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.
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.
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