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。虽然获取和存储学习信息的参数和规则已经很好地建立起来，并且在从秀丽隐杆线虫到哺乳动物的物种之间非常相似，但相比之下，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，它使动物能够减少对重复无害刺激的反应。例如，惊吓反射是刻板的，但高度可修改的，因此，重复出现的惊吓刺激抑制了惊吓反射。在人类中，惊吓习惯缺陷是几种认知障碍的重要特征。我们之前已经证明斑马鱼幼虫表现出具有里程碑式行为和药理特征的习惯化学习。为了确定习惯化学习的基因和途径，我们对脊椎动物的学习突变体进行了首次遗传筛选。该筛选确定了一组18个突变体，这些突变体在短期适应声刺激方面存在缺陷。从这个筛选中，我们发现脊椎动物特异性妊娠相关血浆蛋白-a （papp-a）基因是一个以前未知的习惯化所需的基因。PAPP-A编码一种蛋白酶，这种蛋白酶可以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，从而增加IGF受体信号。虽然IGF受体信号在突触可塑性、学习和认知表现中的作用已被充分证明，但papp-a基因在神经系统和习惯化中的作用尚不清楚。本提案的目的是确定papp-a在习惯学习中的作用。本研究的实验将：(1)确定惊吓习惯的关键因素papa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，因为习惯化和惊吓调节的缺陷已经在精神障碍中被描述，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.