Neurophysiological biomarkers of cognition in Dup15 syndrome: From mouse models to patients (Project)

项目：摘要 该提案是真正的翻译，因为它从临床观察和移动 对小鼠和小鼠中认知障碍的生物标志物进行严格的定量 模特和病人这样的研究将作为其他研究的模式。 神经发育障碍综合治疗中心然后，这些生物标志物可以 未来的研究，将与基因表达直接相关。首先，我们将确定一个基于机制的 认知功能障碍的电生理生物标志物和对 治疗与ID高度相关的基因明确定义的综合征。 认知的测量在量化细微的个体差异或 捕获临床异质性，可能为预后和干预提供信息。我们集团 在EEG生物标志物与行为的整合方面具有相当的专业知识， 患有神经发育障碍的儿童。其次，我们将在小鼠中进行平行研究， 模型，以验证和更好地了解生物标志物的遗传基础， 并开始测试可能改变细胞激活模式和 这些小鼠模型的行为。具体来说，我们将测试异常振荡如何破坏 在清醒的行为动物中的信息流，使我们能够直接将电生理学 认知的变化。 创新的方法来研究小鼠模型和 患者Jeste实验室的人类脑电图实验将使用新的分析方法 测量信号复杂度和量化静息状态频谱功率的技术 挑战人群。老鼠实验将使用定制的高密度 来自数百个神经元的电生理记录， 多个皮层区域新的基于注意力的多模态集合转移任务设计 Golshani实验室记录灵活决策过程中大型神经元群体的活动 以及注意力转移，这是一个在这种疾病中受到影响的认知领域。最后我们将 使用新一代的微型显微镜来记录大型 在学习过程中，海马神经元的数量在几天内增加，这使我们第一次能够 在学习和灭绝过程中，在同一组神经元中遵循种群动态。 重要的是，这些研究植根于在系统层面上获得对ID的新理解 希望在机制和基于证据的个体治疗方法中找到一致性， 与这一异质性的疾病群体。

Project: Abstract The proposal is truly translational, as it draws from clinical observation and moves towards rigorous quantification of biomarkers of cognitive impairment in both mouse models and patients. Such a study will serve as a model for studies of other neurodevelopmental disorders in our comprehensive Center. These biomarkers can then, in future studies, be directly related to gene expression. First, we will identify a mechanism-based electrophysiological biomarker of cognitive dysfunction and potential responsiveness to treatment in a genetically well-defined syndrome highly associated with ID. Standardized measures of cognition are limited in their ability to quantify subtle individual differences or to capture clinical heterogeneity that may inform prognosis and intervention. Our group has considerable expertise in the integration of EEG biomarkers with behavior to better characterize children with neurodevelopmental disorders. Second, we will perform parallel studies in mouse models, in order to validate and better understand the genetic basis of biomarker identified in humans and to begin to test treatments that may alter both the cell activation patterns and behavior in these mouse models. Specifically we will test how abnormal oscillations disrupt information flow in awake behaving animals, allowing us to directly link electrophysiological changes to cognition. Innovative methods to study electrophysiological markers in both mouse models and patients. The human EEG experiments in the Jeste Lab will make use of new analysis techniques to measure signal complexity and to quantify resting state spectral power from challenging populations. The mouse experiments will make use of custom-made high density electrophysiological recordings from hundreds of neurons with silicon probes targeted to multiple cortical regions. New attention-based multimodal set shifting task designed in the Golshani lab to record the activity of large neuronal populations during flexible decision making and attentional set shifting, a cognitive domain that is affected in the disorder. Finally, we will use a new generation of miniaturized microscopes to record the activity patterns of large populations of hippocampal neurons over days during learning, allowing us for the first time to follow population dynamics in the same group of neurons during learning and extinction. Importantly, these studies are rooted in gaining a new understanding of ID at a systems level with a desire to find convergence in mechanisms and evidence-based treatments for individuals with this heterogeneous group of disorder.