Memory engrams: Recalling the past and imagining the future Science  03 Jan 2020: Vol. 367, Issue 6473, eaaw4325 DOI: 10.1126/science.aaw4325 Memory engrams: Recalling the past and imagining the future Sheena A. Josselyn, et.al. Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada. Department of Psychology, University of Toronto, Toronto, Ontario M5S 3G3, Canada. Department of Physiology, University of Toronto, Toronto, Ontario M5G 1X8, Canada. Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Brain, Mind & Consciousness Program, Canadian Institute for Advanced Research (CIFAR), Toronto, Ontario M5G 1M1, Canada. RIKEN-MIT Laboratory for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. [paraphrase] In 1904, Richard Semon introduced the term “engram” to describe the neural substrate for storing memories. An experience, Semon proposed, activates a subset of cells that undergo off-line, persistent chemical and/or physical changes to become an engram. Subsequent reactivation of this engram induces memory retrieval. Although Semon’s contributions were largely ignored in his lifetime, new technologies that allow researchers to image and manipulate the brain at the level of individual neurons has reinvigorated engram research. We review recent progress in studying engrams, including an evaluation of evidence for the existence of engrams, the importance of intrinsic excitability and synaptic plasticity in engrams, and the lifetime of an engram. Together, these findings are beginning to define an engram as the basic unit of memory. The idea that memory is stored as enduring changes in the brain dates back at least to the time of Plato and Aristotle (circa 350 BCE), but its scientific articulation emerged in the 20th century when Richard Semon introduced the term “engram” to describe the neural substrate for storing and recalling memories. Essentially, Semon proposed that an experience activates a population of neurons that undergo persistent chemical and/or physical changes to become an engram. Subsequent reactivation of the engram by cues available at the time of the experience induces memory retrieval. After Karl Lashley failed to find the engram in a rat brain, studies attempting to localize an engram were largely abandoned. Spurred by Donald O. Hebb’s theory that augmented synaptic strength and neuronal connectivity are critical for memory formation, many researchers showed that enhanced synaptic strength was correlated with memory. Nonetheless, the causal relationship between these enduring changes in synaptic connectivity with a specific, behaviorally identifiable memory at the level of the cell ensemble (an engram) awaited further advances in experimental technologies. The resurgence in research examining engrams may be linked to two complementary studies that applied intervention strategies to target individual neurons in an engram supporting a specific memory in mice. One study showed that ablating the subset of lateral amygdala neurons allocated to a putative engram    disrupted subsequent memory retrieval (loss of function). The second study showed that artificially reactivating a subset of hippocampal dentate gyrus neurons that were active during a fearful experience (and, therefore, part of a putative engram) induced memory retrieval in the absence of external retrieval cues (gain of function). Subsequent findings from many labs used similar strategies to identify engrams in other brain regions supporting different types of memory. There are several recent advances in engram research. First, eligible neurons within a given brain region were shown to compete for allocation to an engram, and relative neuronal excitability determines the outcome of this competition. Excitability-based competition  also guides the organization of multiple engrams in the brain and determines how these engrams interact. Second, research examining the nature of the off-line, enduring changes in engram cells (neurons that are critical components of an engram) found increased synaptic strength and spine density in these neurons as well as preferential connectivity to other downstream engram cells. Therefore, both increased intrinsic excitability and synaptic plasticity work hand in hand to form engrams, and these mechanisms are also implicated in memory consolidation and retrieval processes. Third, it is now possible to artificially manipulate memory encoding and retrieval processes to generate false memories, or even create a memory in mice without any natural sensory experience (implantation of a memory for an experience that did not occur). Fourth, “silent” engrams were discovered in amnesic mice; artificial reactivation of silent engrams induces memory retrieval, whereas natural cues cannot. Endogenous engram silencing may contribute to the change in memory over time (e.g., systems memory consolidation) or in different circumstances (e.g., fear memory extinction). These findings suggest that once formed, an engram may exist in different states (from silent to active) on the basis of their retrievability. Although initial engram studies focused on single brain regions, an emerging concept is that a given memory is supported by an engram complex, composed of functionally connected engram cell ensembles     dispersed across multiple brain regions, with each ensemble supporting a component of the overall memory. The ability to identify and manipulate engram cells and brainwide engram complexes  has introduced an exciting new era of memory research. The findings from many labs are beginning to define an engram as the basic unit of memory. However, many questions remain. In the short term, it is critical to characterize how information is stored in an engram, including how engram architecture affects memory quality, strength, and precision; how multiple engrams interact; how engrams change over time; and the role of engram silencing in these processes. The long-term goal of engram research is to leverage the fundamental findings from rodent engram studies to understand how information is acquired, stored, and used in humans and facilitate the treatment of human memory, or other information-processing, disorders. The development of low- to noninvasive technology may enable new human therapies based on the growing knowledge of engrams in rodents.