Chemical modulation of memory formation in larval zebrafish
Chemical modulation of memory formation in larval zebrafish
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DOI：
10.1073/pnas.1107156108
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发表时间：
2011-09-13
影响因子：
11.1
通讯作者：
Granato, Michael
中科院分区：
文献类型：
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作者：
Wolman, Marc A.;Jain, Roshan A.;Granato, Michael
基于整个生物体的小分子筛选已被证明在识别新型治疗化学品方面很强大，但这种方法尚未被用于识别新的认知增强剂。在这里，我们提出了一个自动化的高通量系统测量非联想学习行为的斑马鱼幼虫。使用这个系统，我们报告说，间隔训练块的重复视觉刺激引起蛋白质合成依赖的长期适应性在斑马鱼幼虫，持续长达24小时。此外，重复的声刺激诱导了强大的短期习惯化，可以通过刺激频率进行调制，并通过跨模态刺激瞬间disabituated。为了表征短期习惯化背后的神经化学途径，我们筛选了1,760种具有已知靶点的生物活性化合物。虽然我们发现了大量的短期学习的功能保护之间的幼虫斑马鱼和哺乳动物模型，我们还发现了一些化合物与以前未知的作用，在学习。这些化合物包括已知与Src家族激酶和细胞周期蛋白依赖性激酶2抑制剂相互作用的肉豆蔻酸类似物，表明高通量化学筛选结合高分辨率行为测定为发现新型认知调节剂提供了强有力的方法。
Whole organism-based small-molecule screens have proven powerful in identifying novel therapeutic chemicals, yet this approach has not been exploited to identify new cognitive enhancers. Here we present an automated high-throughput system for measuring nonassociative learning behaviors in larval zebrafish. Using this system, we report that spaced training blocks of repetitive visual stimuli elicit protein synthesis-dependent long-term habituation in larval zebrafish, lasting up to 24 h. Moreover, repetitive acoustic stimulation induces robust short-term habituation that can be modulated by stimulation frequency and instantaneously dishabituated through cross-modal stimulation. To characterize the neurochemical pathways underlying short-term habituation, we screened 1,760 bioactive compounds with known targets. Although we found extensive functional conservation of short-term learning between larval zebrafish and mammalian models, we also discovered several compounds with previously unknown roles in learning. These compounds included a myristic acid analog known to interact with Src family kinases and an inhibitor of cyclin dependent kinase 2, demonstrating that high-throughput chemical screens combined with high-resolution behavioral assays provide a powerful approach for the discovery of novel cognitive modulators.