Neuroimmune Mechanisms of Psychiatric Disorders

 描述（由申请人提供）：来自流行病学、遗传学和临床神经科学的越来越多的证据表明精神分裂症（SZ）和其他发育性精神疾病的病理生理学中存在神经免疫机制。一类新的母体免疫激活（MIA）的动物模型，表达发育表型特征相关的SZ，已被开发;然而，鲜为人知的机制，MIA的结果在大脑发育，连接和行为的变化。加州大学戴维斯分校康特中心寻求弥合这一差距。在过去三年的试点资金支持下，该团队共同努力，开发假设，设计实验并收集初步数据，以开发当前的应用程序。该中心由来自分子和细胞生物学，系统和行为神经科学，生物医学工程，神经影像学和临床神经科学的研究人员组成，以及跨物种和规模进行的一系列高度集成的研究，以测试MIA通过改变后代大脑中的免疫分子而导致SZ的假设，这反过来又改变了发育过程中的皮层连接，功能和行为。将在多个年龄的小鼠和非人灵长类动物（NHP）模型中测量突触变化、基因表达、结构和功能连接、神经炎症和行为，以确定MIA效应的时间和层次。如果可能，将在人体中进行平行研究，以确定MIA动物模型的临床相关性。该中心将追求两个具体目标，以确定：1）MIA是否通过在整个发育过程中免疫分子和基因网络的失调信号改变神经回路，从而增加后代神经发育精神障碍的风险; 2）MIA后代大脑结构和功能变化的出现和进展的时间与多巴胺失调、神经炎症的发生相关，和SZ相关的行为障碍的MIA NHP，并比较这些数据的首次发作SZ。这些项目将测量多个年龄段的平行小鼠和NHP MIA模型中突触连接、基因表达、结构和功能连接、神经炎症和行为的变化，以确定这些变化的相对时间和层次，并了解潜在的机制。在小鼠和NHP模型中的这些研究将通过对SZ死后人体组织中突触连接和基因表达的新分析来补充。

 DESCRIPTION (provided by applicant): Growing evidence from epidemiology, genetics and clinical neuroscience implicates neuroimmune mechanisms in the pathophysiology of schizophrenia (SZ) and other developmental psychiatric disorders. A new class of animal models of maternal immune activation (MIA), expressing developmentally phenotypic features related to SZ, has been developed; however, little is known about the mechanisms by which MIA results in changes to brain development, connectivity and behavior. The UC Davis Conte Center seeks to bridge that gap. Supported by pilot funding for the past three years, this team has worked together to develop hypotheses, design experiments and collect preliminary data to develop the present application. The Center comprises an accomplished group of investigators from molecular and cell biology, systems and behavioral neuroscience, biomedical engineering, neuroimaging, and clinical neuroscience and a highly integrated set of studies conducted across species and scale to test the hypothesis that MIA contributes to SZ by altering immune molecules in the brains of offspring, which, in turn, alters cortical connectivity, function and behavior during development. Synaptic changes, gene expression, structural and functional connectivity, neural inflammation and behavior will be measured in mouse and non-human primate (NHP) models at multiple ages to determine the timing and hierarchy of the effects of MIA. When possible, parallel studies in humans will be conducted to establish the clinical relevance of the MIA animal models. The Center will pursue two Specific Aims to determine: 1) if MIA increases risk for neurodevelopmental psychiatric disorders in offspring by altering neural circuitry through dysregulated signaling of immune molecules and gene networks throughout development; 2) the timing of the appearance and progression of structural and functional changes in the brains of MIA offspring relative to the onset of dopamine dysregulation, neural inflammation, and SZ-related behavioral disturbances in the MIA NHP and compare these data to those seen in first-episode SZ. The projects will measure changes in synaptic connectivity, gene expression, structural and functional connectivity, neural inflammation, and behavior in parallel mouse and NHP MIA models at multiple ages to determine the relative timing and hierarchy of these changes and understand the underlying mechanisms. These studies in the mouse and NHP model will be complemented by novel analyses of synaptic connectivity and gene expression in post mortem human tissue from SZ.