The term engram was coined by the little-known but influential memory researcher Richard Semon.
Karl S. Lashley's search for the engram found that it could not exist in any specific part of the rat's brain, but that memory was widely distributed throughout the cortex. One possible explanation for Lashley's failure to locate the engram is that many types of memory (e.g. visual-spatial, smell, etc.) are used in the processing of complex tasks, such as rats running mazes. The consensus view in neuroscience is that the sorts of memory involved in complex tasks are likely to be distributed among a variety of neural systems, yet certain types of knowledge may be processed and contained in specific regions of the brain. Overall, the mechanisms of memory are poorly understood. Such brain parts as the cerebellum, striatum, cerebral cortex, hippocampus, and amygdala are thought to play an important role in memory. For example, the hippocampus is believed to be involved in spatial and declarative learning, as well as consolidating short-term into long-term memory.
In Lashley's experiments (1929, 1950), rats were trained to run a maze. Tissue was removed from their cerebral cortices before re-introducing them to the maze, to see how their memory was affected. Increasing the amount of tissue removed degraded memory, but more remarkably, where the tissue was removed from made no difference.
Later, Richard F. Thompson sought the engram in the cerebellum, rather than the cerebral cortex. He used classical conditioning of the eyelid response in rabbits in search of the engram. He puffed air upon the cornea of the eye and paired it with a tone. (This puff normally causes an automatic blinking response. After a number of experiences associating it with a tone, the rabbits became conditioned to blink when they heard the tone even without a puff.) The experiment monitored several brain regions, trying to locate the engram.
One region that Thompson's group studied was the lateral interpositus nucleus (LIP). When it was deactivated chemically, the rabbits lost the conditioning; when re-activated, they responded again, demonstrating that the LIP is a key element of the engram for this response.
This approach, targeting the cerebellum, though successful, examines only basic, automatic responses, which almost all animals possess, especially as defense mechanisms.
Studies have shown that declarative memories move between the limbic system, deep within the brain, and the outer, cortical regions. These are distinct from the mechanisms of the more primitive cerebellum, which dominates in the blinking response and receives the input of auditory information directly. It does not need to "reach out" to other brain structures for assistance in forming some memories of simple association.
An MIT study found that behavior based on high-level cognition, such as the expression of a specific memory, can be generated in a mammal by highly specific physical activation of a specific small subpopulation of brain cells. By reactivating these cells by physical means in mice, such as shining light on neurons affected by optogenetics, a long-term fear-related memory appears to be recalled.
Another study used optogenetics and chemogenetics to control neuronal activity in animals encoding and recalling the memory of a spatial context to investigate how the brain determines the lifetime of memories. The results found by the researchers have defined a role for specific hippocampal inhibitory cells (somatostatin expressing cells) in restricting the number of neurons involved in the storage of spatial information and limiting the duration of the associated memory.
In 2016, an MIT study found that memory loss in early stages of Alzheimer's disease could be reversed by strengthening specific memory engram cell connections in the brains of Alzheimer mouse models.
In June 2017, a study at Lund University, Sweden, demonstrated that an individual cerebellar Purkinje neuron is in a sense “programmable,” and can encode a temporal response pattern.