Neurobehavioral and molecular studies of gene-environment interactions in schizo

精神分裂症的发病机制可能涉及遗传易感性和 环境因素在非遗传因素中，微生物感染与 精神疾病发病率上升。我们相信，基于已确定的遗传基因的实验模型 突变和可测量的环境因素可以大大提高我们对 与精神分裂症相关的基因-环境相互作用（GEI）机制。项目5的主要目标是 为了表征基于项目1-4鉴定的基因的GEI新小鼠模型， 与DISC 1有关，并与精神分裂症有关。我们将评估神经行为的影响， 暴露于母体免疫激活或出生后早期慢性 弓形虫感染 我们预测，DISC 1和/或其伙伴中的基因操作将与相关基因协同作用。 环境因素产生的神经行为和分子改变与 精神分裂症和相关精神障碍。 特异性目的1将检验免疫激活和突变DISC 1的产前相互作用将 协同导致成年后代中精神分裂症样神经行为异常。具体目标2将 检验出生后早期弓形虫慢性感染与 突变DISC 1将协同产生类似于阳性的神经行为异常， 精神分裂症的认知症状此外，与项目6合作，我们将评估 免疫复合物在弓形虫感染的DISCI突变小鼠神经行为病理学中的作用。 具体目标3将识别基因-环境相互作用的基因表达特征。 该项目将描述GEI相关的神经行为和分子后果， 精神分裂症结果将有助于确定可能介导相互作用的特定分子途径 精神分裂症发病机制中基因突变和环境损伤之间的关系。

The pathogenesis of schizophrenia is likely to involve multiple interactions between genetic vulnerability and environmental factors. Among non-genetic factors, microbial infections have been associated with the increased incidence of mental diseases. We believe that experimental models based on identified genetic mutations and measurable environment factors can significantly advance our understanding of the mechanisms of gene-environment interactions (GEI) relevant to schizophrenia. The main goal of Project 5 is to characterize new mouse models of GEI based on the genes that are identified by Projects 1-4, interact with DISC1, and have been associated with schizophrenia. We will evaluate the neurobehavioral effects and molecular biomarkers of GEI in mice exposed to either maternal immune activation or early postnatal chronic infection with Toxoplasma gondii. We predict that genetic manipulations in DISC1 and/or its partners will synergistically interact with relevant environmental factors to produce the neurobehavioral and molecular alterations consistent with aspects of schizophrenia and related mental disorders. Specific Aim 1 will test the hypothesis that prenatal interaction of immune activation and mutant DISC1 will synergistically lead to schizophrenia-like neurobehavioral abnormalities in adult offspring. Specific Aim 2 will test the hypothesis that early postnatal interactions between chronic infection with Toxoplasma gondii and mutant DISC1 will synergistically produce the neurobehavioral abnormalities resembling positive and cognitive symptoms of schizophrenia. In addtion, in collaboration with Project 6, we will evaluate a role of immunocomplexes in the neurobehavioral pathology in Toxoplasma-infected DISCI mutant mice. Specific Aim 3 will identify the gene expression signatures of gene-environment interactions. The project will characterize the neurobehavioral and molecular consequences of GEI relevant to schizophrenia. The results will help identify the specific molecular pathways that may mediate interplay between the genetic mutations and environmental insults in the pathogenesis of schizophrenia.