The search for the physical location of a memory has long driven neuroscience, leading to the concept of the engram. An engram is the physical or biochemical change in the brain that serves as the storage mechanism for a specific memory. This term provides a framework for understanding how the brain transforms a fleeting moment of learning into a stable, retrievable piece of information. The modern study of the engram seeks to identify the precise cells and connections that constitute this memory trace.
The Conceptual Search for Memory
Early in the 20th century, the psychologist Karl Lashley attempted to locate the physical engram by systematically removing parts of the cerebral cortex in rats. He trained the animals to navigate mazes and then performed lesions to see which specific area held the memory. Lashley’s experiments were a failure in their primary goal, as he could not find a single, localized spot where the memory was stored.
He found that memory loss was proportional only to the amount of tissue removed, not the specific location. This led him to propose two principles: mass action, where the cortex acts as a whole in complex learning, and equipotentiality, where intact brain parts can take over damaged functions. Lashley concluded that memory was widely distributed throughout the brain.
This conceptual search shifted with the theoretical work of Donald Hebb, who proposed a mechanism for how distributed memory might form. Hebb suggested that when two neurons or systems of cells are repeatedly active at the same time, the connection between them strengthens. This idea, often summarized as “neurons that fire together, wire together,” provided the blueprint for the modern understanding of the engram as a distributed network.
The Biological Basis of Engram Formation
The modern engram is now understood to be an ensemble of neurons—a sparse population of cells—that are selectively activated during a learning experience. These specific cells are recruited into the memory trace through a competition-based process, where neurons that are more excitable at the time of learning are preferentially selected. Once recruited, these engram cells undergo lasting physical and biochemical changes to stabilize the memory.
The mechanism for this change is a form of synaptic plasticity known as Long-Term Potentiation (LTP), which is a long-lasting increase in the strength of synaptic transmission. During initial learning, the presynaptic neuron releases the neurotransmitter glutamate, which binds to receptors on the receiving, postsynaptic neuron. Repeated, intense stimulation causes a substantial depolarization in the postsynaptic cell, which is necessary for the memory trace to form.
This strong depolarization removes a magnesium ion block from a specific type of receptor called the NMDA receptor. Once unblocked, the NMDA receptor allows calcium ions to flood into the postsynaptic neuron, acting as a second messenger. The influx of calcium triggers a cascade of molecular events that result in the insertion of more AMPA receptors into the synapse, physically strengthening the connection between the two neurons. This molecular “wiring” of the neuronal ensemble is the physical substrate of the engram, forming a circuit that requires less effort to activate in the future. The hippocampus is a major brain structure where this process of initial engram encoding for new memories often occurs.
Accessing and Modifying Stored Memories
A memory is recalled when the original engram, the specific neuronal ensemble, is reactivated. This process demonstrates the sufficiency of the engram: activating the cells that encoded the memory is enough to retrieve the experience. Research has also shown that engrams are not static structures but are dynamic, undergoing a process called systems consolidation over time. During this process, the memory trace shifts from being dependent on the hippocampus to being stored in more stable, distributed circuits across the neocortex, typically during periods of sleep.
The existence and function of engrams are studied using advanced techniques like optogenetics, which allows scientists to control the activity of genetically modified neurons using light. By tagging the specific neurons active during a learning event (like fear conditioning in mice) with light-sensitive proteins, researchers can later shine a fiber-optic light into the brain to physically turn the memory “on” or “off.” Activating the tagged cells in a neutral context can instantly trigger the memory’s behavioral expression, such as fear-induced freezing, providing causal proof that these cells are the physical memory trace.
This ability to manipulate the engram has opened pathways for understanding and treating memory-related disorders. For example, by reactivating and modifying a fear engram, scientists are exploring methods to dampen the emotional response associated with traumatic memories, relevant to post-traumatic stress disorder (PTSD) research. The dynamic nature of the engram, particularly its instability upon retrieval, offers a window for therapeutic intervention, where the memory can be modified before it is restabilized, or reconsolidated.