The molecular mechanisms of spacing effect

间隔训练后形成的记忆，每次训练之间有休息间隔的重复训练比集中训练后形成的记忆更稳定，重复训练没有休息间隔。这种对记忆的“间隔效应”早在100多年前就有报道。然而，目前还不清楚为什么休息时间会增强记忆。在果蝇中，间隔训练产生CREB依赖的长期记忆(LTM)，而集中训练抑制LTM。因此，我们检测了间隔对CREB和CREB上游转录因子c-fos表达的影响。我们发现在间歇训练中CREB和c-fos的表达显著增加，而在集中训练中则没有。C-fos的转录活性是由ERK激活的，而ERK是由MEK依赖的磷酸化激活的。我们还发现，在间隔训练中，ERK的磷酸化水平显著增加。然而，有趣的是，ERK的磷酸化在每个休息时间段增加，在每个训练时间段减少。MEK抑制剂仅能抑制LTM的形成。这些结果表明，ERK的激活需要间隔训练的休息间隔。

Memory formed after spaced training, repeated training with rest intervals between each training, is more stable than memory formed after massed training, repeated training without rest intervals. This "spacing effect" on memory was reported more than 100 yrs ago. However, it is still not clear why rest intervals strengthen memory. In Drosophila, spaced training produces CREB-dependent long-term memory(LTM) whereas, massed training suppresses LTM. Therefore, we examined spacing effect on expressions of CREB and c-fos, an upstream transcription factor of CREB. We found significant increase in expressions of CREB and c-fos during spaced training but not massed training. Transcriptional activity of c-fos is activated by ERK, which is activated by MEK-dependent phosphorylation. We also found significant increase in phosphorylation of ERK during spaced training. Interestingly, however, ERK phosphorylation was increased during each rest intervals and decreased during each training period. MEK inhibitors exclusively impaired LTM formation. These results suggest that rest intervals of spaced training is required for activation of ERK.