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，但是这些反射的强度和速度会被在反射激发之前发生的环境刺激所改变。这种运动反射调节依赖于感觉信息、注意力和动机的处理。在脊椎动物中，受环境刺激调节的一种特征明显的运动反射是惊吓反应，一种对突然感觉刺激的快速全身反应。在惊吓刺激之前显示阈下刺激抑制惊吓反应。这种前脉冲抑制（PPI）现象已经在鸽子、小鼠和人类中描述过。在人类中，PPI在几种认知障碍中受损，包括精神分裂症，并在服用抗精神病药物后恢复。尽管它的临床重要性，但是，PPI的分子和细胞途径还没有很好地理解。我们最近发现，斑马鱼幼虫表现出前脉冲抑制，这种抑制是由一些已知的调节哺乳动物PPI的相同的药理学试剂调制。此外，我们设计了一个实验装置，使我们能够筛选高通量的突变体与缺陷的惊吓反应调制，包括PPI。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。本方案的实验将：（1）筛选相当于1，500个诱变基因组的惊吓反应调节缺陷，如PPI和阈下敏感性（2）确定分离的突变体中的缺陷（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）通过测试它们在另外的惊吓调节范例、习惯化中的性能;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直接相关，因为PPI的缺陷已经在几种疾病中描述，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，PPI还影响烟草和MDMA（摇头丸）使用者以及父母有酗酒史的儿童。

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.