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When neurons are recruited to form the memory engram, they are driven to activate the expression of a series of immediate-early genes (IEGs). While these IEGs have been used relatively indiscriminately to identify the so-called engram neurons, recent research has demonstrated that different IEG ensembles can be physically and functionally distinct within the memory engram. This inherent heterogeneity of the memory engram is driven by the diversity in the functions and distributions of different IEGs. This process, which we call molecular sorting, is analogous to sorting the entire population of engram neurons into different sub-engrams molecularly defined by different IEGs. In this chapter, we will describe the molecular sorting process by systematically reviewing published work on engram ensemble cells defined by the following four major IEGs: Fos, Npas4, Arc, and Egr1. By comparing and contrasting these likely different components of the memory engram, we hope to gain a better understanding of the logic and significance behind the molecular sorting process for memory functions., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Synaptic connections between hippocampal mossy fibers (MFs) and CA3 pyramidal neurons are essential for contextual memory encoding, but the molecular mechanisms regulating MF-CA3 synapses during memory formation and the exact nature of this regulation are poorly understood. Here we report that the activity-dependent transcription factor Npas4 selectively regulates the structure and strength of MF-CA3 synapses by restricting the number of their functional synaptic contacts without affecting the other synaptic inputs onto CA3 pyramidal neurons. Using an activity-dependent reporter, we identified CA3 pyramidal cells that were activated by contextual learning and found that MF inputs on these cells were selectively strengthened. Deletion of Npas4 prevented both contextual memory formation and this learning-induced synaptic modification. We further show that Npas4 regulates MF-CA3 synapses by controlling the expression of the polo-like kinase Plk2. Thus, Npas4 is a critical regulator of experience-dependent, structural, and functional plasticity at MF-CA3 synapses during contextual memory formation., (Copyright © 2018 Elsevier Inc. All rights reserved.)