Memory can be defined as representations of daily experiences that are stored for hours, months, years or even a lifetime. These records of life events are not formed instantaneously but instead are gradually transformed from a labile to a more stable state. This process of stabilization has been termed consolidation (Lechner, Squire, & Byrne, 1999) and occur at both synaptic and systems levels. Experience dependent synaptic changes take place in the hours after learning (Yap & Greenberg, 2018) and due to the relatively well-defined time frame, the molecular processes underlying these neuronal adaptations have been extensively studied (Alberini and Kandel, 2015, Bailey et al., 1996, Yap and Greenberg, 2018). In contrast, the delayed and sustained mechanisms that occur at a systems level in the days and weeks after learning remain poorly understood.

In the last decade the field has witnessed significant progress in the understanding of where memories are located in the brain (Josselyn & Tonegawa, 2020). It is currently thought that memory traces are contained within the subpopulation of cells that are activated during learning and reactivated during memory retrieval. These cells are commonly referred to as engram cells in reference to the term coined by Richard Semon. Already in 1904, he used the term “engram” to describe the neural substrate of memory (Josselyn, Kohler, & Frankland, 2017). The development of genetic tools that allow for the expression of fluorescent proteins for visualization and/or opto- or chemogenetic molecules for manipulation of the neurons activated during learning (Ortega-de San Luis & Ryan, 2022) paved the way to these discoveries.

In this review, we discuss in an engram-centered manner the current understanding of the molecular and cellular mechanisms that take place within defined brain structures as well as across regions and that regulate the early and late stages of memory consolidation at both synaptic and systems levels. Our focus is on memory engrams in the hippocampus (HPC) and medial prefrontal cortex (mPFC) given the critical role for these structures in memory formation and maintenance. Finally, we highlight some open questions that remain to be answered.