Signaling and Circadian Modulation Regulating Associative Memory in Aplysia

描述（由申请人提供）：为了充分理解学习和记忆的形成，有必要了解负责记忆的诱导和巩固的基本机制，以及负责调节这些基本过程的过程。许多因素调节记忆的形成过程，包括总体健康状况、压力、动机、年龄和一天中的时间。我们研究的长期目标是了解生物钟对长期联想记忆形成的调节，包括潜在的分子机制、生理功能和行为后果。在加利福尼亚，昼夜节律钟调节着长期记忆的形成，因此，动物在白天训练时形成强大的长期记忆，而在夜间训练时则没有长期记忆。我们将通过行为学、药理学和生物化学的方法来研究应用于海鼠操作性、联想式学习、食物不可食用（LFI）学习以及生物钟调节的信号通路。在Specific Aim 1中，我们将确定LFI所需的激酶信号通路，并确定这些激酶的激活是否受到生物钟的调节。具体来说，我们将确定PKG、MARK和PKA信号是否为LFI所必需。Aim 2的目的是确定生物钟是否调节LFI记忆的学习诱导转录，以及转录因子ApC/EBP是否参与LFI。具体目标3在分子水平上考察了夜间训练动物的效果，当时它们只形成短期记忆，并研究了将部分记忆转化为长期记忆的方法。在Aim 4中，我们研究了长期记忆形成中的负调控因素。我们将研究生物钟是否调节p38激酶活性或磷酸酶活性。本研究将有助于我们对联想操作学习的分子机制的理解，并极大地促进我们对生物钟调节输出行为的理解。提出的实验的一个目的是确定如何缓解夜间长期记忆形成的昼夜节律抑制，以改善夜间的记忆形成。因此，本研究将为未来改善记忆和表现的治疗方法提供研究基础。

DESCRIPTION (provided by applicant): To fully understand learning and the formation of memory, it is necessary to understand both the basic mechanisms responsible for the induction and consolidation of memory, as well as the processes responsible for the modulation of those basic processes. Many factors modulate the processes of memory formation including general health, stress, motivation, age and the time of day. The long-term objectives of our research are to understand the modulation of long-term associative memory formation by the circadian clock including the underlying molecular mechanisms, the physiological function and the behavioral consequences. The circadian clock regulates long-term memory formation in Aplysia californica, such that animals form robust long-term memory when trained during the day, but no long-term memory when trained at night. We will investigate the signaling pathways involved in an operant, associative form of learning in Aplysia, learning that food is inedible (LFI), and modulation by the circadian clock using behavioral, pharmacological and biochemical assays. In Specific Aim 1, we will identify the kinase signaling pathways necessary for LFI and determine whether the activation of these kinases is modulated by the circadian clock. Specifically, we will determine whether PKG, MARK and PKA signaling are necessary for LFI. The goal of Aim 2 is to determine whether the circadian clock modulates learning-induced transcription for LFI memory and whether the transcription factor ApC/EBP is involved in LFI. Specific Aim 3 examines the effect, at the molecular level, of training animals at night when they only form short-term memories and investigates methods of converting the partial memory into long-term memory. In Aim 4, we examine negative regulatory elements in long-term memory formation. We will investigate whether the circadian clock regulates p38 kinase activity or phosphatase activity. This research will significantly contribute to our understanding of the molecular mechanisms underlying associative operant learning in Aplysia as well as greatly furthering our understanding of the regulation of output behaviors by the circadian clock. One objective of the proposed experiments is to determine how circadian suppression of long-term memory formation at night may be relieved to improve memory formation at night. Thus, this research will provide a basis of research for future therapeutic treatments to improve memory and performance.