Neural Oscillatory Biomarkers for Genetics and Animal Models of Schizophrenia

描述(申请人提供)：精神分裂症遗传学和动物模型的神经振荡生物标记物项目摘要：神经振荡是可在不同频率测量的大脑的电活动。它们可以在许多水平上获得，从动物的单细胞到局部场电位，到人类头皮的大规模同步活动。精神分裂症患者在感觉和认知任务中表现出神经振荡活动受损，如感觉门控、工作记忆、执行功能，甚至在休息和处理单调的视觉和听觉刺激时也是如此。新的证据表明，在与精神分裂症相关的认知和功能障碍相关的振荡活动中可能存在常见的潜在异常。我们已经修改和开发了实验范式，这些范式将引起从基本感觉到更复杂的认知表现的振荡反应。我们计划分离精神分裂症中常见的跨任务振荡异常。此外，由于可以用类似的方式在动物和人类身上测量神经振荡，因此有可能使用类似的神经振荡测量作为疾病生物标记物来进行平行的动物和人类研究。为此，这些电生理范式的构建方式是，它们在临床群体表型和小动物应用中都具有潜在的可行性，以便本研究在精神分裂症患者中验证的神经振荡生物标记物以及这些神经振荡表型的后续遗传学发现可以应用于动物的翻译研究。利用整合行为科学中的构建翻译研究机制，我们建议在啮齿类动物中启动类似的范式。这一应用的基本神经科学部分是使用与人类实验密切匹配的实验范式建立类似的啮齿动物模型，然后对精神分裂症患者发现的异常神经振荡的病理生理起源进行初步的机制研究。这一努力应该为解释临床结果并最终将神经振荡用作研究精神分裂症从基因到病理生理学及其治疗的分子路径的翻译工具奠定必要的基础。神经振荡的神经发生正在紧张的研究中。然而，需要系统地研究它们在精神分裂症人群中作为疾病表型的作用。这样描述和验证的潜在的新型生物标记物应该会显著缩短从发现生物标记物到在动物模型中进行基因鉴定和新药开发的研究周期。 公共卫生相关性：精神分裂症是最严重的精神疾病之一，会导致患者严重残疾。这项研究将使用脑电波作为潜在的生物标志物，以确定精神分裂症和相关功能障碍的病理生理和分子原因，这将导致找到更具体和更好的治疗方法。

DESCRIPTION (provided by applicant): Neural Oscillatory Biomarkers for Genetics and Animal Models of Schizophrenia Project Summary: Neural oscillations are electrical activities of the brain measurable at different frequencies. They can be obtained at many levels, ranging from single cell to local field potentials in animals, to large-scale synchronized activities in human scalp. Patients with schizophrenia exhibit impaired neural oscillatory activities during sensory and cognitive tasks such as sensory gating, working memory, executive functions, and even at rest and during processing of monotonous visual and auditory stimuli. New evidence suggests that there may be common underlying abnormalities in oscillatory activities that are associated with schizophrenia-related cognitive and functional impairments. We have modified and developed experimental paradigms that will elicit oscillatory responses from basic sensory to more complex cognitive performance. We plan to isolate the common oscillatory abnormality in schizophrenia across tasks. In addition, since neural oscillations can be measured in animals and in humans in a similar fashion, it is possible to carry out parallel animal and human research using similar neural oscillatory measures as disease biomarkers. Towards this aim, these electrophysiological paradigms are constructed in a way that they are potentially feasible both in clinical population phenotyping and in small animal implementation, so that neural oscillatory biomarkers validated by this study in schizophrenia patients, and subsequent genetic findings from these neural oscillation phenotypes, can be applied to translational research in animals. Using the Building Translational Research in Integrative Behavioral Science mechanism, we propose to initiate similar paradigms in rodents. The basic neuroscience component of this application is to establish analogous rodent models using experimental paradigm closely matched with that of the human experiments, and then to conduct initial mechanistic studies on the pathophysiological origins of the abnormal neural oscillations found in patients with schizophrenia. This effort should lay the necessary groundwork for interpreting clinical findings and ultimately using neural oscillations as a translational tool in studying the molecular path from genes to pathophysiology and their treatment in schizophrenia. The neurogenesis of neural oscillations is under intense study. However, systematic investigations of their roles as disease phenotypes in schizophrenia populations are needed. The potentially novel biomarkers thus described and validated should significantly shorten the research cycle from biomarker discovery to gene identification and novel drug development in animal models. PUBLIC HEALTH RELEVANCE: Schizophrenia is one of the most severe mental illnesses and causes significant disability in people suffered from it. This study will use brain electrical waves as potential biomarkers for identifying the pathophysiological and molecular causes for schizophrenia and related dysfunctions, which should lead to finding more specific and better treatment.