Long-lasting, consolidated memories require not only positive biological processes that facilitate long-term memories (LTM) but also the suppression of inhibitory processes that prevent them. The mushroom body neurons (MBn) in Drosophila melanogaster store protein synthesis-dependent LTM (PSD-LTM) as well as protein synthesis-independent, anesthesia-resistant memory (ARM). The formation of ARM inhibits PSD-LTM but the underlying molecular processes that mediate this interaction remain unknown. Here, we demonstrate that the Ras→Raf→rho kinase (ROCK) pathway in MBn suppresses ARM consolidation, allowing the formation of PSD-LTM. Our initial results revealed that the effects of Ras on memory are due to postacquisition processes. Ras knockdown enhanced memory expression but had no effect on acquisition. Additionally, increasing Ras activity optogenetically after, but not before, acquisition impaired memory performance. The elevated memory produced by Ras knockdown is a result of increased ARM. While Ras knockdown enhanced the consolidation of ARM, it eliminated PSD-LTM. We found that these effects are mediated by the downstream kinase Raf. Similar to Ras, knockdown of Raf enhanced ARM consolidation and impaired PSD-LTM. Surprisingly, knockdown of the canonical downstream extracellular signal-regulated kinase did not reproduce the phenotypes observed with Ras and Raf knockdown. Rather, Ras/Raf inhibition of ROCK was found to be responsible for suppressing ARM. Constitutively active ROCK enhanced ARM and impaired PSD-LTM, while decreasing ROCK activity rescued the enhanced ARM produced by Ras knockdown. We conclude that MBn Ras/Raf inhibition of ROCK suppresses the consolidation of ARM, which permits the formation of PSD-LTM.

中文翻译：

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Ras充当果蝇中两种形式的整合记忆之间的分子开关。

持久的合并记忆不仅需要促进长期记忆（LTM）的积极生物学过程，而且还需要抑制阻止它们的抑制过程。果蝇中的蘑菇体神经元（MBn）存储依赖蛋白质合成的LTM（PSD-LTM）以及不依赖蛋白质合成的抗麻醉性记忆（ARM）。ARM的形成抑制了PSD-LTM，但是介导这种相互作用的潜在分子过程仍然未知。在这里，我们证明MBn中的Ras→Raf→rho激酶（ROCK）通路抑制ARM整合，从而形成PSD-LTM。我们的初步结果表明，Ras对记忆的影响归因于采集后过程。Ras组合式增强了记忆表达，但对采集没有影响。另外，采集后（而不是采集前）以光遗传方式提高Ras活性会损害记忆性能。Ras击倒产生的内存增加是ARM增加的结果。尽管Ras组合式降低了ARM的整合能力，但它消除了PSD-LTM。我们发现这些作用是由下游激酶Raf介导的。与Ras相似，Raf的关闭增强了ARM的合并能力，并削弱了PSD-LTM。出人意料的是，经典下游细胞外信号调节激酶的敲低没有重现Ras和Raf敲低观察到的表型。而是，发现对岩石的Ras / Raf抑制作用是抑制ARM的原因。组成性活性ROCK增强了ARM，削弱了PSD-LTM，而降低ROCK活性则拯救了由Ras组合产生的增强ARM。