Metrics and tools for phenotyping sociality and development in animal models

描述(由申请人提供)： 影响数百万人的重大精神疾病，如精神分裂症和自闭症谱系障碍，都有共同的症状，受折磨的人对社会提示没有适应性反应。这一统一的特征有助于唤起人们对理解社会性的行为、基因组、神经和发育基础的重要性，因为这些是这些毁灭性疾病显现的基础。识别、分析和治疗此类疾病的现代生物医学方法需要动物模型，这项SBIR第一阶段建议提供了一种新的行为表型分析方法，揭示了小鼠社会性的开始和发展，并能够识别与正常发育的偏差。传统上，行为表型分析使用绝对的测量方法，如探索、睡眠、焦虑、进食、攻击等。我们的方法与这一传统背道而驰，而是使用群体背景下个体的运动学测量。我们监控连续参数，如活动/不活动、位置、联系人、组大小和配置。我们拥有研究群体行为和群体中个人行为的实验室基础；现在可以将方法从实验室转移到市场上。STAR Enterprise在设计和建造自动化、可控的啮齿动物栖息地(用于航天研究)方面有着出色的历史，可以将这种专业知识与其在小鼠和大鼠行为发育方面的知识结合起来。我们将创造一个受控的测试环境，在这个环境中，通过摄像机观察出生8天、12天和16天的幼鼠群体。插件程序将自动分析20分钟的数字化视频样本，以检测社会性的开始，识别群体中个人之间耦合活动的发展外观，并根据群体以群体为单位显示的聚集形成模式。还将在个人层面对群体进行分析。这些群体和个人数据将与同一只小鼠作为独立的青春期前青少年和成年小鼠的行为数据相关联，使用更传统的表型测量方法。因此，我们既可以开发我们的新方法，也可以用传统的指数交叉验证它们。最后，我们将进一步展示这些方法的敏感性、效力和实际应用，将它们用于含有已知影响社会性的基因工程敲除缺陷的突变小鼠。公共卫生相关性：在开发和使用人类行为和精神障碍的动物模型时，准确评估行为和社会性的发展至关重要。我们开发的行为规程和工具将促进行为障碍动物模型的创建，并使在整个发育过程中对社会性的准确和可靠测量成为可能，这将服务于心理健康研究社区，包括实验室、制药和生物技术部门。 公共卫生相关性： 使用一种新的行为测量方法，我们将创建一种设备(硬件和软件)，使科学家能够快速评估实验室小鼠是否正在发展正常的社会行为。在研究和治疗自闭症和精神分裂症等涉及对社会线索反应的改变的疾病时，迫切需要这种生物医学评估工具。

DESCRIPTION (provided by applicant): Major mental illnesses such as schizophrenia and the Autism Spectrum Disorder, which affect millions of people, share a common symptom, the afflicted people do not respond adaptively to social cues. This unifying feature has helped call attention to the importance of understanding the behavioral, genomic, neural, and developmental foundations of sociality, for these are the substrates on which these devastating diseases are manifested. Modern biomedical approaches to recognizing, analyzing, and remediating such disorders require animal models, and this SBIR Phase I proposal presents a novel approach to behavioral phenotyping that reveals the onset and development of sociality in mice, and can recognize deviations from normal development. Traditionally, behavioral phenotyping uses categorical measures, such as exploration, sleep, anxiety, feeding, aggression, etc. Our approach departs from this tradition and instead uses kinematic measures of individuals in a group context. We monitor continuous parameters such as activity/inactivity, position, contact, group size and configuration. We have the laboratory foundation for studying group behavior and individuals' behavior in the group; it is now possible to move the approach from the lab to the marketplace. Star Enterprises has an excellent history in designing and building automated, well-controlled habitats for rodents (used in spaceflight research) and can combine that expertise with its knowledge of behavioral development in mice and rats. We will create a controlled testing environment in which groups of infant mice are observed by video camera at 8-, 12-, and 16- days of age. Plug-in programs will automatically analyze 20-min digitized video samples to detect the onset of sociality, recognizing the developmental appearance of coupled activity among the individuals in the group, and by patterns of aggregon formation shown by the group as unit. Groups will also be analyzed at the level of the individual. These group and individual data will be correlated to behavioral data of the same mice as independent, pre-pubertal juveniles and as adults, using more traditional phenotyping measures. Thus, we can both develop our new methods and cross-validate them with conventional indices. Finally, we will further demonstrate the sensitivity, power, and practical application of these methods by using them with mutant mice containing genetically-engineered knock-out deficits known to affect sociality. PUBLIC HEALTH RELEVANCE: Accurately assessing the development of behavior and sociality is critical in developing and using animal models for human behavioral and mental disorders. The behavioral protocols and tools we develop will facilitate the creation of behavioral-disorder animal models and make possible accurate and reliable measures of sociality throughout development, which will serve the mental health research community, including the laboratory, pharmaceutical, and biotechnology sectors. PUBLIC HEALTH RELEVANCE: Using a novel approach to behavioral measurement, we will create an apparatus (hardware and software) that will enable scientists to rapidly assess whether laboratory mice are developing normal social behavior. Such biomedical assessment tools are urgently needed for studying and remediating illnesses such as autism and schizophrenia that involve alterations in responses to social cues.