How to recover lost memories 07.06.2015

Most often, when they talk about amnesia, they mean its anterograde or retrograde variety. It is easy to distinguish them: anterograde amnesia - a violation of memory about what happened after the onset of the disease; retrograde - impaired memory of what happened before the onset of the disease. Both can happen to a person due to a brain injury, or due to severe stress, or due to a severe neurological disease (for example, Alzheimer's syndrome). Obviously, the specific cause of amnesia is that some neurons related to recording and storing information, for some reason, stop working as they should. But what is the essence of these problems? Some (and most) defend the hypothesis that information is simply lost from neural circuits so that it cannot be recovered. Others believe that we are dealing with an access problem here, that the information is still in the brain store, but it has become blocked, and we cannot get to it.

Apparently, the hypothesis of blocked access is still true - the results of the experiments of Susumu Tonegawa and employees of his laboratory at the Massachusetts Institute of Technology speak in its favor. Tonegawa himself received the Nobel Prize in 1987 for the discovery of the genetic principle of the formation of antibody diversity, but then switched to cellular memory mechanisms. And here he and his colleagues achieved outstanding success. So, for example, just last year they released several papers in which they described how the brain remembers the sequence of events and how working memory is corrected when we suddenly realize that we did something wrong. Finally, in their Nature paper last year, they talked about reprogramming emotional memory: by influencing hippocampal neurons, the researchers were able to literally turn bad memories into good ones.

In 2012, Tonegawa's group was able to confirm the existence of engram cells in the hippocampus (one of the main memory centers). An engram is understood as a trace left by a stimulus; if we talk about neurons, then a repeated signal - a sound, a smell, a certain environment, etc. - should provoke some physical and biochemical changes in them. If the stimulus is then repeated, then the "trace" is activated, and the cells in which it is present will recall the entire memory from memory. In other words, our engram ("key") neurons are responsible for accessing the recorded information, and in order for them to work themselves, they must be affected by a key signal. But, in addition, such cells must be able to somehow preserve traces of stimuli. In practice, this means that intercellular synapses should be strengthened between engram cells: the stronger they are, the more reliable the signal will pass between them, the stronger the neurons will remember a certain stimulus. However, until recently, there were no experimental confirmations here - no one knew whether specific biochemical changes actually occur in such neurons associated with the memorization of a stimulus.

The researchers used the same methods of optogenetics that allowed them to confirm the very existence of "key" cells a few years ago. Recall that the essence of optogenetics is that a neuron introduces a photosensitive protein that forms an ion channel in the cell membrane: a light signal opens the channel, ions are redistributed on both sides of the membrane, and the neuron either "turns on" or "falls asleep", depending on what is needed in a particular experience. First, they found cells in the hippocampus of mice that turned on memories when they themselves were activated by light. These cells, as the authors of the work write in their article in Science, really strengthened intercellular connections - in other words, they together formed a neural switch, which, on a signal, opened access to a certain block of information. Increased intercellular contact means that the cell needs more proteins that serve the synapse, that is, everything rests on the process of protein biosynthesis. Synthesis in neurons was turned off with an antibiotic, and this was done immediately after the mouse memorized something. Synapses in this case remained fragile, and, most importantly, the mouse could not remember anything the next day when it was exposed to the same stimulus that was active during training. It turned out a real retrograde amnesia - the memory of what happened before the antibiotic treatment disappeared, and it was impossible to restore it with the help of ordinary stimuli.

But the same engram cells that were supposed to respond to a key stimulus and that were silent due to weakened synapses carried optogenetic modifications. And now, if they were activated with the help of a light pulse, then the memory of the animals returned. If we discard the details about special switch cells, synapses and protein synthesis, it turns out that neuroscientists restored memory with the help of a light flash to the brain.

But the emphasis should still be placed on engram neurons, no matter how strange their name may seem for unusual hearing. Previously, Tonegawa's laboratory was able to show that not just one cell is responsible for turning on memory, but a neural circuit of several such neurons. Based on the new data, the researchers propose the following diagram of how memory is organized in the brain of mammals (and, perhaps, in general, in most animals with a central nervous system). Its main point is that different structures are responsible for storing and activating memory - groups of engram cells take care of other neural circuits that store blocks of information, and activation neurons can in some sense be compared with librarians lending out books on demand. Moreover, the relationship between activation neurons and storage neurons can be different, for example, one activating network can act on several memory units at once, and specific relationships between those and others still need to be studied properly.

Of course, this does not mean that the deterioration or loss of memory is only due to malfunctions in engram cells, problems can begin in the "main storage" as well. However, from a practical point of view, it is still useful to know which nerve cells need to be acted upon in order to restore long-forgotten memories, because it may be that the memories themselves have not gone away, you just need to “wake up” the cells that are responsible for them.