In search of lost memories

Alzheimer's disease makes memories inaccessible

Kirill Stasevich, "Science and Life"

The main and one of the first symptoms of Alzheimer's disease is memory loss – a person first remembers the recent past, and then it comes to old memories. However, according to researchers from the laboratory of Suzumi Tonegawa at the Massachusetts Institute of Technology, memory in Alzheimer's syndrome is actually preserved, access to it simply disappears (“Lost” memories can be found). If we translate this into a computer-digital language, we can say that the path to the file disappears from memory, but the file itself is still there.

Professor Tonegawa is one of the most famous people in modern neuroscience, although he used to study the molecular genetics of antibodies, and even received the Nobel Prize in 1987 for the discovery of the genetic principle of antibody diversity. However, he subsequently switched to research on the cellular mechanisms of memory, achieving outstanding results here. Tonegawa and his team managed to identify in the hippocampus (which serves as one of the main memory centers in the brain) neurons responsible for specific memories – by manipulating the activity of such nerve cells, neuroscientists managed to turn bad memories into good ones, suppress depression by activating positive memories, and even make the brain remember what it forgot.

One of the most important results of Tonegawa's group was that they were able to confirm the existence of so-called engram cells in the hippocampus. An engram is understood as a trace left by an irritant; if we talk about neurons, then a repeated signal – a sound, a smell, a certain situation, etc. – should provoke some physical and biochemical changes in them. If the stimulus is repeated later, then the "trace" is activated, and the cells in which it exists will recall the entire memory from memory.

In other words, engram ("key") neurons are responsible for accessing recorded information, and in order for them to work, 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. That is, different structures are responsible for storing and activating memory – groups of engram cells take care of other nerve chains that store blocks of information, and neurons of activation can in some sense be compared with librarians who issue books on request.

In the experiments on memory restoration, which we wrote about last summer, it was just about the fact that the disappeared memories did not really disappear anywhere, just the "librarian" cells that are responsible for their storage lost activity – roughly speaking, fell asleep. And in order to restore memories, access to which is blocked, for example, with retrograde amnesia (the so-called violation of memory about what happened before some critical moment – for example, before a brain injury or before severe stress), you just need to wake up the necessary engram cells.

In experiments on mice, retrograde amnesia was arranged for animals with the help of a special antibiotic that weakens synapses – the interneuronal connections turned out to be fragile, and the cell chain functioned poorly: information about what happened before the drug was administered did not linger in the mice's head.

In a new article in Nature (Roy et al., Memory retrieval by activating engram cells in mouse models of early Alzheimer's disease), researchers report that it is also possible to regain memory in the case of Alzheimer's disease. In fact, there is nothing purely human in it, the same pathology associated with abnormal protein accumulations can be provoked in animals, and mice genetically predisposed to this neurodegenerative disease were used for new experiments.

Both of them were launched into a cage in which the mice were slightly electrocuted through the floor. A few hours later, the animals remembered that nothing good should be expected from the electrocellular, and when they were put back there, they froze in place, demonstrating the usual response to stress for rodents. However, after a few days, the memory of the electric shock was preserved only in normal animals. Those who had alzheimer's processes in their neurons forgot about the stress they had experienced – the type of cell did not include any unpleasant memories.

But if the engram cells responsible for this particular stressful experience were activated artificially, optogenetically, then in mice with "alzheimer's" memory woke up, and they, once in an electroshock cell, froze in place, like ordinary mice. It was also possible to show that the engram cells of mice predisposed to neurodegenerative processes form fewer dendritic spines – the so-called protrusions on the cell membrane in those places where a neuron can form a synapse, an intercellular connection with another neuron, and join the neural chain.

The "librarian" cells could not establish a sufficiently strong connection with the neurons of the entorhinal cortex, which would give them sensory "keys" related to a specific memory. Therefore, the appearance of the terrible cage did not impress the sick mice, although the unpleasant experience of being in it did not go anywhere from their memory. If constant contact between the entorhinal cortex and engram cells could be established – again without the help of optogenetic methods – then the memory returned to the animals completely, and even after a week they remembered when and where to be afraid, although then no memory stimulators were applied to them.

This leads to several important conclusions. Firstly, it was again possible to confirm the theory that memory deterioration may be associated not so much with the disappearance of the actual information, but with its inaccessibility.

Secondly, the engram cells, which help to find the right "file", control not only conditionally fresh memories that have just been formed, but also quite old ones.

Thirdly, in Alzheimer's disease – at least in its initial stages – the same "access problem" arises, so that the memory of patients, obviously, could be returned if we had a tool for activating the notorious engram cells. However, optogenetic methods that allow you to turn neurons on and off very accurately involve genetic modification of cells (briefly about the principles of optogenetics can be read here), and it is hardly possible to apply them to a person.

One can only hope that neuroscientists will be able to develop some clinical method that allows activating human neurons without complex genetic manipulations.

Portal "Eternal youth" http://vechnayamolodost.ru  21.03.2016