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。虽然用于获取和存储学习信息的参数和规则已经很好地建立，并且在从C.从线虫到哺乳动物，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，学习不能直接衡量，但可以通过表现来衡量。一种很容易量化的基本学习形式是非关联学习，包括敏感化和习惯化。习惯被定义为对刺激的注意力减少。例如，惊吓反射是定型的，但高度可变，使得重复呈现惊吓刺激抑制惊吓反射。在人类中，习惯化缺陷是认知障碍的核心特征，包括精神分裂症。 斑马鱼幼虫表现出显着的剧目的行为，我们发现，幼虫表现出非联想学习（习惯化）具有里程碑意义的行为和药理学特征。此外，我们还设计了一种实验装置，使我们能够对非联想学习（习惯化）的基因和途径进行遗传和小分子筛选。该提案的目的是产生一个大型的突变体集合，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。本提案的实验将：（1）筛选相当于1，000个化学诱变基因组和500个携带基因断裂插入突变的菌株，以确定短期习惯性缺陷（通过自动高速视频分析）;（2）筛选具有已知靶点的小分子文库，以鉴定增加或减少习惯化的因子，以确定进入非生物学行为基础途径的入口点。联想学习;和（3）定位和克隆选择的突变体（通过组合的候选/定位克隆方法）。这些研究与人类疾病的研究相关，因为惊吓调节的缺陷已在几种精神障碍中描述，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。 公共卫生相关性：学习和记忆是基本的过程，但学习和记忆的分子机制知之甚少。使用遗传学方法，该提案旨在确定控制学习的基本形式-习惯化的新基因和途径。这与精神健康和药物滥用的研究直接相关，因为习惯化缺陷是精神分裂症的核心特征，并且因为像习惯化这样的惊吓缺陷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.