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

基本信息

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
项目类别：
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

项目摘要

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。虽然获取和存储学习信息的参数和规则已经确定从秀丽隐杆线虫到哺乳动物，各个物种之间都非常相似，相比之下，驱动学习的分子机制尚不清楚。习惯是一个简单形式的非联想学习，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，但可以高度修改，例如重复出现惊吓刺激会抑制惊吓反射。在人类中，惊吓习惯缺陷是多种认知障碍的一个重要特征。我们之前证明斑马鱼幼虫表现出具有里程碑意义的习惯学习行为和药理学特征。识别潜在的基因和途径习惯化学习，我们对脊椎动物的学习突变体进行了第一次基因筛选。这筛选鉴定出一组 18 个突变体，这些突变体在对声刺激的短期习惯方面存在缺陷。从在此筛选中，我们鉴定了脊椎动物特异性妊娠相关血浆蛋白-a (papp-a) 基因作为习惯所需的先前未知的基因。 PAPP-A 编码一种已知的蛋白酶裂解胰岛素样生长因子结合蛋白，从而增加局部 IGF 的可用性，从而 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明，学习和认知表现，papp-a 基因在神经系统中的作用以及习惯程度未知。该提案的目的是确定 papp-a 的作用：习惯化学习。本提案中的实验将：（1）确定时间和空间 papp的要求——对惊吓习惯至关重要； (2) 确定 papp-a 是否调节通过 IGF 受体信号传导形成习惯。这些研究与人类健康研究相关，正如在精神障碍中描述的习惯和惊吓调节的缺陷，包括精神分裂症、注意力缺陷障碍和自闭症，在患有自闭症的个体中也很常见滥用药物史。