Signaling and Circadian Modulation Regulating Associative Memory in Aplysia

描述(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。许多因素调节着记忆的形成过程，包括一般的健康、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时联想记忆形成的调控，包括其潜在的分子机制、生理功能和行为后果。生物钟调节着海兔长期记忆的形成，因此动物在白天训练时会形成强大的长期记忆，但在晚上训练时就不会形成长期记忆。我们将使用行为、药理学和生化分析来研究海兔学习的可操作性、关联性形式所涉及的信号通路，学习食物是不能食用的(LFI)，以及生物钟的调节。在特定的目标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生物钟的调节。具体地说，我们将确定PKG、Mark和PKA信号是否对LFI是必要的。目标2的目的是确定生物钟是否调节学习诱导的LFI记忆转录，以及转录因子APC/EBP是否参与LFI。《特殊目的3》在分子水平上研究了夜间训练只形成短期记忆的动物的效果，并研究了将部分记忆转化为长期记忆的方法。在目标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。这项研究将有助于我们理解海兔联想操作学习的分子机制，也将极大地加深我们对生物钟对输出行为的调控的理解。这项拟议的实验的一个目标是确定如何缓解夜间对长期记忆形成的昼夜节律抑制，以改善夜间记忆形成。因此，这项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.