Neurobiological basis of dysconnectivity in a genetic risk model of psychosis

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，到目前为止，调查仍在进行 解开这些现象难以捉摸的病理生理学基础的方法有限。 对与DISTINCT紧密关联的特定拷贝数变体(CNV)进行建模 神经发育结果为研究同样的基因缺陷提供了一个非同寻常的机会 跨物种。22q11.2微缺失(22q11DS)是精神病的一个公认的潜在风险因素， 至少是一般人口基本税率的25倍。这款CNV提供了一款特别有价值的 研究模型，因为已经确定了大量的患者队列并广泛地描述了 无论是行为层面还是神经解剖层面。重要的是，人类22号染色体之间的紧密同源性 而小鼠16号染色体的一部分允许对原因CNV进行精确建模。鼠标模型允许 直接评估与CNV相关的大脑机制，同时减少由于遗传和 环境因素。在临床前物种中识别类似的功能连接枢纽 老鼠可能提供了对这些连接的难以捉摸的生物学基础的关键洞察 改装。然而，到目前为止，真正的翻译研究中，同样的基因缺陷在动物和 人类患者几乎是不存在的。在这里，我们建议阐明结构的细胞基础 和功能大规模的连接性改变，在这种特定的背景下很好地表征了遗传 病因学，在平行的小鼠和人类研究中使用新的方法。具体来说，我们的目标是：1)绘制地图 人22q11.2缺失携带者和人类22q11.2缺失携带者的宏观网络及其发育轨迹 22q11DS小鼠模型，以正常发育对照组和野生型小鼠为对照，进行比较研究 远距离连接中断的细胞相关性；2)研究大尺度的发育救援 神经和行为层面的连通性缺陷；以及3)调查 连通性改变，使用不同物种的社会偏好和社会回报的平行任务。总而言之， 这项工作将为未来神经发育基因和基因的翻译研究提供关键的原则证据 它们对大规模连通性改变的贡献，并将告知神经连通性是否可能是 评估新治疗方法的可行生物标记物(对行为的补充)。

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.