IN A MODEL OF SCHIZOPHRENIA

精神分裂症模型中的靶向神经元删除

基本信息

批准号：
6392612
负责人：
LYNN D SELEMON
金额：
$ 26.53万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-09-01 至 2004-05-31
项目状态：
已结题

项目摘要

The developmental hypothesis of schizophrenia suggests that prenatal perturbation of early brain development results in a latent defect expressed in post-adolescent life in the form of profound mental illness. In the Section of Neurobiology at Yale, a primate animal model of schizophrenia has been developed over the past decade which produces behavior deficits in working memory capacity, perhaps the most prominent cognitive deficit observed in schizophrenic patients, and mimics several prominent morphologic correlates of the disease. Irradiation of the fetal rhesus monkey brain during a critical period in early gestation results in deletion of developing thalamic neurons and, ultimately in the adult monkey, in behavioral deficits on tasks that are mediated by the prefrontal cortex, features that have been reported in schizophrenic patients. The goal of the study is (1) to determine the extent to which anatomical abnormalities generated in the non-human primate brain by fetal exposure to x-irradiation replicate anomalies previously described in postmortem studies of the human schizophrenic brain and (2) to utilize this animal model to explore morphological disruption of the cortex that is not feasible in the disease human brain. These goals will be achieved by a comprehensive anatomical investigation of the fetally x-irradiated primate model with particular focus on the dorsolateral prefrontal cortex, including application of the latest stereologic methodology to assess neuronal and glial density, cell size, as well as cortical and ventricular volume, morphometric analysis of neuronal dendritic structure, and quantitation of chemically identified cell populations. In addition, ultra-structural analyses, which is not feasible in postmortem human brains will be used to directly examine the neuropil compartment of the prefrontal cortex. These finding should provide insights into neurodevelopmental mechanisms leading to cognitive dysfunction and cortical pathology in schizophrenia.

精神分裂症的发展假设表明，早期大脑发育的产前扰动会导致后期后生活中以深刻的精神疾病的形式表达的潜在缺陷。在耶鲁大学的神经生物学部分中，过去十年中已经开发了一种精神分裂症的灵长类动物模型，该模型会导致工作记忆能力的行为缺陷，这也许是精神分裂症患者中观察到的最突出的认知缺陷，并模仿这种疾病的几种突出的形态相关性。早期妊娠的关键时期，胎儿恒河猴大脑的辐射导致丘脑神经元的缺失，最终在成年猴中，在前额叶皮层介导的任务中的行为缺陷，在精神分裂症患者中已报道的特征。该研究的目的是（1）确定非人类灵长类动物大脑产生的解剖异常，通过胎儿暴露于X-辐射复制的复制异常，以前在人类精神分裂症后的术后研究中所描述的异常和（2）利用（2）这种动物模型探索在人脑中不可行的皮质的形态破坏。这些目标将通过对胎儿X辐照的灵长类动物模型进行全面的解剖学研究来实现，尤其关注背外侧前额叶皮层，包括应用最新的立体学方法学评估神经元和神经胶质密度，细胞的大小，以及皮质和心脏的大小神经元树突结构的体积，形态分析以及化学鉴定的细胞群的定量。此外，在尸体人类大脑中不可行的超结构分析将用于直接检查前额叶皮质的神经纤维室。这些发现应提供有关导致精神分裂症认知功能障碍和皮质病理学的神经发育机制的见解。