Behavior-based chemical screening for GABAergic and startle modifying drugs

描述（由申请人提供）：神经活性化合物是神经科学研究中最强大的工具之一。识别具有新活性的新化合物可能有助于神经科学研究。然而，这些神经活性药物很难识别。在这里，我们提出了一种新的方法来识别影响斑马鱼惊吓和焦虑相关行为的神经活性化合物。这些研究旨在加快神经活性药物的发现步伐，并为理解脊椎动物的行为提供小分子工具。焦虑症，如广泛性焦虑症、恐慌症和创伤后应激障碍是广泛存在的破坏性疾病。尽管需要改进精神科药物，但精神科疾病和其他神经系统疾病的药物发现成功率低于其他治疗领域。为了满足对新型神经活性药物的巨大需求，开发新的神经活性药物发现方法至关重要。但是，缺乏对导致精神疾病的生化机制的详细了解，如何才能发现新的神经活性药物呢？遗传学和药理学是了解神经系统分子信号通路的两种主要方法。然而，传统的药物遗传学方法严重偏向于系统生物学的基因组方面。用于研究单一药物作用的全基因组应用正变得越来越普遍。相比之下，对化学物质如何影响特定基因型和表型的大规模分析发展得要慢得多。一个原因是基于表型的化学筛选在大多数模式生物中并不实用或成本效益高。考虑到通过低通量和非系统方法发现的小分子的影响，系统的基于行为的化学筛选可能会提供很多东西。基于斑马鱼表型的化学筛选是一种非常规的识别新型生物活性化合物的方法。很可能在现代化学文库中已经存在具有有价值的神经活性的尚未鉴定的化合物。然而，体外分析过于简单，在哺乳动物中进行表型分析的通量太低，无法有效识别这些有价值的分子。与大型脊椎动物不同，斑马鱼足够小，可以很容易地与化学库中的化学物质一起排列在96孔板的单个孔中。因此，基于斑马鱼行为的化学筛选为系统地评估化学物质如何影响完整的脊椎动物神经系统提供了机会。

DESCRIPTION (provided by applicant): Neuroactive compounds are among the most powerful tools available for neuroscience research. Identifying novel compounds with new activities would likely aid neuroscience research. However, these neuroactive drugs are difficult to identify. Here, we propose a new approach to identify neuroactive compounds that affect startle and anxiety-related behaviors behaviors in living zebrafish. These studies aim to accelerate the pace of neuroactive drug discovery and provide small-molecule tools for understanding vertebrate behavior. Anxiety disorders such as generalized anxiety disorder, panic disorder and post-traumatic stress disorder are widespread and devastating illnesses. Despite the need for improved psychiatric medicines, drug discovery success rates for psychiatric illnesses and other disorders of the nervous system are lower than for other therapeutic areas. To meet the vast unmet need for novel neuroactive drugs, it will be essential to develop new approaches to neuroactive drug discovery. But, lacking a detailed understanding of the biochemical mechanisms that cause psychiatric disease, how can novel neuroactive drugs be discovered? Genetics and pharmacology are the two dominant approaches for understanding molecular signaling pathways in the nervous system. However, traditional pharmacogenetic approaches are heavily biased towards the genome side of systems biology. Genome-wide applications for investigating the effects of single drugs are becoming more common. By contrast, large-scale analyses of how chemicals affect specific genotypes and phenotypes have been much slower to develop. One reason is that phenotype based chemical screens have not been practical or cost-effective using most model organisms. Given the impact of small molecules that were discovered via low throughput and non-systematic approaches, it is likely that systematic behavior-based chemical screening has much to offer. Phenotype based chemical screens in the zebrafish are a non-conventional approach for identifying novel bioactive compounds. It is likely that uncharacterized compounds with valuable neuroactive activity already exist in the wells of modern chemical libraries. However, in vitro assays are too simplistic and phenotypic assays in mammals too low throughput, to efficiently identify these valuable molecules. Unlike larger vertebrates, zebrafish are small enough to be easily arrayed in the individual wells of a 96-well plate along with chemicals from a chemical library. As a result, behavior-based chemical screens in the zebrafish provide the opportunity to systematically assess how chemicals affect the intact vertebrate nervous system.