The role of pregnancy associated plasma protein-a in habituation learning

妊娠相关血浆蛋白-a在习惯化学习中的作用

• 批准号: 8619242
• 负责人: Michael Granato
• 金额: $ 8万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-09 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8619242
• 关键词: Acoustics; Animals; Applications Grants; Attention; Attention Deficit Disorder; Autistic Disorder; Behavior; Behavioral; Biological; Caenorhabditis elegans; Cells; Characteristics; Cleaved cell; Cognition Disorders; Cognitive; Collection; Complex; Defect; Development; Drosophila genus; Drug Targeting; Drug abuse; Exhibits; Fetal Alcohol Syndrome; Genes; Genetic; Genetic Screening; Genome; Human; Individual; Injection of therapeutic agent; Insulin-Like Growth Factor Receptor; Insulin-Like Growth-Factor-Binding Proteins; Larva; Learning; Link; Mammals; Memory; Mental Health; Mental disorders; Messenger RNA; Molecular; Molecular Genetics; Nervous system structure; Nonsense Codon; Organism; Pathway interactions; Peptide Hydrolases; Performance; Plasma Proteins; Play; Pregnancy; Pregnancy-Associated Plasma Protein-A; Process; Reaction; Receptor Signaling; Recording of previous events; Reflex action; Reporting; Research Project Grants; Role; Schizophrenia; Sensory; Signal Transduction; Somatomedins; Stereotyping; Stimulus; Synaptic plasticity; Time; Transgenic Organisms; Vertebrates; Zebrafish; addiction; base; cell type; clinically relevant; experience; genome sequencing; in vivo; learned behavior; mutant; neural circuit; novel; promoter; public health relevance; research study; response; screening

The process by which organisms alter their 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. Habituation is a simple form of non-associative learning that enables animals to reduce their reaction to repeated harmless stimuli. For example, the startle reflex is stereotyped but highly modifiable, such that repeated presentation of startling stimuli suppresses the startle reflex. In humans, startle habituation deficits are an important feature of several cognitive disorders. We previously demonstrated that zebrafish larvae exhibit habituation learning with landmark behavioral and pharmacological characteristics. To identify genes and pathways underlying habituation learning, we conducted the first genetic screen for learning mutants in vertebrates. This screen identified a set of 18 mutants with defects in short-term habituation to acoustic stimuli. From this screen we identified the vertebrate specific pregnancy associated plasma protein-a (papp-a) gene as a previously unknown gene required for habituation. PAPP-A encodes a protease known to cleave insulin-like growth factor binding proteins, thereby increasing local IGF availability and hence IGF receptor signaling. While IGF receptor signaling has well documented roles in synaptic plasticity, learning and cognitive performance, the roles of papp-a gene in the nervous system and for habituation are unknown. The objective of this proposal is to determine the role of papp-a for habituation learning. The experiments in this proposal will: (1) determine the temporal and spatial requirements of papp-a critical for startle habituation; and (2) determine if papp-a regulates habituation through IGF receptor signaling. These studies are relevant to the study of human heath, as deficits in habituation and startle modulation have been described in mental disorders, including schizophrenia, attention deficit disorder, and autism, and are also common in individuals with a history drug abuse.

生物体根据经验改变其行为的过程被称为 学习虽然已经描述了用于获取和存储学习信息的参数和规则， 已经建立，并且在从C.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。习惯是一种 一种简单的非联想学习形式，使动物能够减少对重复的反应。 无害的刺激例如，惊吓反射是刻板的，但高度可变， 反复出现惊吓刺激会抑制惊吓反射。在人类中，惊吓习惯 缺陷是几种认知障碍的重要特征。 我们之前证明了斑马鱼幼虫表现出对地标的习惯性学习 行为和药理学特征。为了确定基因和途径， 为了研究适应性学习，我们进行了第一次脊椎动物学习突变体的遗传筛选。这 筛选确定了一组18个突变体，这些突变体在对声音刺激的短期习惯化方面存在缺陷。从 在这次筛选中，我们鉴定了脊椎动物特异性妊娠相关血浆蛋白-a（papp-a） 基因作为一个以前未知的基因所需的习惯。PAPP-A编码一种蛋白酶， 切割胰岛素样生长因子结合蛋白，从而增加局部IGF的可用性， IGF受体信号传导。虽然IGF受体信号传导在突触可塑性中的作用已得到充分证实， 学习和认知能力，papp-a基因在神经系统中的作用， 习惯是未知的。本建议的目的是确定papp-a的作用， 习惯化学习本实验将：（1）确定时间和空间 papp-a对惊吓习惯化的关键要求;以及（2）确定papp-a是否调节 通过IGF受体信号传导的习惯化。这些研究与人类健康研究有关， 因为习惯和惊吓调节的缺陷已被描述为精神障碍，包括 精神分裂症，注意力缺陷障碍和自闭症，也常见于患有 吸毒史