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: 7522246
• 负责人: DANIEL R STORM
• 金额: $ 33.67万
• 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/7522246
• 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; Computer information processing; 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; LY294002; 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; Numbers; PD-98059; PDPK1 gene; Parahippocampal Gyrus; Pathway interactions; Pattern; Peptides; Performance; Pharmaceutical Preparations; Phobic anxiety disorder; Phosphatidylinositide 3-Kinase Inhibitor; Phospho-Specific Antibodies; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Phosphorylation; Pike fish; Protein Kinase; Protein Kinase Inhibitors; Protein-Serine-Threonine Kinases; Public Health; 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; inhibitor/antagonist; kinase inhibitor; memory retrieval; metabotropic glutamate receptor type 1; new technology; protein kinase inhibitor; 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，通过重新巩固或消失来加强或改变存储的记忆。尽管包括MAP激酶（MAPK）级联在内的几种信号通路与修复有关，但潜在的信号事件并不完全确定。该资助的总体目标是识别有助于提取海马依赖性上下文记忆的信号元件。这些研究可能会导致识别特定的药物靶点，可以利用修改记忆检索。这个建议是基于这个实验室的观察，涉及PI3激酶和MAPK在上下文记忆检索。我们发现，在提取背景记忆的过程中，PI3激酶在海马的几个区域被激活，包括CA1区，CA3区和齿状回。此外，在体内海马CA1区抑制PI3激酶可逆地阻断了上下文记忆提取。此外，PI3激酶抑制剂阻断了与记忆恢复相关的MAPK活性的增加。这表明海马中PI3激酶的激活对于记忆提取至关重要，并且可能是提取期间MAPK激活所必需的。我们的数据还表明，cAMP依赖性蛋白激酶（PKA）的活性是必要的检索上下文记忆。关于PI3激酶在记忆提取中的作用以及PI3激酶信号传导与提取过程中其他信号传导事件之间的关系，存在许多未回答的问题。背景记忆提取过程中PI3激酶的激活机制是什么？在背景记忆提取过程中，PI3激酶和MAPK在同一神经元中被激活吗？在获得和提取背景记忆的过程中，海马体中的相同神经元是否被激活？PKA在提取中被激活了吗？Akt活性是记忆提取所必需的吗？CA3区或齿状回PI3激酶的激活是否也是背景记忆提取所必需的？ 公共卫生相关性该基金专注于记忆提取背后的分子事件，这是信息处理的基本步骤。这项研究可能会确定药物的靶点，可用于调节记忆检索，并在临床上有用。例如，损害记忆恢复的药物可用于治疗恐惧症。