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.
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