Writing the Engram: Epigenetic Mechanisms of Memory Allocation

Memory allocation, the selective recruitment of neurons into ensembles that encode, store and retrieve experience, so-called engram cells, designates the initial step of every memory's formation. Historically thought to be governed primarily by intrinsic neuronal excitability, recent studies highlight a critical role for transcriptional and epigenetic heterogeneity in biasing neuronal engram inclusion. Here, we review mechanisms that influence this process, including CREB-mediated excitability, transcriptional priming and epigenetic modulation, and emphasise the surprisingly understudied link of how electrical properties and the epigenetic landscape converge to shape allocation. We then describe emerging methodologies for the manipulation and interrogation of these processes that will be crucial for disentangling not only local intracellular dynamics, but also their propagation across distributed brain networks. Doing so will prove instrumental to assess the possibility that several cognitive dysfunctions-that display aberrant excitability and epigenetic changes-may arise from memory misallocation, stressing the translational potential of this work. Lastly, beyond the role of the intrinsic neuronal properties, we discuss underexplored physiological influences, including metabolic state, hormonal signalling, sleep, gut-brain communication, and the potential contribution from other cell types such as astrocytes and interneurons that may shape engram selection. By integrating molecular, cellular and systems perspectives, with a sharpened emphasis on the importance of epigenetic mechanisms, we suggest that understanding allocation may benefit from a holistic viewpoint beyond the current excitability-focused and neuron-centric point of view.