Neurodevelopmental Behavioral Core

神经发育行为核心

• 批准号: 8380411
• 负责人: Michela Fagiolini
• 金额: $ 26.06万
• 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/8380411
• 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; 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 建模人类神经发育障碍的转基因和敲除小鼠的能力彻底改变了该领域的研究。神经发育疾病包括许多在儿童时期发作的行为和认知综合征，包括自闭症谱系障碍（ASD），注意力缺陷多动障碍（ADHD），图雷特综合征，结节性硬化症综合体（TSC），Neurofibromatisos，Neurofibromatisos I（NF1），fragile x（f fragile x（f x cans），以及许多合成型，connice be nott connice be notts connice be notts conntrome syntrome。 最近的数据表明，影响注意力，学习和社交互动的早期赤字不仅是 自身受损，但也可能通过扰动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，不仅要解决小鼠这些发育障碍症状的建模，而且还在研究其潜在的神经生物学原因，对正常发育变化的影响以及测试新治疗方面的兴趣。专门针对神经生物学和认知障碍的神经发育行为核心将在解决这些优先级方面发挥重要作用。 操纵基因表达（敲除，敲除，条件，特定的病毒载体传递，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。解剖特定基因或途径的功能需要分子，生化，解剖学，生理，成像和病理研究。但是，由于行为是神经系统的最终输出，因此行为的测量绝对是不可或缺的 揭示了导致神经系统正常发育的过程，并确定神经发育疾病的新疗法和新治疗方法。然而，测量小鼠中任何给定基因操纵的行为表型结果是一项艰巨的任务，尤其是对于高水平的大脑功能。尽管波士顿儿童医院IDDRC的几个实验室具有一些特定的行为表型方案的经验，但没有一个实验室具有必要的经验，能力或技术，可以完全，全面评估与神经发育障碍的全光谱相关的整个相关行为成果范围内的神经发育模型。我们计划通过执行以下操作来解决此问题： a）开发最先进的基础架构，以使IDDRC研究者能够全面地表征神经系统功能和复杂行为在神经发育障碍沿其发育轨迹的模型中。 b）利用人类神经发育障碍的小鼠替代模型来测试新型的治疗剂和疗法。 c）培训新的和成熟的研究人员及其学生如何以可靠，可重复且准确的方式使用行为测定，以理解和衡量神经发育障碍。 神经发育行为核心旨在通过向我们所有研究人员提供广泛的协议，培训和设备来提高此IDDRC的小鼠模型行为测试/表型的质量和广度。一条新突变系列的全面表征通常包括针对一般健康，神经反射，感觉能力和运动功能的初始观察测试，然后进行更具体的措施，以仔细评估认知，感知和情绪相关的行为（社交互动，发声，情感，情感和焦虑）。表型通常从出生到成年。这将扩展我们对正常行为改变的理解 发育以及神经发育障碍及其临床影响。早期药物开发将通过提供以神经为重点的临床前药物测试服务来提高药物开发，该服务将有助于研究人员产生原理证明（动物功效）数据以及早期阶段的安全性和初步毒性评估。将鼓励协作，减少重复，并通过多个PIS研究同一鼠标模型生成的数据集的汇总将创建有价值的数据源。 这些活动总的来说，将有助于对神经发育障碍的小鼠模型及其行为表型的更深入，更完整的了解，而不是个人研究人员可以自己实现的。当前，对于每种感兴趣的老鼠，可以进行的研究范围受到个人研究人员可用的资源的限制。对于大多数实验室来说，购买和维护许多专业研究所需的设备并不具有成本效益 探索所有表型。我们有信心，共同的行为设施将以较低的成本为调查人员提供访问广泛测试的优势，并具有必要的专业知识，从而使调查人员可以自由地扩大他们的分析超出原始目标。我们还将能够遵循从出生到成年的每个表型的发展，核心将有助于开发新的模型和结果指标。成功开发了测试和完善鼠标的新方法 我们认为，模型将极大地受益于国家和国际神经发育障碍社区。