洛克菲勒大学Priya Rajasethupathy小组揭示了丘脑皮质转录门协调记忆稳定。该项研究成果发表在2025年11月26日出版的《自然》上。

为了深入了解这一过程，研究人员创造了一个行为任务，让老鼠在几周的时间里形成多种记忆，但只巩固了一些，而忘记了其他记忆。然后，课题组研究人员监测了在巩固记忆和遗忘记忆之间分化的特定电路分子程序。该课题组确定了多个不同的转录波，即在丘脑皮层回路中定义记忆持久性的细胞宏观状态。值得注意的是，一小部分转录调节因子协调了广泛的分子程序，使进入这些宏观状态成为可能。靶向CRISPR敲除研究表明，尽管这些转录调节因子对记忆形成没有影响，但它们在记忆稳定中具有突出的、诱导的和显著的时间依赖性作用。特别是，钙调素依赖性转录因子CAMTA1需要维持数天的初始记忆，而转录因子TCF4和组蛋白甲基转移酶ASH1L则需要随后维持数周的记忆。这些结果确定了一个关键的CAMTA1-TCF4-ASH1L丘脑皮质转录级联，这是记忆稳定所必需的，并提出了一个模型，在这个模型中，电路特异性转录程序的顺序募集能够在越来越长的时间尺度上维持记忆。

据了解，使记忆能够在数天、数周甚至数月的时间尺度上持续存在的分子机制，小组仍然知之甚少。

附：英文原文

Title: Thalamocortical transcriptional gates coordinate memory stabilization

Author: Terceros, Andrea, Chen, Celine, Harada, Yujin, Eilers, Tim, Gebremedhin, Millennium, Hamard, Pierre-Jacques, Koche, Richard, Sharma, Roshan, Rajasethupathy, Priya

Issue&Volume: 2025-11-26

Abstract: The molecular mechanisms that enable memories to persist over long timescales from days to weeks and months are still poorly understood1. Here, to develop insights into this process, we created a behavioural task in which mice formed multiple memories but only consolidated some, while forgetting others, over the span of weeks. We then monitored circuit-specific molecular programs that diverged between consolidated and forgotten memories. We identified multiple distinct waves of transcription, that is, cellular macrostates, in the thalamocortical circuit that defined memory persistence. Of note, a small set of transcriptional regulators orchestrated broad molecular programs that enabled entry into these macrostates. Targeted CRISPR-knockout studies revealed that although these transcriptional regulators had no effects on memory formation, they had prominent, causal and strikingly time-dependent roles in memory stabilization. In particular, the calmodulin-dependent transcription factor CAMTA1 was required for initial memory maintenance over days, whereas the transcription factor TCF4 and the histone methyltransferase ASH1L were required later to maintain memory over weeks. These results identify a critical CAMTA1–TCF4–ASH1L thalamocortical transcriptional cascade that is required for memory stabilization and put forth a model in which the sequential recruitment of circuit-specific transcriptional programs enables memory maintenance over progressively longer timescales.

DOI: 10.1038/s41586-025-09774-6

Source: https://www.nature.com/articles/s41586-025-09774-6