Kogan J H, Frankland P W, Blendy J A, Coblentz J, Marowitz Z, Schütz G, Silva A J
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Curr Biol. 1997 Jan 1;7(1):1-11. doi: 10.1016/s0960-9822(06)00022-4.
The cAMP responsive element binding protein (CREB) is a transcription factor the activity of which is modulated by increases in the intracellular levels of cAMP and calcium. Results from studies with Aplysia, Drosophila and mice indicate that CREB-activated transcription is required for long-term memory. Furthermore, a recent study found that long-term memory for olfactory conditioning can be induced with a single trial in transgenic Drosophila expressing a CREB activator, whereas in normal flies, with presumably lower CREB-mediated transcription levels, conditioning requires multiple spaced trials. This suggests that CREB-mediated transcription is important in determining the type of training required for long-term memory of olfactory conditioning in Drosophila. Interestingly, studies with cultured Aplysia neurons indicated that removing a CREB repressor promoted the formation of long-term facilitation, a cellular model of non-associative memory.
Here, we have confirmed that mice lacking the alpha and Delta CREB proteins (CREBalphaDelta-) have abnormal long-term, but not short-term, memory, as tested in an ethologically meaningful task. Importantly, additional spaced training can overcome the profound memory deficits of CREBalphaDelta- mutants. Increasing the intertrial interval from 1 to 60 minutes overcame the memory deficits of the CREBalphaDelta- mice in three distinct behavioral tasks: contextual fear conditioning, spatial learning and socially transmitted food preferences.
Previous findings and results presented here demonstrate that CREB mutant mice have profound long-term memory deficits. Importantly, our findings indicate that manipulations of CREB function can affect the number of trials and the intertrial interval required for committing information to long-term memory. Remarkably, this effect of CREB function is not restricted to simple conditioning tasks, but also affects complex behaviours such as spatial memory and memory for socially transmitted food preferences.
环磷酸腺苷反应元件结合蛋白（CREB）是一种转录因子，其活性受细胞内环磷酸腺苷（cAMP）和钙水平升高的调节。对海兔、果蝇和小鼠的研究结果表明，长期记忆需要CREB激活的转录。此外，最近一项研究发现，在表达CREB激活剂的转基因果蝇中，单次试验即可诱导嗅觉条件反射的长期记忆，而在正常果蝇中，由于CREB介导的转录水平可能较低，条件反射需要多次间隔试验。这表明CREB介导的转录对于确定果蝇嗅觉条件反射长期记忆所需的训练类型很重要。有趣的是，对培养的海兔神经元的研究表明，去除CREB阻遏物可促进长期易化的形成，长期易化是一种非联合记忆的细胞模型。
在此，我们已经证实，缺乏α和δ CREB蛋白的小鼠（CREBαδ-）在一项具有行为学意义的任务测试中，具有异常的长期记忆，但短期记忆正常。重要的是，额外的间隔训练可以克服CREBαδ-突变体严重的记忆缺陷。将试验间隔时间从1分钟增加到60分钟，在三种不同的行为任务中克服了CREBαδ-小鼠的记忆缺陷：情境恐惧条件反射、空间学习和社会传递性食物偏好。
先前的研究结果和本文呈现的结果表明，CREB突变小鼠存在严重的长期记忆缺陷。重要的是，我们的研究结果表明，对CREB功能的操纵可以影响将信息存储到长期记忆所需的试验次数和试验间隔时间。值得注意的是，CREB功能的这种影响不仅限于简单的条件反射任务，还会影响复杂行为，如空间记忆和社会传递性食物偏好的记忆。
