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.

ADVANCES

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.