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: 8240050
• 负责人: DANIEL R STORM
• 金额: $ 33.44万
• 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/8240050
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Animals; Antibodies; Area; Attenuated; Back; Beryllium; Bilateral; Brain-Derived Neurotrophic Factor; Cells; Cyclic AMP-Dependent Protein Kinases; Data; Dominant-Negative Mutation; Drug Delivery Systems; Elements; Event; Extinction (Psychology); Figs - dietary; Galactosidase; Genetic Transcription; Glutamates; Grant; Health; 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; Mitogen-Activated Protein Kinase Kinases; 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; Protein Kinase; Protein Kinase Inhibitors; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; 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; 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）：内存检索是内存形成的动态方面，可以通过重新溶解或灭绝来加强或改变存储的内存。尽管包括MAP激酶（MAPK）级联反应在内的几种信号通路与检索有关，但基础信号事件未完全定义。该赠款的一般目标是确定有助于检索海马依赖性的上下文记忆的信号元素。这些研究可能导致鉴定可以利用的特定药物靶位点，以修改记忆检索。该建议基于该实验室的观察结果，该观察结果将PI3激酶和MAPK牵涉到上下文记忆检索中。我们发现在检索上下文记忆期间，在海马的多个区域中激活了PI3激酶，包括CA1，CA3和齿状回的区域。此外，在体内抑制pi3激酶在体内的CA1区域CA1中可逆地阻塞上下文记忆检索。另外，PI3激酶的抑制剂阻止了与记忆检索相关的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，并且在检索过程中激活MAPK可能是必需的。我们的数据还表明，检索上下文记忆需要依赖CAMP的蛋白激酶（PKA）活性。关于PI3激酶在记忆检索中的作用以及PI3激酶信号传导与其他检索过程中其他信号事件之间的关系，有许多未解决的问题。在检索上下文记忆期间，PI3激酶激活PI3激酶的机制是什么？在上下文记忆检索中，PI3激酶和MAPK是否在同一神经元中激活？在获取和检索上下文记忆期间，海马中的同一神经元是否激活了同一神经元？ PKA是否在检索中激活？内存检索需要AKT活动吗？上下文记忆检索中还需要PI3激酶在区域CA3或齿状回（DG）中激活吗？公共卫生相关性该赠款的重点是记忆检索的基本事件，这是信息处理的基本步骤。这项研究可以识别可用于调节记忆检索并在临床上有用的药物靶位点。例如，可损害记忆检索的药物可用于治疗恐惧症。

项目成果

How I learned to stop worrying and love calcineurin.

我如何学会停止担忧并热爱钙调神经磷酸酶。

• DOI: 10.1038/nn0508-527
• 发表时间: 2008
• 期刊: Nature neuroscience
• 影响因子: 25
• 作者: Sindreu,CarlosBalet;Storm,DanielR
• 通讯作者: Storm,DanielR

Type 1 adenylyl cyclase is essential for maintenance of remote contextual fear memory.

• DOI: 10.1523/jneurosci.2413-08.2008
• 发表时间: 2008-11-26
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Shan Q;Chan GC;Storm DR
• 通讯作者: Storm DR