Role of PI3 Kinase and MAP Kinase in Memory Retrieval

PI3 激酶和 MAP 激酶在记忆检索中的作用

• 批准号: 7620032
• 负责人: DANIEL R STORM
• 金额: $ 33.41万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7620032
• 关键词: 1-Phosphatidylinositol 3-Kinase; 7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester; Abbreviations; Affect; Animals; Antibodies; Area; Attenuated; Back; Bilateral; Brain-Derived Neurotrophic Factor; Cells; Cyclic AMP; Cyclic AMP Response Element; Cyclic AMP-Dependent Protein Kinases; Data; Dominant-Negative Mutation; Drug Delivery Systems; Elements; Event; Extinction (Psychology); Extracellular Signal Regulated Kinases; Figs - dietary; Galactosidase; Genetic Transcription; Glutamates; Grant; Hippocampus (Brain); Image; In Vitro; Injection of therapeutic agent; Kinetics; Label; LacZ Genes; Lead; MAP Kinase Activation Pathway; MAP Kinase Modules; MEKs; Measurable; Measurement; Measures; Mediating; Memory; Metabotropic Glutamate Receptors; Methods; Mitogen-Activated Protein Kinases; Modeling; Molecular; Monitor; Mouse Strains; Mus; N-Methyl-D-Aspartate Receptors; Neurons; PDPK1 gene; Parahippocampal Gyrus; Pathway interactions; Pattern; Peptides; Performance; Pharmaceutical Preparations; Phobic anxiety disorder; Phosphatidylinositide 3-Kinase Inhibitor; Phospho-Specific Antibodies; Phosphorylation; Pike fish; Protein Kinase; Protein Kinase Inhibitors; Protein-Serine-Threonine Kinases; Reporter; Retrieval; Role; Shock; Signal Pathway; Signal Transduction; Site; Slice; Techniques; Technology; Testing; Time; Training; base; conditioned fear; dentate gyrus; hippocampal pyramidal neuron; in vivo; information processing; inhibitor/antagonist; kinase inhibitor; memory retrieval; metabotropic glutamate receptor type 1; new technology; protein kinase inhibitor; public health relevance; receptor; research study; voltage

DESCRIPTION (provided by applicant): Memory retrieval is a dynamic aspect of memory formation that either reinforces or alters stored memories through reconsolidation or extinction. Although several signaling pathways including the MAP kinase (MAPK) cascade are implicated in retrieval, the underlying signaling events are incompletely defined. The general objective of this grant is to identify signaling elements that contribute to retrieval of hippocampus-dependent, contextual memory. These studies may lead to the identification of specific drug target sites that can be exploited to modify memory retrieval. This proposal is based upon observations made by this lab that implicate PI3 kinase and MAPK in contextual memory retrieval. We discovered that PI3 kinase is activated in several areas of the hippocampus including areas CA1, CA3 and the dentate gyrus during retrieval of contextual memory. Furthermore, inhibition of PI3 kinase in area CA1 of the hippocampus in vivo reversibly blocked contextual memory retrieval. In addition, inhibitors of PI3 kinase blocked increases in MAPK activity associated with memory retrieval. This suggests that activation of PI3 kinase in the hippocampus is critical for memory retrieval and may be required for activation of MAPK during retrieval. Our data also indicate that cAMP-dependent protein kinase (PKA) activity is required for retrieval of contextual memory. There are a number of unanswered questions concerning the role of PI3 kinase in memory retrieval and the relationship between PI3 kinase signaling and other signaling events during retrieval. What is the mechanism for activation of PI3 kinase during retrieval of contextual memory? Are PI3 kinase and MAPK activated in the same neurons during contextual memory retrieval? Are the same neurons in the hippocampus activated during acquisition and retrieval of contextual memory? Is PKA activated in retrieval? Is Akt activity required for memory retrieval? Is activation of PI3 kinase in area CA3 or the dentate gyrus (DG) also required for contextual memory retrieval? PUBLIC HEALTH RELEVANCE This grant focuses on the molecular events underlying memory retrieval, a fundamental step in information processing. This study may identify drug target sites that can be used to modulate memory retrieval and be useful clinically. For example, drugs that impair memory retrieval may be used in the treatment of phobias.

描述（由申请人提供）：记忆提取是记忆形成的一个动态方面，通过重新巩固或消除来加强或改变存储的记忆。虽然包括MAP激酶（MAPK）级联在内的几种信号通路与检索有关，但潜在的信号事件尚未完全定义。这项资助的总体目标是确定有助于检索海马体依赖的上下文记忆的信号元件。这些研究可能会导致确定特定的药物靶点，可以利用来修改记忆检索。这一建议是基于本实验室所做的关于PI3激酶和MAPK在上下文记忆检索中的作用的观察。我们发现，PI3激酶在海马的几个区域被激活，包括区域CA1， CA3和齿状回在检索上下文记忆。此外，体内海马CA1区PI3激酶的抑制可可逆地阻断情境记忆检索。此外，PI3激酶抑制剂阻断了与记忆检索相关的MAPK活性的增加。这表明，海马PI3激酶的激活对于记忆恢复至关重要，并且可能需要在恢复过程中激活MAPK。我们的数据还表明，camp依赖性蛋白激酶（PKA）活性是检索上下文记忆所必需的。关于PI3激酶在记忆检索中的作用以及PI3激酶信号传导与检索过程中其他信号传导事件之间的关系，还有许多未解之谜。背景记忆提取过程中PI3激酶的激活机制是什么？在情境记忆提取过程中，PI3激酶和MAPK是否在相同的神经元中被激活？在情境记忆的获取和检索过程中，海马体中的相同神经元是否被激活？PKA在检索中被激活了吗？记忆恢复需要Akt活动吗？上下文记忆检索是否也需要CA3区或齿状回（DG）的PI3激酶的激活？这项资助的重点是记忆检索的分子事件，这是信息处理的一个基本步骤。这项研究可能会确定药物靶点，可以用来调节记忆检索和临床有用。例如，损害记忆恢复的药物可以用于治疗恐惧症。