Neurodevelopmental Behavioral Core

神经发育行为核心

• 批准号: 8509729
• 负责人: Michela Fagiolini
• 金额: $ 25.24万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8509729
• 关键词: Accounting; Address; Adult; Animals; Anxiety; Attention; Attention deficit hyperactivity disorder; Behavior; Behavioral; Behavioral Assay; Biochemical; Birth; Boston; Brain; Childhood; Clinical; Cognition Disorders; Cognitive; Collaborations; Communities; Complex; Data; Data Analyses; Data Set; Data Sources; Development; Disease; Drug Delivery Systems; Emotions; Ensure; Equipment; Ethics; Evaluation; Experimental Designs; Financial compensation; Fragile X Syndrome; Freedom; Gene Expression; Genes; Gilles de la Tourette syndrome; Goals; Health; Housing; Human; Image; Individual; International; Knock-in Mouse; Knock-out; Knockout Mice; Laboratories; Learning; Measures; Mental Retardation and Developmental Disabilities Research Centers; Modeling; Molecular; Moods; Motor; Mouse Strains; Mus; NF1 gene; Nervous System Physiology; Nervous system structure; Neurobiology; Neurodevelopmental Disorder; Neurofibromatosis 1; Neurologic; Operative Surgical Procedures; Outcome; Outcome Measure; Output; Pathway interactions; Pediatric Hospitals; Phenotype; Physiological; Process; Protocols documentation; Reflex action; Research; Research Design; Research Infrastructure; Research Personnel; Resources; Rett Syndrome; Role; Safety; Sensory; Services; Site; Small Interfering RNA; Social Interaction; Staging; Students; Symptoms; Syndrome; Technology; Testing; Therapeutic Agents; Toxic effect; Training; Transgenic Mice; Tuberous sclerosis protein complex; Vendor; Viral Vector; animal efficacy; autism spectrum disorder; base; behavior measurement; behavior test; cost; cost effective; design; developmental disease; drug development; drug testing; experience; gene function; interest; mouse model; mutant; nervous system development; novel strategies; novel therapeutics; pre-clinical; vocalization

D1. OBJECTIVES The capacity to generate transgenic and knockout mice that model human neurodevelopmental disorders has revolutionized research in this field. Neurodevelopmental disorders include many behavioral and cognitive syndromes that have onset during childhood, including autism spectrum disorders (ASD), attention-deficit hyperactivity disorder (ADHD), Tourette syndrome, Tuberous Sclerosis Complex (TSC), Neurofibromatosis type I (NF1), Fragile X (FXS), and Rett syndrome, many of which can be modeled in mice. Recent data suggest that early deficits that impact attention, learning, and social interaction are not only impairing in themselves, but may also alter the beneficial influence of normal environmental experience by perturbing experience-dependent brain development. There is, therefore, growing interest not only in addressing the modeling of symptoms of these developmental disorders in mice, but also in studying their underlying neurobiological causes, their impact on normal developmental changes and in testing new treatments. A neurodevelopmental behavioral core focused specifically on neurobiological and cognitive disorders will have a major role in addressing these priorities. Manipulation of gene expression (knock-out, knock-in, conditional, site-specific viral vector delivery, siRNA silencing, etc.) provides exciting opportunities for understanding gene function in relation to many different neurodevelopmental disorders. Dissecting the function of a specific gene or pathway requires molecular, biochemical, anatomical, physiological, imaging and pathological studies. However, since behavior is the final output of the nervous system, measurement of behavior is absolutely integral to revealing the processes responsible for the normal development of the nervous system and for determining the bases for and new treatments of neurodevelopmental diseases. Measuring the behavioral phenotypic outcome(s) of any given gene manipulation in mice is, however, a challenging task, particularly for high level brain function. While several laboratories in the IDDRC at Children's Hospital Boston have experience in a few particular behavioral phenotype protocols, no single lab has the requisite experience, capacity or technology to fully, comprehensively assess neurodevelopmental models across the whole range of relevant behavioral outcomes related to the full spectrum of neurodevelopmental disorders. We plan to address this problem by doing the following: a) Developing a state-of-the-art infrastructure to enable IDDRC investigators to comprehensively characterize nervous system function and complex behaviors in mouse models of neurodevelopmental disorders along their developmental trajectories. b) Exploiting mouse surrogate models o f human neurodevelopmental disorders to test novel therapeutic agents and therapies. c) Training new and established investigators and their students in how to use behavioral assays in a reliable, reproducible, and, accurate manner for understanding and measuring neurodevelopmental disorders. The Neurodevelopmental Behavioral Core is designed to raise the quality and breadth of mouse model behavioral testing/phenotyping at this IDDRC by providing a wide array of protocols, training, and equipment to all our investigators. Comprehensive characterization of a new mutant line will typically include an initial battery of basic observational tests for general health, neurological reflexes, sensory abilities and motor function, followed by more specific measures focused on careful evaluation of cognitive, perceptual, and mood-related behaviors (social interaction, vocalization, emotion and anxiety). Phenotype will typically be followed from birth until adulthood. This will extend our understanding of behavioral changes during normal development as well as of neurodevelopmental disorders and their clinical impact. Early stage drug development will be advanced by providing a neuro-focused preclinical drug testing service that will help investigators generate proof of principle (animal efficacy) data and early stage safety and preliminary toxicity assessments. Collaboration will be encouraged, duplication reduced, and the pooling of data sets generated by multiple PIs studying the same mouse model will create a valuable data source. Collectively these activities will contribute to a deeper and more complete understanding of mouse models of neurodevelopmental disorders and their behavioral phenotype than individual investigators can achieve on their own. Currently, for every mouse of interest, the scope of studies that can be performed is limited by the resources available to an individual researcher. It is not cost-effective for most laboratories to purchase and maintain the equipment needed for many specialized types of studies, and investigators must turn to collaboration with other laboratories or commercial vendors to obtain such resources, or simply not explore all phenotypes. We are confident that a shared behavioral facility will offer the advantage to investigators of access to a wide range of tests at a lower cost, with the necessary expertise, giving the investigators freedom to expand their analyses beyond their original goals. We will also be able to follow the development of each phenotype from birth until adulthood and the core will facilitate development of new models and outcome measures. Successful development of new approaches to testing and refining mouse models will greatly benefit, we believe, the national and international neurodevelopmental disorders community.

D1。目标 产生转基因和基因敲除小鼠来模拟人类神经发育障碍的能力使这一领域的研究发生了革命性的变化。神经发育障碍包括许多在儿童时期起病的行为和认知综合征，包括自闭症谱系障碍(ASD)、注意缺陷多动障碍(ADHD)、多动症(Tourette)、结节性硬化症(TSC)、I型神经纤维瘤病(NF1)、脆性X(FXS)和Rett综合征，其中许多可以在小鼠身上建立模型。最近的数据表明，影响注意力、学习和社交的早期缺陷不仅是 但也可能通过扰乱依赖经验的大脑发育来改变正常环境经验的有益影响。因此，人们越来越感兴趣的不仅是在小鼠身上建立这些发育障碍症状的模型，而且还在研究它们的潜在神经生物学原因，它们对正常发育变化的影响，以及测试新的治疗方法。一个专门关注神经生物学和认知障碍的神经发展行为核心将在解决这些优先事项方面发挥重要作用。 基因表达的操纵(敲除、敲入、有条件的、特定部位的病毒载体传递、siRNA沉默等)为了解与许多不同神经发育障碍有关的基因功能提供了令人兴奋的机会。剖析特定基因或途径的功能需要分子、生化、解剖学、生理学、成像和病理学研究。然而，由于行为是神经系统的最终输出，对行为的测量绝对是不可或缺的 揭示负责神经系统正常发育的过程，并确定神经发育疾病的基础和新的治疗方法。然而，测量小鼠任何给定基因操作的行为表型结果(S)是一项具有挑战性的任务，特别是对于高水平的大脑功能。虽然波士顿儿童医院IDDRC的几个实验室在几个特定的行为表型方案方面拥有经验，但没有一个实验室拥有全面、全面地评估与全系列神经发育障碍相关的所有行为结果的神经发育模型所需的经验、能力或技术。我们计划采取以下措施来解决这个问题： A)开发最先进的基础设施，使IDDRC的研究人员能够全面表征神经系统功能和神经发育障碍小鼠模型中沿着其发育轨迹的复杂行为。 B)利用人类神经发育障碍的小鼠代理模型来测试新的治疗剂和疗法。 C)培训新的和现有的研究人员及其学生如何以可靠、可重复和准确的方式使用行为分析来理解和测量神经发育障碍。 神经发育行为核心旨在通过为我们所有的研究人员提供广泛的方案、培训和设备来提高该IDDRC的小鼠模型行为测试/表型鉴定的质量和广度。新突变系的综合特征通常包括对一般健康、神经反射、感觉能力和运动功能的一系列基本观察测试，然后是更具体的措施，重点是仔细评估认知、感知和与情绪相关的行为(社交互动、发声、情绪和焦虑)。表型通常会从出生到成年。这将扩大我们对正常情况下行为变化的理解 以及神经发育障碍的发展及其临床影响。将通过提供以神经为重点的临床前药物测试服务来推进早期药物开发，该服务将帮助研究人员生成原理证据(动物疗效)数据以及早期安全性和初步毒性评估。将鼓励协作，减少重复，将研究同一鼠标模型的多个PI生成的数据集汇集在一起，将创建一个有价值的数据源。 总的来说，这些活动将有助于更深入和更完整地理解神经发育障碍的小鼠模型及其行为表型，而不是单个研究人员自己能够实现的。目前，对于每个感兴趣的鼠标，可以进行的研究范围受到单个研究人员可用资源的限制。对于大多数实验室来说，购买和维护许多专门类型研究所需的设备并不划算，研究人员必须求助于与其他实验室或商业供应商合作来获得此类资源，或者干脆不 探索所有的表型。我们相信，共享的行为设施将为调查人员提供以较低成本获得广泛测试的优势，并拥有必要的专业知识，使调查人员能够自由地扩大他们的分析范围，使其超出最初的目标。我们还将能够跟踪每种表型从出生到成年的发育情况，核心将促进新模型和结果衡量标准的发展。成功开发测试和提纯小鼠的新方法 我们相信，模型将极大地惠及国内和国际神经发育障碍界。