Igaz Lionel Muller, Bekinschtein Pedro, Vianna Monica M R, Izquierdo Ivan, Medina Jorge H
Instituto de Biología Celular y Neurociencia Eduardo de Robertis, Facultad de Medicina, Universidad de Buenos Aires, (1113) Buenos Aires, Argentina.
Neurotox Res. 2004;6(3):189-204. doi: 10.1007/BF03033221.
For several decades, neuroscientists have provided many clues that point out the involvement of de novo gene expression during the formation of long-lasting forms of memory. However, information regarding the transcriptional response networks involved in memory formation has been scarce and fragmented. With the advent of genome-based technologies, combined with more classical approaches (i.e., pharmacology and biochemistry), it is now feasible to address those relevant questions--which gene products are modulated, and when that processes are necessary for the proper storage of memories--with unprecedented resolution and scale. Using one-trial inhibitory (passive) avoidance training of rats, one of the most studied tasks so far, we found two time windows of sensitivity to transcriptional and translational inhibitors infused into the hippocampus: around the time of training and 3-6 h after training. Remarkably, these periods perfectly overlap with the involvement of hippocampal cAMP/PKA (protein kinase A) signaling pathways in memory consolidation. Given the complexity of transcriptional responses in the brain, particularly those related to processing of behavioral information, it was clearly necessary to address this issue with a multi-variable, parallel-oriented approach. We used cDNA arrays to screen for candidate inhibitory avoidance learning-related genes and analyze the dynamic pattern of gene expression that emerges during memory consolidation. These include genes involved in intracellular kinase networks, synaptic function, DNA-binding and chromatin modification, transcriptional activation and repression, translation, membrane receptors, and oncogenes, among others. Our findings suggest that differential and orchestrated hippocampal gene expression is necessary in both early and late periods of long-term memory consolidation. Additionally, this kind of studies may lead to the identification and characterization of genes that are relevant for the pathogenesis of complex psychiatric disorders involving learning and memory impairments, and may allow the development of new methods for the diagnosis and treatment of these diseases.
几十年来，神经科学家们已经提供了许多线索，指出新生基因表达在持久记忆形成过程中发挥作用。然而，关于记忆形成过程中涉及的转录反应网络的信息一直稀缺且零散。随着基于基因组技术的出现，结合更经典的方法（即药理学和生物化学），现在以前所未有的分辨率和规模来解决那些相关问题——哪些基因产物受到调节，以及这些过程何时对于记忆的正确存储是必要的——成为可能。使用大鼠的单次试验抑制性（被动）回避训练，这是迄今为止研究最多的任务之一，我们发现了两个对注入海马体的转录和翻译抑制剂敏感的时间窗口：训练时以及训练后3 - 6小时。值得注意的是，这些时期与海马体cAMP/PKA（蛋白激酶A）信号通路在记忆巩固中的作用完美重叠。鉴于大脑中转录反应的复杂性，尤其是那些与行为信息处理相关的反应，显然有必要采用多变量、平行导向的方法来解决这个问题。我们使用cDNA阵列筛选与抑制性回避学习相关的候选基因，并分析记忆巩固过程中出现的基因表达动态模式。这些基因包括参与细胞内激酶网络、突触功能、DNA结合和染色质修饰、转录激活和抑制、翻译、膜受体以及癌基因等的基因。我们的研究结果表明，在长期记忆巩固的早期和晚期，海马体中差异且协调的基因表达都是必要的。此外，这类研究可能会导致识别和表征与涉及学习和记忆障碍的复杂精神疾病发病机制相关的基因，并可能有助于开发诊断和治疗这些疾病的新方法。
