Development of automated neurobehavioral assay for rodent stroke model assessment

描述(申请人提供)：开发用于评估啮齿动物中风模型的自动神经行为测试数百万老年人患有中风，这是美国仅次于心脏病和癌症的第三大死亡原因。中风幸存者患有运动和认知障碍、焦虑、社会关系变化和抑郁，导致全球最致残的健康状况之一。临床批准的用于预防或治疗中风的唯一药物类别是抗血栓药和溶栓剂。有效的神经保护剂是减少中风所致残疾的迫切需要的策略。啮齿动物大脑中动脉闭塞(MCAO)可导致多种行为表型，包括归巢活动、运动、运动协调和认知功能障碍。由于该模型模拟人类中风症状，已成为识别新靶点和治疗药物最常用的中风模型。然而，有效的神经保护剂的发现一直受到阻碍，部分原因是缺乏对行为结果的全面和定量的长期评估。到目前为止，啮齿动物中风模型的特征和治疗评估的重点是由人类评估者使用神经学评分系统或使用个人特殊评估(例如旋转杆测试)来调查运动障碍。人工评分既耗时又主观。大多数传统的行为分析需要将动物从它们的家中移到专门的操作设备中。在新的环境下进行动物运输和检测不仅费时费力，而且会给动物带来压力，从而影响检测结果和药物效果。为了改善这种情况，我们利用了我们最近开发的啮齿动物行为监测平台SmartCageTM，并与斯坦福大学的Co-PI R.Giffard博士合作，取得了可喜的初步结果。针对计划宣布(PA-08-071)，标题：实验室到市场：脑与行为研究工具(SBIR[R43/R44]，第一阶段长达两年)，我们现在提出一个SBIR第一阶段项目，以开发将被整合到SmartCageTM中的模块化设备，并系统地验证一组自动化、更客观的分析方法，用于定量和长期评估小鼠MCAO卒中后的神经结局。有两个具体的目标：目标1.设计和设计特殊的模块化设备，转杆，‘脚断层’栅格和‘笼形’外壳，可以灵活地结合到我们最近开发的SmartCage平台中。除了现有SmartCage中已经确定的参数，例如运动(通过红外阵列)、焦虑样行为(使用黑匣子)和认知(使用触摸屏)之外，这一创新系统还将实现对感觉运动协调和社交互动的自动评估。目的2.应用增强型SmartCage对小鼠MCAO后的归巢、神经行为和认知功能进行研究，建立全面的表型分析和药物疗效评价方案。我们相信，通过商业推广，我们的SmartCage系统具有各种灵活的模块和经过验证的分析协议，将因其与传统方法和仪器相比的简单性、自动化和定量评估而在神经科学界，特别是在中风研究领域得到广泛应用。此外，拟议的第一阶段项目自然将导致第二阶段的应用，重点是发现用于中风治疗的新型神经保护剂，使用这些自动化的神经行为表型分析，与专门制造新的化学实体以对抗缺血诱导的神经元死亡的学院和公司合作。 公共卫生相关性：中风困扰着全世界数百万人，是导致老年人长期严重残疾的主要原因。目前的药物治疗仅依赖于抗血栓药和溶栓剂。为了发现可以减少中风引起的神经元死亡和由此导致的残疾的新药，我们需要有效的功能结果评估工具包。在这里，我们建议开发自动化的、全面的神经行为分析工具包，以促进中风研究和药物开发。

DESCRIPTION (provided by applicant): Development of automated neurobehavioral assay for rodent stroke model assessment Millions of elderly people suffer from stroke, which is the third leading cause of death in the US, after heart disease and cancer. Stroke survivors suffer from motor and cognitive impairment, anxiety, social relation changes and depression, leading to one of the most disabling health conditions worldwide. The only clinically approved classes of drugs used to prevent or treat stroke are antithrombotics and thrombolytics. Effective neuroprotective agents represent a critically needed strategy to reduce stroke-induced disabilities. Middle cerebral artery occlusion (MCAO) in rodents creates a wide spectrum of behavioral phenotypes including impairments in homecage activity, locomotion, motor coordination, and cognitive deficits. Because this model mimics human stroke symptoms, it has become the most commonly used stroke model for the identification of new target and therapeutic agents. However, discovery of effective neuroprotective agents has been hampered, in part, due to lack of comprehensive and quantitative long-term evaluation of behavioral outcomes. To date, characterization of rodent stroke models and evaluation of treatments have focused on the investigation of motor deficits either by human evaluators employing a neurological scoring system or by using individual special assessments (e.g. rotarod test). Human scoring is time consuming and subjective. Most conventional behavioral assays require removing animals from their homecages to a specialized operant apparatus. Animal transportation and testing in a new environment are not only laborious and time-consuming, but also causes stress to the animals, which can confound the test outcomes and drug effects. To improve this situation, we took advantage of our recently developed rodent behavioral monitoring platform, termed SmartCageTM and obtained promising initial results in collaboration with the Co-PI, Dr. R. Giffard, Stanford University. In response to the Program Announcement (PA-08-071), Title: Lab to Marketplace: Tools for Brain and Behavioral Research (SBIR [R43/R44], up to two years in Phase I), we now propose an SBIR Phase I project to develop modular devices to be incorporated into the SmartCageTM and systematically validate a panel of automated, more objective assays for quantitative and long-term evaluation of neurological outcome following MCAO stroke in mice at their homecages. There are two specific aims: Aim 1. Design and engineer special modular devices, rotarod, 'foot fault' grid and 'cagemate' enclosure, which can be flexibly incorporated into our recently developed SmartCage platform. This innovative system will enable automated assessments of sensorimotor coordination and social interaction, in addition to those already established parameters e.g., locomotion (by IR array), anxiety-like behavior (using dark box) and cognition (with touchscreen) in the existing SmartCage. Aim 2. Investigate mouse homecage neurobehavior and cognitive function following MCAO using the enhanced SmartCage and establish comprehensive protocols for phenotypic analysis and drug effect evaluation. We believe that through commercial dissemination, our SmartCage system with a variety of flexible modules and validated assay protocols will be widely used in the neuroscience community, particularly in the stroke research arena, because of its simplicity, automation and quantitative assessment, compared to the conventional methods and instruments. Furthermore, the proposed Phase I project will naturally lead to a Phase II application focused on the discovery of novel neuroprotectants for stroke treatment using these automated, neurobehavioral phenotype assays in collaboration with academies and companies that specialized in making new chemical entities against ischemia-induced neuronal death. PUBLIC HEALTH RELEVANCE: Stroke afflicts millions of people worldwide and is the leading cause of serious long-term disabilities in the elderly. Current drug treatment solely depends on antithrombotics and thrombolytics. To discover new drugs that can reduce stroke-induced neuronal death and its resultant disabilities, we need effective functional outcome assessment toolkit. Here we proposed to develop automated, comprehensive neurobehavioral assays with toolkit to facilitate stroke research and drug discovery.