Epigenetic control of long-lasting cortical memory representations

记忆是我们经历的记录，对塑造未来的行为至关重要。在理解记忆是如何形成的方面已经取得了重大进展，然而，人们对一些记忆如何转变为持久记忆(远程记忆)知之甚少。最近的研究表明，记忆存储在学习时选择的神经元群体或神经元集合中，并在记忆被提取时重新激活。然而，稳定皮质神经元群并确保在学习过程中激活的稀疏神经元子集被招募来成功重建几天前和几周前发生的学习事件的各个方面的分子和细胞过程是未知的。在这里，我们认为大脑皮质网络中记忆的长期存储是由表观遗传机制支持的。内侧前额叶皮质(MPFC)的DNA甲基化调节与远程记忆有关，我们最近提供了DNA甲基化与神经元整体稳定性之间的联系。我们假设DNA甲基化引导皮层神经元集合内的可塑性变化，以确保其在远程记忆回忆过程中重新激活。为了测试这一点，我们将探索支持远程恐惧记忆的mPFC群体的DNA甲基化和转录场景。此外，我们将建立皮层DNA甲基化机制、记忆持续时间和相关神经元集合稳定性之间的因果关系。这将通过功能损失和功能获得的实验相结合来实现。最后，我们将研究皮质神经元集合中的DNA甲基化机制是否指导支持远程记忆存储的神经元结构变化。这项拟议的研究计划承诺将开始揭示记忆维持的未被探索的细胞和分子基础。

Memories are the record of our experiences and are essential in shaping future behaviors. Significant progress has been made in the understanding of how memories are formed, however, how some memories transform into persistent memories (remote memory) is poorly understood. Recently it has been shown that memories are stored within the neuronal population – or neuronal ensemble – selected at the time of learning and reactivated when the memory is retrieved. However, the molecular and cellular processes that underlie the stabilization of cortical neuronal ensembles and ensure that the sparse subset of neurons activated during learning is recruited to successfully recreate aspects of a learning event that occurred days and weeks before are unknown. Here, we propose that long-term storage of memory in cortical networks is supported by epigenetic mechanisms. DNA methylation regulation in the medial prefrontal cortex (mPFC) has been associated with remote memory and we recently provided a link between DNA methylation and neuronal ensemble stability. We hypothesize that DNA methylation guides plasticity changes within cortical neuronal ensembles that ensure its reactivation during remote memory recall. To test this, we will probe the DNA methylation and transcriptomic landscapes of mPFC ensembles supporting remote fear memory. Furthermore, we will establish causality between cortical DNA methylation mechanisms, the duration of memory and the stability of associated neuronal ensembles. This will be achieved through a combination of loss- and gain-of-function experiments. Lastly, we will investigate whether DNA methylation mechanisms within cortical neuronal ensembles guide neuronal structural changes that support remote memory storage. The proposed research program promises to start uncovering the unexplored cellular and molecular basis of memory maintenance.