Gene Expression in Long-term Memory

长期记忆中的基因表达

• 批准号: 6468294
• 负责人: CRISTINA M ALBERINI
• 金额: $ 33.69万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6468294
• 关键词: amygdala; antisense nucleic acid; behavior test; behavioral /social science research tag; behavioral genetics; biological signal transduction; cAMP response element binding protein; cyclin dependent kinase; enhancer binding protein; fear; gene expression; hippocampus; immunocytochemistry; insulinlike growth factor; intermolecular interaction; laboratory rat; long term memory; memory; oligonucleotides; phosphorylation; protein binding; protein biosynthesis; protein protein interaction; protein structure function; temporal lobe /cortex; transcription factor; western blottings

DESCRIPTION (provided by applicant): Long-term memory formation consists of multiple phases. A new memory is initially labile. To become stable this new memory undergoes a process known as consolidation that, in the case of declarative memories, occurs within the medial temporal lobes and requires gene expression. When recalled, memories reenter a new phase of vulnerability and seem to require a "reconsolidation" process in order to be maintained. The goal of this project is to characterize, particularly in the temporal lobe regions hippocampus and amygdala, the gene expression regulation underlying different phases of long-term memory formation. It has been shown that members of the transcription factor family cAMP response element binding protein (CREB) play an essential role in the consolidation of long-term memory. However, the cascade of events activated downstream of CREB is still poorly understood. In Inhibitory Avoidance (IA) learning, a significant and persistent activation (phosphorylation) of CREB and CREB-dependent gene expression occur in the hippocampus. We have recently found that a CREB-downstream evolutionarily conserved molecular event essential for IA long-term memory consolidation is the induction of another transcription factor, a member of the CCAAT enhancer binding protein (C/EBPBeta). Preliminary data suggest that, together with C/EBPBeta, another member of the C/EBP family C/EBPdelta, may play a role in memory consolidation. We have also identified a number of putative CREB-C/EBPdownstream genes. Two of these, Insulin-like growth factor-Il (IGF-II) and cyclin-dependent kinase 5 (CDK5), may have a critical role as modulators of the synaptic morphological changes that underlie memory storage. In contrast, the molecular mechanisms of "reconsolidation" are not yet known. In this project we propose to continue our characterization of the gene cascade underlying memory formation, and specifically to: 1- Characterize the anatomical and temporal profiles of CREB-C/EBPBeta activation and asses the contribution of this molecular pathway to the storage of medial temporal lobe-dependent memories; 2- Determine whether C/EBPdelta plays an essential role as a memory activator or repressor. 3- Determine the role of the target genes CDK5 and IGF-II. 4. Characterize the molecular basis of the memory "reconsolidation" process. The proposed experiments will provide significant insight into the molecular mechanisms of memory consolidation. An understanding of the molecular changes underlying memory formation may indicate new strategies for the treatment of memory disorders.

描述（由申请人提供）：长期记忆的形成包括 多个阶段。新的记忆最初是不稳定的。为了使这个新的稳定 记忆经历一个称为巩固的过程，在这种情况下 陈述性记忆，发生在内侧颞叶内，需要基因 表达。当回忆起来时，记忆重新进入脆弱的新阶段 似乎需要一个“重新整合”过程才能维持。目标 该项目的目的是表征，特别是颞叶区域 海马和杏仁核的基因表达调控不同 长期记忆形成的阶段。事实证明，该组织的成员 转录因子家族 cAMP 反应元件结合蛋白 (CREB) 发挥作用 在巩固长期记忆中发挥着重要作用。然而， CREB ​​下游激活的级联事件仍然知之甚少。在 抑制性回避（IA）学习，一种显着且持续的激活 CREB（磷酸化）和 CREB ​​依赖性基因表达发生在 海马体。我们最近发现 CREB ​​下游进化 IA长期记忆巩固所必需的保守分子事件是 另一个转录因子（CCAAT 增强子的成员）的诱导 结合蛋白（C/EBPβ）。初步数据表明，连同 C/EBPβ 是 C/EBP 家族 C/EBPdelta 的另一个成员，可能在 记忆巩固。我们还确定了一些假定的 CREB-C/EBP下游基因。其中两个，胰岛素样生长因子-II (IGF-II) 和细胞周期蛋白依赖性激酶 5 (CDK5) 可能具有关键作用 记忆存储基础上的突触形态变化的调节剂。 相比之下，“再巩固”的分子机制尚不清楚。 在这个项目中，我们建议继续对基因级联进行表征 底层记忆形成，特别是： 1- 表征 CREB-C/EPBβ 激活的解剖学和时间特征并评估 该分子途径对内侧颞叶存储的贡献 脑叶依赖性记忆； 2- 确定 C/EBPdelta 是否至关重要 作为记忆激活剂或抑制剂的作用。 3-确定目标的角色 基因 CDK5 和 IGF-II。 4. 表征记忆的分子基础 “重新整合”过程。所提出的实验将提供重要的 深入了解记忆巩固的分子机制。一种理解 记忆形成背后的分子变化可能表明新的 治疗记忆障碍的策略。