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）：记忆检索是记忆形成的一个动态方面，它通过重新巩固或消除来强化或改变存储的记忆。尽管包括 MAP 激酶 (MAPK) 级联在内的多种信号传导途径与修复有关，但潜在的信号传导事件尚未完全定义。该资助的总体目标是确定有助于检索海马依赖性上下文记忆的信号元件。这些研究可能会导致特定药物靶位点的识别，这些靶位点可用于修改记忆检索。该提议基于该实验室的观察结果，该观察表明 PI3 激酶和 MAPK 与上下文记忆检索有关。我们发现，在情景记忆检索过程中，PI3 激酶在海马体的多个区域（包括 CA1、CA3 和齿状回）被激活。此外，体内海马 CA1 区 PI3 激酶的抑制可逆地阻断情境记忆检索。此外，PI3 激酶抑制剂可阻断与记忆恢复相关的 MAPK 活性的增加。这表明海马中 PI3 激酶的激活对于记忆检索至关重要，并且可能是检索过程中 MAPK 激活所必需的。我们的数据还表明，cAMP 依赖性蛋白激酶 (PKA) 活性是上下文记忆检索所必需的。关于 PI3 激酶在记忆检索中的作用以及检索过程中 PI3 激酶信号传导与其他信号传导事件之间的关系，还有许多悬而未决的问题。情境记忆检索过程中 PI3 激酶激活的机制是什么？在情境记忆检索过程中，PI3 激酶和 MAPK 是否在同一神经元中被激活？在获取和检索情境记忆的过程中，海马体中的相同神经元是否被激活？检索时 PKA 是否被激活？记忆检索需要 Akt 活动吗？上下文记忆检索是否也需要激活 CA3 区或齿状回 (DG) 中的 PI3 激酶？ 公共卫生相关性 这项资助重点关注记忆检索背后的分子事件，这是信息处理的基本步骤。这项研究可能会确定可用于调节记忆检索并在临床上有用的药物靶位点。例如，损害记忆提取的药物可用于治疗恐惧症。