Understanding the physical basis of memory: Molecular mechanisms of the engram

Understanding the physical basis of memory: Molecular mechanisms of the engram

Memory, defined as the storage and use of learned information in the brain, is necessary to modulate behavior and critical for animals to adapt to their environments and survive. Despite being a cornerstone of brain function, questions surrounding the molecular and cellular mechanisms of how information is encoded, stored, and recalled remain largely unanswered. One widely held theory is that an engram is formed by a group of neurons that are active during learning, which undergoes biochemical and physical changes to store information in a stable state, and that are later reactivated during recall of the memory. In the past decade, the development of engram labeling methodologies has proven useful to investigate the biology of memory at the molecular and cellular levels. Engram technology allows the study of individual memories associated with particular experiences and their evolution over time, with enough experimental resolution to discriminate between different memory processes: learning (encoding), consolidation (the passage from short-term to long-term memories), and storage (the maintenance of memory in the brain). Here, we review the current understanding of memory formation at a molecular and cellular level by focusing on insights provided using engram technology.

Animals extract information from the environment through learning and modify their behavior accordingly. Memory is the ability to store and recall that knowledge. In short, memory involves four different phenomena: encoding, consolidation, storage, and recall. Encoding is the process by which information reaching the brain through perception is written in the brain. Consolidation allows information to be selected and made stable for long-term periods. The stable storage of memory involves permanent modifications to retain the information, and recall is the process that enables the reactivation of the pertinent information upon specific and precise cues to allow the modification of behavior.

In nineteen oh four, Richard Semon proposed the idea of the "engram" and defined it as "the enduring though primary latent modification in the irritable substance produced by a stimulus

(from an experience)." An engram, sometimes understood as a synonym for memory trace, is formed by a group of neurons that (one) become activated by a specific learning experience, (two) are modified by this experience, and (three) are reactivated by re-exposure to the same experience, inducing a change in the behavior of the animal. Engram cells, therefore, are at least a part of the physical place or substrate where learning leaves imprints in the brain. Sets of engram cells can be found sparse in many areas of the brain, forming an engrome, or engram complex.

The coding problem

To understand memory, it is necessary, but not sufficient, to describe the biological mechanisms that enable memory formation, maintenance, and expression. As well as explaining the processes required for memory, we must also explain how specific memories are formed as discrete engrams. In other words, we need to understand how specific pieces of information translate into the brain in a way that allows the animal to manage separate memories associated with concrete events. This question of how mental representations are organized in the brain is a long-standing problem. Descartes proposed that the mind was organized in ideas, which are material representations of both what is presented in front of the mind and resulting from the operation of the mind itself, a thought. The problem of mental representations, and how to operationalize it into experimental design, remains a core challenge in modern neuroscience.

Early in the nineteen tens, before the discovery of the DNA double helix, the mechanism of inheritance was one of the most fascinating mysteries of biology. How is a single cell, or an embryo, able to carry the astonishingly complex information package to drive the formation of a full organism? Where in that cell is all that information stored and what is the mechanism that translates it into cells, tissues, and organs?

We understand now how biological information is precisely organized in living organisms. After the progress of Gregor Mendel on understanding inheritance, the physical substrate of the information was discovered: the gene-bearing chromosomes. DNA was found to carry genetic traits that were trafficked between bacteria during transformation, and genes were discovered to be made of DNA. The discovery of the DNA structure was the Rosetta stone that made everything else comprehensible. The structure of genes was understood, and the genetic code was finally solved. The golden era of molecular genetics had finally described how biological information was written and read in living organisms. Arguably, the neurobiology of the memory field is still waiting for its golden era.

Neuroscience and experimental psychology have focused on the biology of learning and memory acquisition and retention but have largely sidestepped the question of the coding problem: how the specific information is written in the brain. Whilst we know a great deal about plasticity mechanisms required for learned behavior in general (which will be reviewed later), we are still far from identifying the "double helix" of memory-if one even exists. We do not have a clear idea of how long-term, specific information may be stored in the brain, into separate engrams that can be reactivated when relevant. Understanding engram organization would be the equivalent to understanding how genes are organized in the genome.