Astrocyte-neuron communication and vulnerability to mental illness

星形胶质细胞-神经元通讯和患精神疾病的脆弱性

基本信息

批准号：
10693115
负责人：
Michael Craig Carroll
金额：
$ 60.71万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693115
关键词：
Address Adolescence Adolescent Adolescent Development Adult Astrocytes Autopsy Basal Ganglia Behavior Behavioral Biological Biological Assay Biological Models Biology Brain Brain Mapping Brain region CD47 gene Callithrix Cell model Cells Cognition Cognitive Communication Complement Complement component C4 Complement component C4a Complex Decision Making Development Disease Distant Environment Environmental Risk Factor Etiology Functional disorder Gene Expression Generations Genes Genetic Genetic Risk Genetic Transcription Genomics Goals Human Immune Immunology Incidence Individual Intervention Investigation Link Mediating Mental Health Mental disorders Modeling Molecular Multimedia Mus Neuroanatomy Neurodevelopmental Disorder Neuroimmune Neuroimmunomodulation Neurons Neurosciences Outcome Parents Pathway interactions Phenotype Physiological Physiology Play Population Populations at Risk Research Research Personnel Resources Rewards Risk Risk Assessment Risk Factors Role Route Sampling Schizophrenia Shapes Signal Transduction Social Behavior Social Workers Source Specificity Synapses Testing Thalamic structure Therapeutic Tissue Model Training Work adolescent brain development behavioral phenotyping brain tissue cell type childhood adversity cognitive development course development critical period frontal lobe genetic risk factor human stem cells human tissue innovation interdisciplinary collaboration interest member mouse model neural neuropsychiatry non-genetic nonhuman primate novel novel diagnostics novel strategies novel therapeutic intervention outreach overexpression pharmacologic postnatal psychiatric symptom psychogenetics response risk variant schizophrenia risk social symposium synaptic function synaptic pruning synaptogenesis teacher therapeutic evaluation tool training opportunity transcriptome vulnerable adolescent web site young adult

项目摘要

The pathophysiology of schizophrenia has been unknown, resulting in a lack of innovative therapeutics with novel mechanisms of action. The Conte Center for Neuroimmune Studies was created to build on our discovery that the biology underlying the most significant schizophrenia common genetic risk variants involves neuroimmune mechanisms of synaptic pruning. We have found that risk variants of the complement component C4 genes are correlated with increased C4A expression in the brain and CSF, and that overexpression of human C4A in a mouse model results in excess synaptic pruning and social behavioral deficits. We have further shown that additional neuroimmune molecules encoded at schizophrenia risk loci, CD47 and CSMD1, influence synaptic pruning and complement activity. Lastly, schizophrenia is unusual among neurodevelopmental disorders in its late-adolescent/early-adult onset, and childhood adversity is a major non-genetic risk factor for schizophrenia; yet the biological underpinnings of adolescent psychiatric vulnerability are wholly unknown. We have identified a critical period of circuit refinement in the mouse frontal cortex that we propose can be exploited to better understand the unique vulnerability of adolescent brain development to psychiatric risk factors. The goals of the Center in our next five years are to both deepen the focus on C4-mediated synaptic pruning as a pathophysiological mechanism, and expand the scope of our investigations to create a fuller picture of neuroimmune pathways, their upstream regulators, their cellular effectors, and their downstream circuit-level and behavioral impacts. Project 1 will investigate the role of astrocytes, the main source of C4 in the brain, by manipulating schizophrenia risk genes in these cells and assaying the impacts on synapse formation and function. Project 2 will spatially map the brain’s transcriptional response to C4 overexpression, and test the therapeutic hypothesis that inhibition of C4 activity may rescue over-pruning and associated behavioral phenotypes. Project 3 will examine the circuit specificity of the adolescent critical period, the impacts of gene-by-environment risk factor interactions, and the roles of the brain borders. Project 4 will explore circuit-level interactions between the basal ganglia and frontal cortex in the context of adolescent development, psychiatric risk factors, and risk/reward decision-making. We will also lay the groundwork for expanding neuroimmune studies of psychiatric risk to a non-human primate model, the marmoset. Finally, our Administrative Core will facilitate interdisciplinary collaboration that exploits the full range of expertise across the four labs, and coordinate outward- facing activities including the annual research symposium.

精神分裂症的病理生理学尚不清楚，导致缺乏创新性具有新型作用机理的治疗学。孔戴神经免疫研究中心是创造的目的是基于我们发现的，即生物学是最重要的精神分裂症的基础常见的遗传风险变异涉及突触修剪的神经免疫机制。我们有发现完成组件C4基因的风险变异与增加有关 C4a在大脑和CSF中的表达，以及小鼠模型中人类C4a的过表达导致过度的突触修剪和社会行为缺陷。我们进一步表明精神分裂症基因座，CD47和CSMD1编码的其他神经免疫分子，影响突触修剪和补体活动。最后，精神分裂症在神经发育障碍在其后期/早期发作中，儿童时期的广告是精神分裂症的主要非遗传危险因素；然而，青少年的生物基础精神病脆弱性是完全未知的。我们已经确定了关键的电路时期可以探索我们建议的鼠标额叶皮层的细化，以更好地了解青少年大脑发展对精神病风险因素的独特脆弱性。在接下来的五年中，该中心的目标是加深对C4介导的关注突触修剪作为病理生理机制，并扩大我们研究的范围为了创建更全面的神经免疫道途径，它们的上游调节剂，其细胞效应子及其下游电路级别和行为影响。项目1将调查通过操纵精神分裂症的风险基因，星形胶质细胞的作用是大脑中C4的主要来源在这些细胞中，并主张对突触形成和功能的影响。项目2将在空间上将大脑对C4过表达的转录响应映射，并测试治疗抑制C4活性可能会挽救过度灌肠和相关行为的假设表型。项目3将检查青少年关键时期的电路特异性，基因逐个环境的危险因素相互作用以及大脑边界的作用的影响。项目 4将在上下文中探索基底神经节和额叶皮质之间的电路级相互作用青少年发展，精神病风险因素和风险/回报决策。我们也会为非人类的神经免疫性研究扩大神经免疫性研究的基础私人型号，马尔莫斯特。最后，我们的行政核心将促进跨学科利用四个实验室的全部专业知识的合作，并向外协调面对包括年度研究研讨会在内的活动。