Molecular-genetic analysis of habituation learning

习惯化学习的分子遗传学分析

基本信息

批准号：
8907323
负责人：
Jessica C Nelson
金额：
$ 5.07万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8907323
关键词：
Acoustics Animals Attention Deficit Disorder Basic Science Behavior Behavioral Biological Models Brain Caenorhabditis elegans Cell physiology Cells Complex Defect Development Disease Drosophila genus Environment Exhibits Exposure to Fertilization Genes Genetic Programming Genetic Screening Goals Health Hour Human Hypersensitivity Impairment Individual Injection of therapeutic agent Insulin-Like Growth Factor Receptor Invertebrates Learning Lesion Maps Measures Mediating Mental disorders Messenger RNA Molecular Molecular Genetics Mutate Nervous System Physiology Nervous system structure Neurons Nonsense Codon Pathway interactions Penetrance Phenotype Plasma Proteins Play Pregnancy Process Receptor Signaling Regulation Role Schizophrenia Signal Pathway Signal Transduction Somatomedins Specificity Stimulus Tactile Testing Time Transgenic Organisms Update Visual Zebrafish base behavioral response cell type classical conditioning genetic analysis genome sequencing habituation high throughput screening in vivo insight learned behavior mutant nervous system development neural circuit neuronal circuitry neuropsychiatry novel novel therapeutics null mutation prepulse inhibition promoter public health relevance receptor function research study response small molecule

项目摘要

DESCRIPTION (provided by applicant): Learning reflects the ability of animals to constantly update their behavioral responses with new information obtained from their environments. Habituation is a simple form of learning, and allows animals to cease responding to repeated and non-threatening visual, tactile or acoustic stimuli. In humans, habituation learning is disrupted in schizophrenia and attention deficit disorders. Yet despite its importance, the genetic programs and molecular mechanisms that govern the assembly and function of the neuronal circuits critical for habituation are not well understood. Larval zebrafish exhibit numerous complex behaviors relevant to the study of neuropsychiatric disorders, including prepulse inhibition and startle habituation. The Granato lab has developed an automated, high-throughput assay that measures startle habituation, and has conducted a small molecule screen that revealed that the neuro-pharmacological substrates for startle habituation are conserved between zebrafish and humans. Furthermore, the Granato lab has conducted the first forward genetic screen for genes critical for vertebrate startle habituation. This screen has identified eight mutants with deficits in habituation learning, and the lab has already identified the molecular lesions for three of these mutants. One of the mutant phenotypes is caused by a presumptive null mutation in pregnancy associated plasma protein a (papp-a), a vertebrate specific gene previously not implicated in habituation learning. Although papp-a is expressed in the mammalian brain, its role in nervous system development or function is unknown. Here, I propose to identify where and when this gene acts to regulate habituation (Aim 1). Since papp-a plays a well-documented role in insulin-like growth factor (IGF) signaling, I will determine whether papp-a's regulation of habituation is executed through the canonical IGF signaling pathway or through a novel, IGF signaling independent pathway (Aim 2). To identify additional regulators critical for startle habituation, I will apply whole genome sequencing to identify the genes mutated in two additional habituation mutants isolated in the screen. Combined, these experiments will characterize the function of the papp-a gene in regulating habituation behaviors and identify novel genes required for the regulation of habituation behaviors in a vertebrate context. These studies will illuminate the cellular and molecular mechanisms required for the development and function of cells mediating startle habituation. Given the importance of startle habituation and learning processes for nervous system function in healthy and disease states, the proposed studies are of high relevance to both basic science and human health.

描述（由申请人提供）：学习反映了动物利用从环境中获得的新信息不断更新其行为反应的能力。习惯是一种简单的学习形式，并允许动物停止对重复的和非威胁性的视觉、触觉做出反应。在人类中，习惯性学习在精神分裂症和注意力缺陷障碍中受到干扰，但尽管它很重要，但遗传因素仍然存在。控制对习惯化至关重要的神经元回路的组装和功能的程序和分子机制尚不清楚，斑马鱼幼虫表现出许多与神经精神疾病研究相关的复杂行为，包括前脉冲抑制和惊吓习惯化。，测量惊吓习惯的高通量测定，并进行了小分子筛选，结果表明惊吓习惯的神经药理学底物在斑马鱼和人类之间是保守的。格拉纳托实验室对脊椎动物惊吓习惯至关重要的基因进行了首次正向遗传筛选，该筛选发现了八个在习惯学习方面存在缺陷的突变体，并且该实验室已经确定了其中三个突变体的分子损伤。这是由妊娠相关血浆蛋白 a (papp-a) 的假定无效突变引起的，papp-a 是一种脊椎动物特有的基因，以前与习惯化学习无关，尽管 papp-a 在哺乳动物大脑中表达，但它在神经系统中的作用。在此，我建议确定该基因在何处以及何时发挥作用来调节习惯（目标 1），因为 papp-a 在胰岛素样生长因子 (IGF) 信号传导中发挥着详细的作用，因此我将确定。 papp-a 的习惯调节是通过经典的 IGF 信号通路还是通过一种新颖的 IGF 信号独立通路来执行（目标 2）为了确定对惊吓习惯至关重要的其他调节因子，我将应用全基因组测序来识别基因。结合在屏幕上分离的两个额外的习惯化突变体，这些实验将表征 papp-a 基因在调节习惯化行为中的功能，并鉴定在脊椎动物环境中调节习惯化行为所需的新基因。鉴于惊吓习惯和学习过程对健康和疾病状态下神经系统功能的重要性，拟议的研究与基础科学和人类健康高度相关。