Genetic analysis of motor behavior regulation

描述（由申请人提供）：简单的运动反射在非常基本的水平上连接到大脑中，然而这些反射的强度和速度会被发生在反射引发之前的环境刺激所改变。这种运动反射调节依赖于感觉信息的加工、注意和动机。在脊椎动物中，受环境刺激调节的一种典型的运动反射是惊吓反应，这是对突然的感觉刺激的一种快速的全身反应。在一个令人吃惊的刺激之前显示一个阈下刺激，抑制了惊吓反应。这种脉冲前抑制（PPI）现象已经在鸽子、老鼠和人类中被描述过。在人类中，PPI在包括精神分裂症在内的几种认知障碍中受损，并在服用抗精神病药物后恢复。然而，尽管其具有临床重要性，但PPI背后的分子和细胞途径尚未得到很好的理解。我们最近发现斑马鱼幼虫表现出脉冲前抑制，这种抑制是由一些已知的调节哺乳动物PPI的药物调节的。此外，我们还设计了一种实验装置，使我们能够高通量筛选惊吓反应调制缺陷的突变体，包括PPI。这项提议的目的是产生一个大的突变集合，从而形成一个综合研究的平台，旨在了解反射调节的神经、分子和临床方面，如PPI。本提案中的实验将：(1)筛选相当于1500个突变基因组，以寻找惊吓反应调节中的缺陷，如PPI和亚阈值灵敏度（通过自动高速视频分析）；(2)定义分离突变体的缺陷(a)通过测试它们对已知调节PPI的神经递质激动剂和拮抗剂的敏感性；B)通过测试它们在另一种惊吓调制范式（习惯化）中的表现；(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直接相关，因为PPI的缺陷已被描述为几种疾病，包括精神分裂症、注意力缺陷障碍、强迫症、亨廷顿病和图雷特综合征。此外，烟草和MDMA使用者以及父母有酗酒史的儿童也会受到PPI的影响。

DESCRIPTION (provided by applicant): Simple motor reflexes are wired into the brain at a very basic level, yet the strength and quickness of these reflexes are modified by environmental stimuli that occur just before the elicitation of the reflex. Such motor reflex modulation depends on processing of sensory information, attention and motivation. In vertebrates, a well-characterized motor reflex modulated by environmental stimuli is the startle response, a fast, whole body reaction to sudden sensory stimuli. The display of a sub-threshold stimulus just prior to a startling stimulus, suppresses the startle response. This phenomenon of prepulse inhibition (PPI) has been described in pigeons, mice and humans. In humans, PPI is impaired in several cognitive disorders, including schizophrenia, and returns after administration of antipsychotic drugs. Despite its clinical importance, however, the molecular and cellular pathways underlying PPI are not very well understood. We have recently discovered that zebrafish larvae exhibit prepulse inhibition, and that this inhibition is modulated by some of the same pharmacological agents known to modulate PPI in mammals. Furthermore, we have devised an experimental setup that allows us to screen with high throughput for mutants with defects in startle response modulation, including PPI. 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 reflex regulation, such as PPI. The experiments in this proposal will: (1) screen an equivalent of 1,500 mutagenized genomes for defects in the startle response regulation such as PPI and sub-threshold sensitivity (through automated high-speed video analysis); (2) define the defects in the isolated mutants (a) by testing their sensitivity to neurotransmitter agonists and antagonists known to modulate PPI; b) by testing their performance in an additional startle modulation paradigm, habituation; and (3) map and clone selected mutants (through a combined candidate/positional cloning approach). These studies are directly relevant to the study of human diseases, as defects in PPI have been described in several disorders, including schizophrenia, attention deficit disorder, obsessive-compulsive disorder, Huntington's disease and Tourette's syndrome. Moreover, PPI is also affected in tobacco and MDMA ('ecstasy') users, and in children with a parental history of alcoholism.