Memory Enhancement by a Genetic Increase in cAMP Signals

描述（由申请人提供）：巩固依赖于校园的记忆取决于从头转录和翻译。CRE介导的转录是巩固海马依赖性记忆所需的转录途径之一。钙调素（CaM）刺激的腺苷酸环化酶和Erk/MAP激酶（MAPK）在记忆形成过程中CREE介导的转录的钙激活中起主要作用。该建议的重点是钙调素刺激的腺苷酸环化酶在记忆中的作用，以及在前脑中过表达AC 1的小鼠（AC 1+小鼠）表现出的增强记忆的机制。它是基于本实验室的几项观察，包括发现钙调素刺激的腺苷酸环化酶是巩固依赖于大脑的记忆所必需的，以及远程上下文记忆的持久性。我们还发现，核转位和激活的MAPK在上下文记忆的形成依赖于钙调素刺激的腺苷酸环化酶。我们发现，上下文记忆的持久性可能是通过海马中cAMP/MAPK/MSK 1/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，我们制造了在前脑中过表达AC 1的转基因小鼠品系，AC 1+小鼠。年轻的AC 1+小鼠对新物体和社会识别具有上级记忆，并且具有更持久的远程上下文记忆。然而，老年AC 1+小鼠的空间记忆力不如老年野生型同窝仔，但在年轻的AC 1+小鼠中不受影响。我们建议，钙调素刺激腺苷酸环化酶活性所需的记忆巩固和记忆的持久性，因为它支持激活和核转位的MAPK在记忆形成和昼夜节律振荡的MAPK活性在海马需要维持记忆。我们认为，年轻的AC 1+小鼠表现出更强的记忆力可能是由于通过cAMP/MAPK/ MSK-1/CREB信号通路增强的信号传导以及该通路的昼夜节律振荡的放大。我们建议，在海马MAPK的昼夜振荡可能是由于昼夜振荡的钙调蛋白刺激的腺苷酸环化酶在海马。 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续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庭都是毁灭性的。该基金主要研究记忆形成的分子机制和长期记忆的持久性。在上一个资助期，我们确定了一个改善记忆的潜在分子靶点，一种钙敏感的腺苷酸环化酶，AC 1。这种酶在大脑中的突触处产生信号，从而导致记忆痕迹。我们制作了一只在小鼠脑中过表达AC 1的转基因小鼠。这种老鼠有上级记忆力。这项研究的目的是了解为什么AC 1是记忆所必需的，以及为什么AC 1过表达的小鼠具有上级记忆。

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.