Neurobiological basis of dysconnectivity in a genetic risk model of psychosis

精神病遗传风险模型中连接失调的神经生物学基础

• 批准号: 9791354
• 负责人: CARRIE E BEARDEN
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-25 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9791354
• 关键词: 22q11.2; Adolescence; Adolescent; Adult; Affect; Age; Animals; Autopsy; Axon; Behavior; Behavioral; Biological; Biological Assay; Biological Markers; Brain; Brain Diseases; Chromosomes; Chromosomes, Human, Pair 16; Chromosomes, Human, Pair 22; Clinical; Copy Number Polymorphism; DNA Structure; Defect; Delayed Memory; Development; Diagnostic; Diffusion Magnetic Resonance Imaging; Dimensions; Disease; Environmental Risk Factor; Evaluation; Family; Fiber; Functional disorder; Future; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Goals; Hippocampus (Brain); Human; Human Chromosomes; Image Analysis; Interneurons; Investigation; Learning; Maps; Measures; Mediating; Memory impairment; Methodology; Mind; Minority; Modeling; Mus; Mutation; Myelin; Neurobiology; Neurons; Outcome; Participant; Pathologic; Patients; Phenotype; Population Study; Psychotic Disorders; Rabies virus; Resolution; Rewards; Risk Factors; Role; ST5 gene; Schizophrenia; Sensory; Short-Term Memory; Social Behavior; Social Interaction; Structure; Task Performances; Testing; Time; Translational Research; Treatment Efficacy; Variant; Wild Type Mouse; Work; autism spectrum disorder; base; behavioral study; cohort; conotruncal anomaly face syndrome; density; endophenotype; experimental study; genetic risk factor; hemodynamics; human study; imaging study; insight; microdeletion; migration; mouse model; neural patterning; neurobiological mechanism; neuroimaging; neuropsychiatric disorder; novel; population based; pre-clinical; preference; ranpirnase; relating to nervous system; repetitive behavior; social; social deficits; theories; translational study; white matter

ABSTRACT Developmental neuropsychiatric disorders are increasingly viewed as `developmental dysconnectivity' disorders characterized by pathological patterns of neural connectivity. However, to date investigational approaches to unravel the elusive pathophysiological basis of these phenomena are limited. Modeling specific copy number variants (CNVs) that are strongly associated with distinct neurodevelopmental outcomes offers an extraordinary opportunity to investigate the same genetic defect across species. The 22q11.2 microdeletion (22q11DS) is a well-established potent risk factor for psychosis, conferring at least 25 times the general population base rate. This CNV offers a particularly valuable investigational model, given that large patient cohorts have been identified and extensively characterized at both behavioral and neuroanatomic levels. Importantly, the close homology between human Chromosome 22 and portions of mouse chromosome 16 allows for precise modeling of the causal CNV. Mouse models allow direct assessment of brain mechanisms associated with CNVs while reducing variability due to genetic and environmental factors. The identification of analogous functional connectivity hubs in preclinical species like the mouse may provide critical insight into the elusive biological underpinnings of these connectional alterations. Yet, to date, truly translational studies in which the same genetic defect is modeled in animals and human patients are almost non-existent. Here, we propose to elucidate the cellular underpinnings of structural and functional large-scale connectivity alterations, in the context of this specific well-characterized genetic etiology, using novel methodologies in parallel mouse and human studies. In particular, we aim to: 1) Map macroscale networks, and their developmental trajectories, in human 22q11.2 deletion carriers and the 22q11DS mouse model, in comparison to typically developing controls and wild-type mice, order to investigate the cellular correlates of disrupted long-range connectivity; 2) Investigate developmental rescue of macroscale connectivity defects, at both the neural and behavioral levels; and 3) Investigate social behavioral correlates of connectivity alterations, using parallel tasks of social preference and social reward across species. Collectively, this work will provide a key proof of principle for future translational studies of neurodevelopmental genes and their contribution to large-scale connectivity alterations, and will inform whether neural connectivity may be a viable biomarker (complementary to behavior) for evaluation of novel treatments.

摘要 发育性神经精神障碍越来越多地被视为“发育障碍” 以神经连接的病理模式为特征的疾病。然而，迄今为止， 但揭示这些现象的病理生理学基础的方法是有限的。 对与不同的DNA序列密切相关的特定拷贝数变异（CNVs）进行建模， 神经发育的结果提供了一个非凡的机会，调查同样的遗传缺陷， 跨越物种。22q11.2微缺失（22 q11 DS）是精神病的一个公认的潜在危险因素， 给予一般人口基数的至少25倍。这种CNV提供了一种特别有价值的 研究模型，鉴于已确定并广泛表征了大型患者队列， 包括行为和神经解剖学层面。重要的是，人类22号染色体与 而小鼠16号染色体的一部分允许精确模拟致病CNV。小鼠模型允许 直接评估与CNV相关的脑机制，同时减少遗传和 环境因素在临床前物种中识别类似的功能连接中心，如 老鼠可能提供关键的洞察这些连接的难以捉摸的生物学基础， 改变。然而，到目前为止，真正的转化研究，其中同样的遗传缺陷是在动物和动物模型， 人类患者几乎不存在。在这里，我们建议阐明结构的细胞基础， 和功能性大规模连接性改变，在这种特定的良好表征的遗传背景下， 病因学，在平行小鼠和人类研究中使用新方法。具体而言，我们的目标是：1）地图 宏尺度网络及其发展轨迹，在人类22q11.2缺失携带者和 22 q11 DS小鼠模型，与典型发育对照和野生型小鼠相比，以研究 破坏的长距离连接的细胞相关性; 2）研究宏观尺度的发育拯救 连接缺陷，在神经和行为水平;和3）调查社会行为相关的 连接性改变，使用跨物种的社会偏好和社会奖励的并行任务。总的来说， 这项工作将为未来神经发育基因的翻译研究提供关键的原理证明， 它们对大规模连接改变的贡献，并将告知神经连接是否可能是一种 可行的生物标志物（与行为互补），用于评价新的治疗方法。