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：
7980152
负责人：
DANIEL R STORM
金额：
$ 38.43万
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/7980152
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 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）：海马依赖性内存的合并取决于从头转录和翻译。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起主要作用。该提案的重点是CAM刺激的腺苷循环酶在记忆中的作用以及在前脑（AC1+小鼠）中过表达AC1的小鼠表现出的增强记忆机制。它基于该实验室的几种观察结果，包括发现CAM刺激的腺苷循环酶是巩固海马依赖性内存所必需的，以及远程上下文存储器的持久性。我们还发现，在上下文记忆形成期间，MAPK的核易位和激活取决于CAM刺激的腺苷循环酶。我们发现，在海马中，CAMP/MAPK/MSK1/CREB转录途径的昼夜振荡可以维持上下文记忆的持久性，这是一种取决于CAM刺激的腺苷循环酶。因此，我们在前脑AC1+小鼠中制造了过表达AC1的转基因小鼠菌株。年轻的AC1+小鼠对新颖对象和社会识别以及更持久的远程上下文记忆具有较高的记忆。但是，旧的AC1+小鼠的空间记忆不如旧的野生型同窝仔，但在年轻的AC1+小鼠中不受影响。我们提出，CAM刺激的腺苷环酶活性是记忆巩固和记忆持续性所必需的，因为它支持在记忆形成过程中MAPK的激活和核转运，以及在维持记忆所需的海马中MAPK活性的昼夜节律振荡。我们建议，年轻的AC1+小鼠表现出的更强的记忆可能是由于通过CAMP/MAPK/MSK-1/CREB信号通路的信号增强以及该途径的昼夜节律振荡的扩增。我们建议，海马中MAPK的昼夜节律振荡可能是由于海马中CAM刺激的腺苷循环酶的昼夜节律振荡。公共卫生相关性：大脑具有出色的处理和存储大量信息的能力。因此，对记忆形成和持续性的基础的分子机制具有强烈的兴趣。与包括阿尔茨海默氏病在内的衰老和神经退行性疾病有关的记忆丧失不仅对患者，而且对患者的家庭都是毁灭性的。该赠款重点是记忆形成和长期记忆持续性的分子机制。在最后一个赠款期间，我们确定了一个潜在的分子靶标，以改善记忆，这是一种钙敏感的腺苷酸环化酶AC1。该酶在大脑中的突触中生成信号，从而导致内存迹线。我们在小鼠脑中制作了过表达AC1的转基因小鼠。该鼠标应变具有较高的记忆。该赠款的目标是了解为什么需要AC1来存储器以及为什么AC1过表达的小鼠具有较高的内存。