Automated Analysis of Learning and Memory for Neuro-Developmental Studies

描述（由申请人提供）：非洲爪蟾是一个非常强大的系统，用于研究发育形态发生的遗传学和生物物理学。为了使该领域能够利用这种模式物种的力量进行神经行为研究，我们建议创建一种新的研究工具：一种计算机控制的系统，它可以实现对行为的全自动分析。该系统由200个单独的房间组成，每个房间里都有一只爪蟾幼虫（或者实际上是许多小型模式物种中的任何一种）。计算机控制每个培养皿内的光分布、声音和温度环境，并持续监控每只动物的行为。通过提供这种环境的变化，该系统不仅可以并行观察和分析大量受试者的反应，还可以在各种经典条件反射和其他学习范式中训练动物。该系统将使研究人员能够研究正常和基因或药物修饰的幼虫，并确定任何实验扰动对运动，学习速度，感觉知觉等的影响。我们将设计和创建系统，使尽可能多的实验室最大限度地采用它，并公开提供详细的构建和使用手册。通过创建标准化、模块化、全自动的设备和软件，我们将使任何实验室都能进行强大的行为分析。此外，任何实验室都能够精确地重复另一个实验室的工作，即使涉及到复杂的行为实验。该装置还消除了操作人员的繁琐和主观解释固有的人工实验与动物，并提供了蝌蚪行为的许多方面的完全客观的指标。数据被保存为每个腔室的视频和定量测量在Excel中，允许任何允许的人（甚至远程，通过互联网）分析数据。我们进一步建议使用该装置来研究脑半球偏手性改变的幼虫的行为和学习能力。由于它能够同时处理许多动物，该系统将作为一个重要的原理验证原型，为未来的努力提供筛选大型药物和基因文库的新化合物，以增强记忆和学习，对抗神经毒素或药物成瘾，作为镇静剂或兴奋剂等功能。目前的筛选工作是在简单的单细胞模型中完成的，这并不能提供发现具有重要和有益的神经活性作用的新药的能力。这个系统的创建和它在一个重要的神经生物学问题（大脑侧化的行为后果）上的应用将使神经科学领域取得巨大进展，并将加速发现对认知、行为和记忆具有特定和期望作用的药物和基因产物。我们的应用程序非常适合NIMH的目标，因为它是一个独特的工具，用于自动研究连接神经系统结构和功能的机制。公共卫生相关性：这项工作将对公共卫生产生高度积极的影响：1)为研究界提供研究许多认知和神经疾病的新工具，2)阐明脑侧性逆转对记忆和学习的影响，以及3)能够识别针对脑部疾病和增强学习和记忆能力的新药。这三个结果将导致脑部疾病的新疗法的最终发展。

DESCRIPTION (provided by applicant): Xenopus laevis is an extremely powerful system in which to study the genetics and biophysics of developmental morphogenesis. To allow the field to capitalize on the power of this model species for neurobehavioral work, we propose the creation of a new research tool: a computer-controlled system which enables the fully-automated analysis of behavior. The system consists of 200 individual chambers each containing a single Xenopus larva (or indeed, any of a number of small model species). The computer controls the light distribution, sound, and temperature environment within each dish, and continuously monitors the behavior of each animal. By providing changes in this environment, the system can not only observe and analyze the reactions of a large number of subjects in parallel, but also train the animals in a variety of classical conditioning and other learning paradigms. This system will enable researchers to study normal and genetically or pharmacologically-modified larvae and ascertain effects of any experimental perturbation on movement, learning rate, sensory perception, etc. We will design and create the system to maximize its adoption by as many labs as possible, and make publicly available detailed manuals for its construction and use. By creating a standardized, modular, fully-automated device and software, we will enable any lab to conduct powerful analyses of behavior. Moreover, any lab will be able to repeat another lab's work precisely, even if complex behavioral experiments are involved. This device also eliminates operator tedium and subjective interpretation inherent in manual experiments with animals, and provides completely objective metrics of many aspects of tadpole behavior. The data is saved as movies of each chamber and quantitative measurements in Excel, allowing any permitted person (even remotely, via the internet) to analyze the data. We further propose to use this device to study the behavior and learning ability of larvae with reversed brain asymmetry (altered handedness of brain hemispheres). Because of its ability to handle many animals simultaneously, this system will serve as an important proof-of-principle prototype for future efforts that will enable screening large drug and gene libraries for new compounds that enhance memory and learning, counteract neurotoxins or drug addiction, function as sedatives or stimulants, etc. Current screening efforts are done in simple unicellular models, which do not offer the ability to discover new drugs with important and beneficial neuroactive effects. The creation of this system and illustration of its use on an important neurobiological problem (the behavioral consequences of brain lateralization) will enable great progress in the fields of neuroscience, and will accelerate the discovery of drugs and gene products that have specific and desired effects on cognition, behavior, and memory. Our application is ideally suited to the goals of NIMH, since it is a unique tool for the automated study of the mechanisms linking nervous system structure and function. PUBLIC HEALTH RELEVANCE: This work will have high positive impact on public health by 1) providing a new tool to the research community for research into a number of cognitive and neural diseases, 2) shedding light on the consequences of brain laterality reversal for memory and learning, and 3) enabling identification of new drugs targeting brain disease and augmenting learning and memory abilities. These three outcomes will result in the eventual development of novel therapeutics for brain diseases.