Neural Oscillatory Biomarkers for Genetics and Animal Models of Schizophrenia

精神分裂症遗传学和动物模型的神经振荡生物标志物

• 批准号: 8102707
• 负责人: L Elliot Elliot Hong
• 金额: $ 54.76万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102707
• 关键词: Acute; Address; Agonist; Anatomy; Animal Model; Animals; Antipsychotic Agents; Auditory; Auditory Evoked Potentials; Behavioral Sciences; Biological Markers; Brain; Candidate Disease Gene; Cells; Chronic; Clinical; Clinical Research; Cognitive; Complex; Computer Simulation; Data; Data Analyses; Dimensions; Disease; Dose; Drug Formulations; Electroencephalography; Event; Evoked Potentials; Excitatory Postsynaptic Potentials; Exhibits; Family member; First Degree Relative; Frequencies; Functional disorder; GABA Agents; GABA Agonists; Genes; Genetic; Genotype; Glossary; Glutamate Decarboxylase; Glutamatergic Agents; Glutamates; High Frequency Oscillation; Hippocampus (Brain); Human; Impaired cognition; Investigation; Ketamine; Laboratory Animals; Lead; Location; Measurable; Measures; Methodology; Methods; Microdialysis; Modeling; Molecular; Molecular Target; Mutation; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Neurosciences; Nucleus Accumbens; Pathology; Patients; Pattern; Performance; Personality; Pharmaceutical Preparations; Phenotype; Population; Prefrontal Cortex; Process; Psychotic Disorders; Quantitative Trait Loci; Rattus; Relative (related person); Research; Research Project Grants; Rest; Retrieval; Risk; Rodent; Rodent Model; Role; Sampling; Scalp structure; Schizophrenia; Sensory; Sensory Process; Series; Severities; Short-Term Memory; Signal Transduction; Staging; System; Testing; Time; Translational Research; Translations; auditory stimulus; awake; base; brain electrical activity; clinical phenotype; cognitive function; density; design; disability; disease phenotype; drug development; endophenotype; executive function; follow-up; functional disability; gamma-Aminobutyric Acid; neurogenesis; novel; postsynaptic; pre-clinical; public health relevance; receptor; relating to nervous system; research study; response; sensory gating; severe mental illness; simulation; sound; tool; visual stimulus

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.

描述（由申请人提供）：精神分裂症遗传学和动物模型的神经振荡生物标志物项目摘要：神经振荡是在不同频率下可测量的大脑电活动。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，再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受损的神经振荡活动，例如感觉门控、工作记忆、执行功能，甚至在休息时和处理单调的视觉和听觉刺激时。新的证据表明，可能有共同的潜在异常振荡活动与精神分裂症相关的认知和功能障碍。我们已经修改和开发的实验范式，将引起振荡反应，从基本的感官到更复杂的认知性能。我们计划在不同的任务中分离出精神分裂症中常见的振荡异常。此外，由于神经振荡可以以类似的方式在动物和人类中测量，因此可以使用类似的神经振荡测量作为疾病生物标志物来进行平行的动物和人类研究。为了实现这一目标，这些电生理学范式的构建方式使得它们在临床群体表型和小动物实施中都是潜在可行的，因此本研究在精神分裂症患者中验证的神经振荡生物标志物，以及这些神经振荡表型的后续遗传发现，可以应用于动物转化研究。使用综合行为科学机制中的构建转化研究，我们建议在啮齿动物中启动类似的范式。本申请的基本神经科学组成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中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。这一努力应该奠定必要的基础，解释临床发现，并最终使用神经振荡作为一种翻译工具，在研究的分子路径从基因到病理生理学及其治疗精神分裂症。神经振荡的神经发生正处于紧张的研究中。然而，需要系统的调查，他们的作用，精神分裂症人群的疾病表型。由此描述和验证的潜在的新生物标志物将显著缩短从生物标志物发现到基因鉴定和动物模型中的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，会导致严重的残疾。这项研究将使用脑电波作为潜在的生物标志物，以确定精神分裂症及其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。