Two American teams of researchers, one at the Massachusetts Institute of Technology led by Susumu Tonegawa and a second one under Mark Mayford of the Scripps Research Institute in La Jolla, Calif., exploited this standard test to manipulate the engram for this scary event. Part of the engram is found in the dentate gyrus (DG), a substructure of the hippocampus, in the M.I.T. study, whereas the Scripps study did not specify the location of the engram. Shocking an animal in one context will activate a small subset of DG neurons, around 2 to 4 percent. A different context will be encoded by a separate sparse group of DG cells. The electrical activity in these cells triggers the expression of a small number of so-called immediate early genes.
Both groups used mice that were genetically manipulated so that the increased production of one of these genes within a particular time window triggers a cascade of cellular events that ultimately leaves a permanent molecular tag on the cell that can be made to glow. This labeling allowed the experimentalists to later identify and reactivate the same set of previously firing neurons using either beams of blue light introduced via fiber-optic cable (the M.I.T. group) or delivery of a drug not naturally present in the animal (the Scripps group). These manipulations—deep-brain stimulation on steroids—are made possible by the fantastic marriage of three technologies: pharmacology, optical stimulation and molecular biology [see “Playing the Body Electric,” by Christof Koch; SCIENTIFIC AMERICAN MIND, March/April 2010].
Now I will concentrate on the findings from M.I.T. They had a group of mice explore one particular environment (let's call it A). Later on, bombarding the DG with blue light triggered the minority of neurons that had been active while the rodents were getting used to this context. A few days later the same animals were placed into a new context—cages that looked and smelled different (environment B)—while they were electrically shocked. This robustly activated DG neurons that were furiously encoding anything and everything about this obviously dangerous place so that the mice could avoid it in future. As in all these transgenic mice, the activity molecularly labels these cells for subsequent reactivation.
In the crux of the experiment, the rodents were dropped into the neutral environment A that they had no cause to fear. Indeed, without blue light these animals did not show any freezing. Yet in a beautiful confirmation of the power of optogenetics, when the blue light was turned on, the mice froze! Triggering the neurons that encoded environment B, including its association with the painful shock, induced the memory and made the mice cower in expectation of something bad about to happen. That is, neural circuits in the dentate gyrus of the hippocampus wired up to express an aversive event that happened at B are sufficient to evoke the associated aversive memory, even though the subjects never had experienced anything bad in A. It is an artificial memory—think Total Recall—but to the mice it appeared real enough that they went into their defensive crouch.
This experiment proves that activating on the order of 10,000 interlaced neurons in one very specific region of the brain is sufficient for a specific memory, its engram. Whether these circuits are also necessary for this memory, that is, whether deleting these neurons will remove the memory—shades of Eternal Sunshine of the Spotless Mind—remains to be determined (soon).
Let me end with another evocative quote from a film that routinely tops the list of the best science-fiction movies ever. I leave it to you, esteemed reader, to discover its source. It is a death soliloquy that speaks to the clarity and lucidity of memories, real or false ones:
I've seen things you people wouldn't believe. Attack ships on fire off the shoulder of Orion. I've watched c-beams glitter in the dark near the Tannhäuser Gate. All those moments will be lost in time, like tears in rain. Time to die.