Memory Enhancement by a Genetic Increase in cAMP Signals

cAMP 信号基因增加可增强记忆

基本信息

批准号：
8197421
负责人：
DANIEL R STORM
金额：
$ 38.37万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197421
关键词：
Abbreviations Adenylate Cyclase Age Aging Alzheimer&apos s Disease Animal Model Antibodies Area Brain CREB1 gene Ca(2+)-Calmodulin Dependent Protein Kinase Calcium Calcium Channel Calmodulin Chemosensitization Circadian Rhythms Cyclic AMP Cyclic AMP-Dependent Protein Kinases Defect Depressed mood Drug Delivery Systems E-Box Elements Enzymes Exhibits Family Frequencies Genetic Genetic Transcription Glutamates Goals Grant Hippocampus (Brain)Inferior Knock-out Knockout Mice L-Type Calcium Channels LacZ Genes Lead MEKs Measures Mediating Memantine Memory Memory Loss Memory impairment Methods Mitogen Activated Protein Kinase 1 Mitogen-Activated Protein Kinases Molecular Molecular Target Monitor Mouse Strains Mus N-Methyl-D-Aspartate Receptors N-Methylaspartate NMDA receptor antagonist Neuraxis Neurodegenerative Disorders Neurons Nimodipine Nuclear Nuclear Translocation Pathway interactions Patients Periodicity Phospho-Specific Antibodies Phosphorylation Phosphotransferases Play Process Prosencephalon Proteins Publishing Pyramidal Cells RPS6KA5 gene Regulation Reporter Reporting Research Response Elements Retina Role Short-Term Memory Signal Pathway Signal Transduction Site Synapses Technology Training Transgenic Mice Translations Wild Type Mouse Work adenylyl cyclase 8 age related aged aging hippocampus base expression vector extracellular signal-regulated kinase 3 improved interest long term memory mRNA Expression mutant novel overexpression promoter public health relevance research study social voltage

项目摘要

DESCRIPTION (provided by applicant): Consolidation of hippocampus-dependent memory depends on de novo transcription and translation. One of the transcriptional pathways required for consolidation of hippocampus-dependent memory is CRE-,mediated transcription. Calmodulin (CaM)-stimulated adenylyl cyclases, and Erk/MAP kinase (MAPK) plays a major role in calcium activation of CRE-mediated transcription during formation of memory. This proposal focuses on the role of CaM-stimulated adenylyl cyclases in memory and the mechanism for enhanced memory exhibited by mice over-expressing AC1 in the forebrain (AC1+ mice). It is based upon several observations made by this lab including the discovery that CaM-stimulated adenylyl cyclases are required for consolidation of hippocampus-dependent memory, as well as the persistence of remote contextual memory. We also discovered that the nuclear translocation and activation of MAPK during contextual memory formation depends upon CaM-stimulated adenylyl cyclases. We found that the persistence of contextual memory may be maintained by the circadian oscillation of the cAMP/MAPK/MSK1/CREB transcriptional pathway in the hippocampus, an oscillation which depends upon CaM-stimulated adenylyl cyclases. Therefore, we made a transgenic mouse strain over-expressing AC1 in the forebrain, AC1+ mice. Young AC1+ mice have superior memory for novel objects and social recognition and more persistent remote contextual memory. However, the spatial memory of old AC1+ mice is inferior to old wild-type littermates, yet unaffected in young AC1+ mice. We propose that CaM-stimulated adenylyl cyclase activity is required for memory consolidation and memory persistence because it supports the activation and nuclear translocation of MAPK during memory formation and the circadian oscillation of MAPK activity in the hippocampus required to maintain memory. We propose that the stronger memory exhibited by young AC1+ mice may be due to enhanced signaling through the cAMP/MAPK/ MSK-1/CREB signaling pathway as well as amplification of the circadian oscillation of this pathway. We propose that the circadian oscillation of MAPK in the hippocampus may be due to circadian oscillation of CaM-stimulated adenylyl cyclases in the hippocampus. PUBLIC HEALTH RELEVANCE: The brain has the remarkable ability to process and store enormous amounts of information. Consequently, there is intense interest in molecular mechanisms underlying the formation and persistence of memory. Memory loss associated with aging and neurodegenerative diseases including Alzheimer's disease is devastating, not only to the patient but also the patient's family. This grant focuses on the molecular mechanisms for memory formation and the persistence of long-term memory. In the last grant period, we identified a potential molecular target for memory improvement, a calcium-sensitive adenylyl cyclase, AC1. This enzyme generates signals at the synapses in the brain, which leads to memory trace. We made a transgenic mouse over-expressing AC1 in mouse brain. This mouse strain has superior memory. The objectives of this grant are to understand why AC1 is required for memory and why AC1 over-expressing mice have superior memory.

描述（由申请人提供）：海马依赖性记忆的巩固依赖于从头转录和翻译。巩固海马依赖性记忆所需的转录途径之一是 CRE 介导的转录。钙调蛋白 (CaM) 刺激的腺苷酸环化酶和 Erk/MAP 激酶 (MAPK) 在记忆形成过程中 CRE 介导的转录的钙激活中发挥重要作用。该提案重点关注 CaM 刺激的腺苷酸环化酶在记忆中的作用，以及前脑中过度表达 AC1 的小鼠（AC1+ 小鼠）所表现出的增强记忆的机制。它基于该实验室的多项观察结果，包括发现 CaM 刺激的腺苷酸环化酶是海马依赖性记忆的巩固以及远程情境记忆的持久性所必需的。我们还发现，上下文记忆形成过程中 MAPK 的核转位和激活取决于 CaM 刺激的腺苷酸环化酶。我们发现，情境记忆的持久性可能是通过海马 cAMP/MAPK/MSK1/CREB 转录途径的昼夜振荡来维持的，这种振荡依赖于 CaM 刺激的腺苷酸环化酶。因此，我们制备了前脑过度表达AC1的转基因小鼠品系，即AC1+小鼠。年轻的 AC1+ 小鼠对新奇物体和社会认知具有出色的记忆力，并且具有更持久的远程情境记忆。然而，年老的 AC1+ 小鼠的空间记忆不如年老的野生型同窝小鼠，但年轻的 AC1+ 小鼠不受影响。我们认为，CaM 刺激的腺苷酸环化酶活性是记忆巩固和记忆持久所必需的，因为它支持记忆形成过程中 MAPK 的激活和核转位，以及维持记忆所需的海马 MAPK 活性的昼夜节律振荡。我们认为，年轻的 AC1+ 小鼠表现出更强的记忆力可能是由于 cAMP/MAPK/MSK-1/CREB 信号通路的信号增强以及该通路的昼夜节律振荡的放大。我们认为海马 MAPK 的昼夜振荡可能是由于海马 CaM 刺激的腺苷酸环化酶的昼夜振荡所致。公共卫生相关性：大脑具有处理和存储大量信息的非凡能力。因此，人们对记忆形成和持久的分子机制产生了浓厚的兴趣。与衰老和包括阿尔茨海默病在内的神经退行性疾病相关的记忆丧失不仅对患者而且对患者的家人来说都是毁灭性的。该资助重点研究记忆形成和长期记忆持续的分子机制。在上一个资助期，我们确定了一个改善记忆的潜在分子靶标，即钙敏感腺苷酸环化酶 AC1。这种酶在大脑突触处产生信号，从而产生记忆痕迹。我们制作了一只在小鼠大脑中过度表达 AC1 的转基因小鼠。该小鼠品系具有超强的记忆力。这笔资助的目的是了解为什么 AC1 是记忆所必需的，以及为什么 AC1 过度表达的小鼠具有优越的记忆力。