Genetic analysis of simple learning behaviors

描述（由申请人提供）：生物体不断更新其行为以响应感官刺激和经验。生物体根据经验改变其行为的过程被称为学习。虽然获取和存储学习信息的参数和规则已经很好地建立起来，并且在从秀丽隐杆线虫到哺乳动物的物种之间非常相似，但相比之下，驱动学习的分子机制还没有得到很好的理解。在动物中，学习是不能直接衡量的，但可以通过表现来衡量。一种易于量化的基本学习形式是非关联学习，包括敏感化和习惯化。习惯化被定义为对刺激的注意力减少。例如，惊吓反射是刻板的，但高度可修改的，因此，重复出现的惊吓刺激抑制了惊吓反射。在人类中，习惯缺陷是包括精神分裂症在内的认知障碍的一个主要特征。斑马鱼的幼虫表现出一系列的行为，我们发现幼虫表现出非联想学习（习惯化），具有里程碑式的行为和药理特征。此外，我们还设计了一个实验装置，使我们能够对非联想学习（习惯化）背后的基因和途径进行遗传和小分子筛选。本提案的目的是生成一个大的突变集合，从而形成一个旨在了解非联想学习的神经、分子和临床方面的综合研究平台。本提案中的实验将：(1)筛选相当于1,000个化学突变的基因组，以及500个携带基因断裂插入突变的菌株，特别是在短期习惯中（通过自动高速视频分析）；(2)筛选具有已知目标的小分子文库，以确定增加或减少习惯化的因素，以确定进入非联想学习途径的切入点；(3)通过候选/位置克隆相结合的方法绘制和克隆所选突变体。这些研究与人类疾病的研究相关，因为惊吓调节的缺陷已经在几种精神障碍中被描述，包括精神分裂症、注意力缺陷障碍和强迫症，并且在有药物滥用史的个体中也很常见。

DESCRIPTION (provided by applicant): Organisms constantly update their behavior in response to sensory stimuli and experiences. The process by which an organism alters its behavior in response to experiences is known as learning. While the parameters and rules for acquisition and storage of learned information have been well established and are quite similar across species ranging from C. elegans to mammals, the molecular mechanisms that drive learning, in comparison, are not well understood. In animals, learning is not directly measurable but can be measured by performance. One basic form of learning that is readily quantifiable is non-associate learning, which includes sensitization and habituation. Habituation is defined as a decrease in attention directed towards a stimulus. For example, the startle reflex is stereotyped but highly modifiable, such that repeated presentation of startling stimuli suppresses the startle reflex. In humans, habituation deficits are a central feature of cognitive disorders, including schizophrenia. Zebrafish larvae display a remarkable repertoire of behaviors and we find that larvae exhibit non-associative learning (habituation) with landmark behavioral and pharmacological characteristics. Moreover, we have devised an experimental setup that allows us perform genetic as well as small molecule screens for genes and pathways specifically underlying non-associative learning (habituation). The objective of this proposal is to generate a large mutant collection, thereby forming a platform for integrative studies aimed to understand the neural, molecular and clinical aspects of non-associative learning. The experiments in this proposal will: (1) screen an equivalent of 1,000 chemically mutagenized genomes, and 500 strains carrying gene-breaking insertional mutations for defects specifically in short-term habituation (through automated high-speed video analysis); (2) screen libraries of small molecules with known targets to identify factors that increase or decrease habituation to define entry points into pathways underlying non-associate learning; and (3) map and clone selected mutants (through a combined candidate/positional cloning approach). These studies are relevant to the study of human diseases, as deficits in startle modulation have been described in several mental disorders, including schizophrenia, attention deficit disorder, and obsessive-compulsive disorder, and are also are common in individuals with a history drug abuse. PUBLIC HEALTH RELEVANCE: Learning and memory are fundamental processes, yet the molecular mechanisms underlying learning and memory are poorly understood. Using a genetic approach, this proposal aims to identify novel genes and pathways that control a fundamental form of learning, habituation. This is directly relevant to the study of mental health and drug abuse, because deficits in habituation are a central feature of schizophrenia, and because startle deficits like habituation, also are common in individuals with a history drug abuse.