Origins of a memory
In August 1953, Henry Molaison underwent a ground-breaking surgery. Suffering from epilepsy since childhood, his seizures were becoming increasingly debilitating and the part of the brain where the seizures originated was to be surgically removed. The good news was that the surgery significantly reduced his seizures. The bad news — he had lost the ability to form new memories. Henry was 27 at the time and lived on to be 82 years old.
In trying to understand the reason for Henry’s memory loss, scientists began to unravel the fundamentals of memory formation and storage. With advances in neuroimaging techniques such as MRI, it became clear that the surgery had removed the seahorse-shaped part of the brain called the hippocampus and surrounding regions including parts of the amygdala. In combination with data from other patients with memory loss, the hippocampus was identified as the seat of new memory formation. The amygdala was found to be responsible for the emotional basis of memory, i.e., associating a particular memory with pleasant or unpleasant emotions. Although Henry’s case was pivotal in furthering our understanding of different kinds of memory (episodic, semantic, procedural, etc.) and the brain regions associated with them, when it came to dissecting and understanding the cellular basis of memory scientists turned to rodents.
Experiments in rodents began with the search for an engram — the physical trace of a single memory that is stored as biochemical changes in the brain. Scientists have developed clever tools to turn genes on/off at will, fluorescently label cells, and stimulate or inhibit specific neurons in the brains of mice. These tools were used to identify which neurons are involved in the formation of a single memory. Memory formation is known to increase gene expression in neurons, but which neurons specifically encode a single memory was not known. Therefore, special transgenic mice were engineered to produce fluorescence only in those neurons where gene expression increased in response to the memory formation. This fluorescent label would light up and help identify engram cells — neurons that encode a single memory.
But how do you ensure memory formation in mice? For this, scientists exploited the innate fear response that is present in all mammals. The genetically engineered mice were placed in a box and subject to mild foot shocks that were paired with a sound tone. The mice learned to associate the sound with the foot shock and froze even when the sound was delivered without a shock. This freezing behavior represented a fear memory. Neurons that encoded this fear memory to associate sound with pain were lit up by fluorescence. Using this method, scientists identified that specific neurons in the mouse hippocampus were involved in memory formation.
The next step was to determine whether these cells were merely involved in memory formation or whether they also contributed to memory recall. For this, scientists used a cool technique called optogenetics. They used light of a specific wavelength to activate only those cells that were previously fluorescently labelled and encoded the fear memory in mice. Mice that had previously undergone fear-conditioning with the sound and foot shock, were placed in a different box without any sound or foot shocks. Their engram cells were light-activated using optogenetics to summon the fear memory. These mice exhibited the same freezing behavior in the safe box even without the sound or the foot shocks! This elegant experiment showed that not only was the fear memory stored in the hippocampal engram cells, but these same cells were activated when the animal recalled the memory and were sufficient to alter their behavior.
This identification of engram cells that encode memory, although ground-breaking, is only the tip of the iceberg. Efforts are underway to further understand the memory formation and retrieval process and whether it can be manipulated to treat conditions ranging from depression to Alzheimer’s disease.
