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

描述（由申请人提供）：生物体根据经验改变其行为的过程被称为学习。虽然用于获取和存储学习信息的参数和规则已经很好地建立，并且在从C.从线虫到哺乳动物，相比之下，驱动学习的分子机制还没有得到很好的理解。习惯化是一种简单的非联想学习形式，使动物能够减少对重复无害刺激的反应。例如，惊吓反射是定型的，但高度可变，使得重复呈现惊吓刺激抑制惊吓反射。在人类中，惊吓习惯缺陷是几种认知障碍的重要特征。 我们以前证明，斑马鱼幼虫表现出具有里程碑意义的行为和药理学特征的习惯化学习。为了确定适应性学习的基因和途径，我们对脊椎动物中的学习突变体进行了第一次遗传筛选。这个屏幕确定了一组18突变体的缺陷，在短期适应声刺激。从这个屏幕上，我们确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编码一种已知可切割胰岛素样生长因子结合蛋白的蛋白酶，从而增加局部IGF可用性，并因此增加IGF受体信号传导。虽然IGF受体信号传导在突触可塑性、学习和认知表现中的作用已得到充分证实，但Papp-a基因在神经系统和习惯化中的作用尚不清楚。这个提议的目的是确定papp-a在习惯化学习中的作用。本实验将：（1）确定Papp-a对惊吓习惯化的时间和空间要求;（2）确定Papp-a是否通过IGF受体信号调节习惯化。这些研究与人类健康研究相关，因为习惯和惊吓调节的缺陷已在精神障碍中描述，包括精神分裂症，注意力缺陷障碍和自闭症，并且在有药物滥用史的个体中也很常见。

DESCRIPTION (provided by applicant): 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.