Development of automated neurobehavioral assay for rodent stroke model assessment

描述（由申请人提供）：用于啮齿动物中风模型评估的自动神经行为测定的开发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。中风幸存者遭受运动和认知障碍、焦虑、社会关系变化和抑郁，导致世界上最致残的健康状况之一。临床上唯一批准的用于预防或治疗中风的药物类别是抗血栓药和溶血栓药。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。啮齿类动物大脑中动脉闭塞（MCAO）可导致广泛的行为表型，包括居家活动、运动、运动协调和认知缺陷。由于该模型模拟了人类中风症状，因此它已成为识别新靶点和治疗剂的最常用的中风模型。然而，有效的神经保护剂的发现受到阻碍，部分原因是缺乏对行为结果的全面和定量的长期评估。迄今为止，啮齿类动物卒中模型的表征和治疗评价集中于通过采用神经学评分系统的人类评价者或通过使用个体特殊评估（例如旋转杆测试）来研究运动缺陷。人工评分既耗时又主观。大多数传统的行为测定需要将动物从它们的家庭笼中移到专门的操作装置中。动物运输和在新环境中的测试不仅费力和耗时，而且会给动物造成压力，这可能会混淆测试结果和药物效果。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，称为SmartCageTM，并与Co-PI，R博士合作获得了有希望的初步结果。吉法，斯坦福大学。针对方案公告（PA-08-071），标题：实验室到市场：大脑和行为研究工具（SBIR [R43/R44]，第一阶段最多两年），我们现在提出SBIR第一阶段项目，以开发将纳入SmartCageTM的模块化设备，并系统地验证一组自动，更客观的测定，用于定量和长期评估MCAO卒中后小鼠在其家中的神经学结局。有两个具体目标：目标1。设计和制造特殊的模块化设备、旋转杆、“脚故障”网格和“笼式”外壳，这些设备可以灵活地集成到我们最近开发的SmartCage平台中。这一创新系统将实现对感觉运动协调和社会互动的自动评估，除了那些已经建立的参数外，运动（通过IR阵列），焦虑样行为（使用黑匣子）和认知（使用触摸屏）在现有的SmartCage。目标二。使用增强的SmartCage研究MCAO后小鼠的家庭行为和认知功能，并建立用于表型分析和药物效果评估的综合方案。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验证的测定方案，将广泛用于神经科学界，特别是中风研究竞技场，因为与传统方法和仪器相比，它简单，自动化和定量评估。此外，拟议的第一阶段项目将自然导致第二阶段的应用，重点是发现新的神经保护剂用于中风治疗，使用这些自动化，神经行为表型测定与专门从事制造新的化学实体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，是老年人严重长期残疾的主要原因。目前的药物治疗仅依赖于抗血栓药物和溶血栓药物。为了发现新的药物，可以减少脑卒中引起的神经元死亡和由此产生的残疾，我们需要有效的功能结果评估工具包。在这里，我们提出了开发自动化，全面的神经行为分析工具包，以促进中风研究和药物发现。

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.