Neuroimmune Mechanisms of Psychiatric Disorders

精神疾病的神经免疫机制

• 批准号: 9256536
• 负责人: Cameron S. Carter
• 金额: $ 200万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9256536
• 关键词: Age; Animal Model; Appearance; Autopsy; Behavior; Behavioral; Biological Markers; Biomedical Engineering; Brain; Cellular biology; Clinical; Cognition; Complement; Cytokine Receptors; Data; Development; Disease; Dopamine; Encephalitis; Environmental Epidemiology; Environmental Risk Factor; Epidemiology; Exhibits; Exposure to; Face; Functional disorder; Funding; Gene Expression; Genes; Genetic; Goals; Human; Immune; Immune signaling; Immune system; Individual; Infection; Inflammation; Inflammatory; Influenza; Investigation; Lead; Link; Major Histocompatibility Complex; Maternal Exposure; Measures; Mental disorders; Modeling; Molecular; Molecular Biology; Mus; Nervous system structure; Neurodevelopmental Disorder; Neuroimmune; Neuroimmunomodulation; Neurosciences; Newborn Infant; Pathway Analysis; Pathway interactions; Patients; Phenotype; Plasma; Play; Proteins; Psychopathology; Psychotic Disorders; Research Personnel; Risk; Role; Schizophrenia; Scientist; Signal Pathway; Structure; Synapses; System; Testing; Therapeutic Intervention; Thick; Time; Work; brain shape; clinically relevant; cytokine; design; experimental study; first episode psychosis; first episode schizophrenia; genetic association; genome wide association study; human tissue; imaging study; immune activation; immune function; in vivo; insight; interest; mouse model; multidisciplinary; neural circuit; neuroimaging; nonhuman primate; novel; offspring; postnatal; public health relevance; relating to nervous system

 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.

 描述（由适用提供）：流行病学，遗传学和临床神经科学植入的越来越多的证据植入了精神分裂症（SZ）和其他发育精神疾病的病理生理学中的神经免疫机制。已经开发了一种新的母体免疫激活动物模型（MIA），表达了与SZ相关的发育表型特征。但是，对于MIA导致大脑发展，连通性和行为的变化的机制知之甚少。加州大学戴维斯分校孔戴中心试图弥合这一差距。在过去三年中，该团队在飞行员资金的支持下，共同努力开发假设，设计实验并收集初步数据以开发本应用程序。 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.突触变化，基因表达，结构和功能连通性，神经炎症和行为将在多个年龄的小鼠和非人类灵长类动物（NHP）模型中测量，以确定MIA效应的时序和层次结构。如果可能，将对人类进行平行研究，以建立MIA动物模型的临床相关性。该中心将追求两个具体的目的，以确定：1）如果MIA通过在整个发育过程中通过失调的免疫分子和基因网络的信号来改变神经通路，来增加后代神经发育障碍的风险； 2）MIA后代的结构和功能变化的外观和进展相对于多巴胺失调，神经感染和MIA NHP中与SZ相关的行为障碍的发作，并将这些数据与第一期SZ中看到的数据进行比较。这些项目将衡量多个年龄的平行小鼠和NHP MIA模型中突触连通性，基因表达，结构和功能连通性，神经炎症以及行为的变化，以确定这些变化的相对时间和层次结构并理解潜在机制。小鼠和NHP模型中的这些研究将通过新的SZ Mortem人体组织中的合成连通性和基因表达的新分析来完成。