Memory Can Be Rebuilt. Remodeling Neuronal Circuits Involved in Memories

The Neurobiology of Memory Lab, founded in 1984 in the Department of Neuroscience of UNAM’s Institute of Cellular Physiology studies how the brain stores and evokes memories. One of the biggest challenges for neuroscience is understanding how brain circuits work and, even more important, how we can intervene them to observe their impact in memory and its evocation. We have tools today such as optogenetics, an innovative technique that allows us to turn “on” or “off” specific neuronal circuits with great precision, while the brain completes any task.

Memory is one of the most valuable tools we have developed during evolution in order to survive. Many animal species depend on it to remember their shelters location or that of places where they may find food. For humans, remembering faces, places, and experiences is an essential part of our daily lives. That’s why, when someone loses the ability to recognize what is familiar or to distinguish the new—what we call reconnaissance memory—their quality of life could be seriously affected. These disorders, known as amnesic syndromes, can appear due to brain injuries or from neurodegenerative pathologies like Alzheimer.

HOW ARE MEMORIES STORED?
From the neurosciences point of view, memory is the process that allows us to keep a neuronal representation of something that is no longer present. Depending on how long this information is preserved, we distinguish short-term memory (minutes or hours), and long-term memory (days or years). A process called consolidation of memory is necessary for us to keep persistent information in the brain. This process allows to stabilize what has been recently learnt in a more durable memory (a long-term memory), thanks to changes in the links between neuronal circuits, both in the structural and the functional levels.

In the lab, we start from the idea that consolidating a memory requires physical changes in the neuronal networks. From many experiments, we have discovered that after learning experiences, neuronal circuits in key regions for memory—such as the hippocampus—can be reorganized. But this doesn’t occur every time; we only saw these changes when learning was intense and repeated; when stimulation was lighter, neurons didn’t reorganize. The most surprising finding was that these structural circuit changes were present not only in young animals, as it was believed in the past, but also in adult animals. This contested the traditional idea about the adult brain being less capable of physically changing with experience.

Later, working with other labs, we demonstrated something very hopeful: in animal models with brain alterations similar to those produced by the Alzheimer pathology, it is possible to revert memory problems, especially those related to spatial reconnaissance memory, through constant exposure to novel stimuli. This stimulation helped improve cognitive performance, and delay the advancement of symptoms. These discoveries have also been confirmed in humans, analyzed with non-invasive neuroimaging techniques.

MEMORY CAN BE UPDATED
As we will see, the combined use of new technologies and experiments with animal models keeps getting us closer to understanding how memory in the human brain works. Recently something truly interesting has been discovered: remembering is not simply “reproducing” an experience, when we evoke that experience, memory enters a labile or unstable state, which allows to modify it or update it if new information is incorporated (figure 1).

Figure 1. The Process of Memory

Memory has several stages. First, when we learn something new, that information is stored temporarily in the short-term memory. If consolidated, it passes to long-term memory. Later, when remembering (evoking) that information, memory can be unstable, which gives a possibility to update it: it can be intensified, partially modified, or even weakened until it disappears.

In our lab, after years of research on how memories are formed and consolidated, we have started to explore as well how they can be modified. We focus on memories associated with taste or visual stimuli recognition and we discovered that they adjust every time they are evoked. This characteristic allows the brain to update information previously stored, adapting it in a better way to environmental changes.

MODIFYING A MEMORY WITH LIGHT
For example, we were able to edit nice memories linked to a specific place through a process known as memory updating. To do so, we used an innovative technique that combines genetics and light: we introduced light-sensible proteins (opsins) in specific neurons, using vectors and genetical promoters that ensure they are expressed only in specific neurons. These opsins allow to accurately activate or inhibit neural circuits using light beams directed through fine optical fibers implanted in the brain. They are like miniature switches inside the brain!

Thanks to this technology, we activated a brain circuit that releases dopamine, a neurotransmitter associated with pleasure, generating a positive spatial memory: the animal learns to associate and prefer a place related to that pleasant sensation. This answer is comparable to the one produced when a place is associated with drug consumption. Understanding how this kind of memory is formed and updated is especially relevant when we talk about intense experiences, like the ones related to addictions.

How do we do it? We start from the base that memory is not stored in a single place inside the brain; it is the result of the integration of several neuronal circuits, each of them giving relevant information. We apply photoinhibition for this: we use light to selectively “turn off” one of those brain circuits that also connects with the region previously stimulated, that is, a convergent circuit where memory is integrated. This intervention is made during memory evocation, a moment when memory is more vulnerable. In doing so, we can unstable it and accelerate the disappearance of the preference response. In other words, when we interfere in the precise moment in which the memory is reactivated, we can modify it and make it disappear eventually.

MEMORY IS NOT STORED IN A SINGLE PLACE INSIDE THE BRAIN; IT IS THE RESULT OF THE INTEGRATION OF SEVERAL NEURONAL CIRCUITS

WHAT IF WE COULD CHANGE PROBLEMATIC MEMORIES?
Studies in animals show that the growing desire for drug consumption is associated with changes in brain circuits that regulate both gratification, and stress and anxiety. By comparing the preference for a place associated with the administration of an addictive drug, after one or 14 days of abstinence, it was seen that animals developed a deeper attraction to that environment associated with the drug after a longer period without consuming it. This indicates that in time anxiety linked to the pleasant memory grows.

Using photoinhibition, precisely muting the circuit coming from the insular cortex to the amygdale, we were able to reduce the exacerbated desire during the evocation of the pleasant memory (14th day) without changing the original memory of reward (1st day). These results show that it is possible to modify hard memories thanks to memory updating processes.

These discoveries have great potential: they could be applied to treat traumatic memories in disorders such as posttraumatic stress or to treat addictions, where pleasant memories generate desire even after long periods of abstinence. Clinical studies already show that some drugs or changes in the environment can make this memory “updating” easier.

As we have seen, neurosciences help us not only to understand the fascinating functioning of the human mind; they also allow us to discover mechanisms to truly improve people’s lives.

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