Electrophysiological Endophenotypes of Schizophrenia in Mouse and Man

小鼠和人精神分裂症的电生理内表型

基本信息

批准号：
8517190
负责人：
Margaret Levin
金额：
$ 57.54万
依托单位：
GALENEA CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-26 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8517190
关键词：
Address Affect Animal Model Animals Area Attention Auditory Behavioral Biological Markers Biological Neural Networks Calcineurin Central Nervous System Diseases Chemicals Clinic Clinical Trials Cognition Cognition Disorders Cognitive Cognitive Therapy Cognitive deficits Data Detection Development Diagnostic Disease Disease model Electroencephalography Family Caregiver Family member Functional disorder Genetic Goals Human Impaired cognition Knock-out Maintenance Measures Mediating Medical Mus Outcome Patients Pharmaceutical Preparations Pharmacotherapy Phencyclidine Phylogenetic Analysis Population Prefrontal Cortex Quality of life Reporting Research Resolution Risk Rodent Schizophrenia Short-Term Memory Symptoms System Technology Testing Therapeutic Translating United States Vision animal model development disease mechanisms study drug candidate drug discovery drug efficacy effective therapy endophenotype frontal lobe healthy volunteer human disease improved in vivo indexing innovation man meetings mouse model neural circuit neurophysiology patient population pre-clinical programs public health relevance relating to nervous system research study response success tool

项目摘要

DESCRIPTION (provided by applicant): Development of new drug therapies for CNS disorders has significantly lagged behind other indication areas, with some estimates suggesting only a 1% success rate for new chemical entities in the United States. Factors contributing to this problem include: lack of disease-relevant functional screens, lack of clinically predictive animal models and absence of reliable and specific biomarkers of disease state. These challenges have particularly impacted the discovery of cognitive therapies for schizophrenia. The cognitive impairments in schizophrenia comprise a core and debilitating component of the illness for which there are currently no effective therapies. Development of animal models that can reliably mirror human cognition is challenging, since the cognitive capacities and behavioral repertoires of animals and humans are fundamentally distinct. One approach to bridging this gap is to define specific aspects of neural activity that are altered in the human disease state and in cognate animal models, and to include such measures in testing candidate drug efficacy. The power of this approach is that it takes advantage of phylogenetic conservation at the level of neural networks to translate directly between species. For example, in accord with previous reports noting a severe dysfunction in the ability of cortical networks to mount coherent gamma oscillations in schizophrenia patients, we have observed alterations in gamma oscillations in the calcineurin knockout (CNKO) and phencyclidine- mediated mouse models of schizophrenia. We observed significant modulation of gamma oscillations in the prefrontal cortex of mice during mnemonic tasks associated with novelty recognition/detection that is impaired in these mouse disease models. In an initial study aimed at identifying human equivalencies of this novelty- related neural activity, we have observed similar changes in gamma oscillations within frontal cortex during a novelty oddball task in a small population of healthy volunteers. These data provide support for the potential utility of neurophysiological endophenotypes within defined neural circuits as objective measures of cognitive disease states that can be translated from animal models to human patients. We propose to identify and validate cortical neurophysiological endophenotypes in both humans and mice that are associated with analogous cognitive behavioral tasks and similarly affected by disease state. A coordinated and reciprocal approach will be applied since human studies have the advantage of direct disease relevance, while rodent systems can provide higher resolution electrophysiological measures and can be manipulated via genetic and pharmacological means to test specific disease hypotheses. We propose that identified electrophysiological endophenotypes of the disease condition that are conserved between rodents and man will provide objective biomarkers for schizophrenia disease state and for assessing drug candidate efficacy during clinical trials, as well as diagnostic tools for personalization of optimal treatment regimes for patients. The research outlined in this proposal thus stands to benefit the large population of patients with schizophrenia and related illnesses.

描述（由申请人提供）：中枢神经系统疾病新药疗法的开发明显落后于其他适应症领域，一些估计表明美国新化学实体的成功率仅为 1%。造成这一问题的因素包括：缺乏与疾病相关的功能筛选、缺乏临床预测动物模型以及缺乏疾病状态的可靠和特异性生物标志物。这些挑战尤其影响了精神分裂症认知疗法的发现。精神分裂症的认知障碍是该疾病的一个核心且令人衰弱的部分，目前尚无有效的治疗方法。开发能够可靠地反映人类认知的动物模型具有挑战性，因为动物和人类的认知能力和行为能力本质上是不同的。弥补这一差距的一种方法是定义在人类疾病状态和同源动物模型中改变的神经活动的特定方面，并将此类措施纳入测试候选药物功效中。这种方法的强大之处在于，它利用神经网络层面的系统发育保守性在物种之间直接进行翻译。例如，根据之前的报道，精神分裂症患者的皮质网络产生相干伽玛振荡的能力存在严重功能障碍，我们在钙调神经磷酸酶敲除（CNKO）和苯环己哌啶介导的精神分裂症小鼠模型中观察到伽玛振荡的改变。我们观察到，在与这些小鼠疾病模型中受损的新奇事物识别/检测相关的助记任务中，小鼠前额皮质中的伽玛振荡发生了显着调节。在一项旨在识别这种与新奇相关的神经活动的人类等效性的初步研究中，我们在一小群健康志愿者中观察到在新奇的奇怪任务期间额叶皮层内伽马振荡的类似变化。这些数据为定义的神经回路内的神经生理学内表型作为认知疾病状态的客观测量的潜在效用提供了支持，这些认知疾病状态可以从动物模型转化为人类患者。我们建议识别和验证人类和小鼠的皮质神经生理学内表型，这些表型与类似的认知行为任务相关并且类似地受到疾病状态的影响。由于人类研究具有直接疾病相关性的优势，而啮齿动物系统可以提供更高分辨率的电生理学测量，并且可以通过遗传和药理学手段进行操作以测试特定的疾病假设，因此将采用协调和互惠的方法。我们建议，确定的在啮齿动物和人类之间保守的疾病状况的电生理内表型将为精神分裂症疾病状态和临床试验期间评估候选药物疗效提供客观的生物标志物，以及为患者提供个性化最佳治疗方案的诊断工具。因此，该提案中概述的研究将使大量精神分裂症及相关疾病患者受益。