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Neuropharmacology

The chemistry of memory

Dopamine, a neurotransmitter associated with reward, controls the duration of memories

One of the leading international research groups involved in studies on memory performed tests on rats and unveiled the biochemical phenomena linked to the persistent storage of memories. The group also showed that the fixation of memory is relatively independent from its acquisition: it is necessary for a person to be exposed to a situation to remember it, but the fact that it has been memorized does not mean it will be remembered for long.

In rats – and very probably in human beings – memories that linger on for long periods of time, sometimes during an entire lifetime, involve the activation of a deep region in the brain: the ventral tegmental area, as demonstrated by the team coordinated by neuroscientist Martín Cammarota, from the Catholic University of Rio Grande do Sul/PUC-RS, in an article published in the August 21 issue of Science. In rats, this region contains 25 thousand neurons, while in humans this region has 450 thousand. This area, which is only a few millimeters thick, is the main producer of the dopamine neurotransmitter in the central nervous system.

In partnership with Jorge Medina, from the University of Buenos Aires, Cammarota, Janine Rossato, Lia Bevilaqua and Iván Izquierdo prepared a series of tests to study how memory is stored. They submitted different groups of rats to two kinds of training. In one kind, the rats were placed on a platform inside a cage and received a subtle electric discharge while going down to explore the environment. This experience, which provokes a mild shock, is usually remembered for a couple of days – the animals forget the shock and go down the platform again if the test is repeated two or three days later – a sign that the memory was not fixed. In the other kind of training, which leads to the persistent registration of the memory, the animals were given a discharge that was twice as strong when they left the platform. They remembered the disagreeable experience two weeks later, a long time for rodents, equivalent to some years for human beings.

Fixation
Between a few minutes and 12 hours after the training, the researchers injected a compound that prevents the action of dopamine, and then a pharmaceutical compound that simulates the effect of this neurotransmitter into the rats’ hippocampus, the region of the brain linked to the storage of memory. The neutralizing of the dopamine allowed the rats to remember the shock two days after the initial training. But it prevented them from remembering the bad experience in the following weeks. “This result shows that the formation and persistence of memory are distinct processes,” explains Cammarota.

The pharmaceutical compound which simulates the action of the dopamine transformed volatile memory into lingering memory: the rats remembered the shock up to two weeks later. But this only happened when the compound was given 12 hours after the training, suggesting that the persistence of the memory is defined half a day after a given experience.

Tests with other compounds also showed that memories do not linger unless the ventral tegmental area, which produces the dopamine, is activated. The activation of the neurons in this region releases dopamine in the hippocampus. In the hippocampus, the dopamine stimulates the production of the brain-derived neurotrophic factor (BDNF), which triggers the synthesis of the proteins that fix the memory. None of this occurs without the activation of the tegmental area right after the training. “The immediate activation, which happens when the brain identifies an important event, is essential for the reactivation of this circuit 12 hours later and for the storage of memory,” says Cammarota.

There are still many doubts about this process. No one knows why the decision to preserve or discard the memory only occurs 12 hours after learning, if it is possible to modify the memory at other moments, nor if this phenomenon, observed when awakening a disagreeable memory (the shock), also holds true for remembering pleasant events. But this discovery will make it possible to develop compounds that act on the dopamine and help fix memories in people with diseases that affect the ability to remember. This finding also opens the way for a new understanding of drug abuse. “Drugs such as cocaine increase the level of dopamine in the brain; dopamine is responsible for feelings of pleasure and reward,” Cammarota explains. “It is possible that an imbalance in this system leads the user to remember the agreeable effects and forget the bad ones.”

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