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The third element of the brain

Juan García Ruiz
March 18th, 2022 · 8 min read
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I am going to tell you a Spanish story of heartbreak. Once upon a time there was a brain ruled by an astrocyte and a neuron. Wait, wait, don’t close the article and stick with me for a bit, it’s getting interesting. The neuron was the center of attention, it was in charge of the communication between the different parts of the brain and between the brain and the rest of the organs. Thanks to the neuron there was movement, senses, consciousness and memory. The astrocyte was happy feeding the neuron, limiting the entry of intruders into the brain through the blood by forming a barrier (the blood-brain barrier), and it also had a say in communication. They were happy together, complemented each other and even depended a little on each other. Or so they wanted to make us think. A handsome young man named Ramón y Cajal, who was a private detective hired by the little astrocyte, appeared on the scene. Day after day he meticulously observed the brain. But there was nothing new under the sun. Here there was the neuron, over there was the astrocyte. Everything seemed in order. Wait a minute… It turns out there’s someone else! There’s a third one! That’s what he literally called it. “The third element.” The little astrocyte was shattered. There always has to be a third party! A little later, Cajal’s student named Pío del Río Hortega took over and devoted himself to a very close study of this third element, which he eventually called microglia. And so much for the romantic drama. Now let’s talk about serious (and much more interesting) things. Microglia, who are you?

Microglia speaking: I am a multifaceted cell, much better than the astrocyte. I am a doctor, and in my spare time I am a security guard. I keep an eye out for trouble, visit every nook and cranny of the brain looking for intruders with my many arms, and contact neurons to see how they are doing. When I detect a stranger, I literally eat it (function: phagocytosis). Other times I keep some of his clothes and show them to a friend who doesn’t mess around so he can identify and take care of him: the T-cell (function: antigen presentation). But I can also call other friends like leukocytes to come help me where there is trouble (function: pro-inflammation). I can also send everyone home when the battle is over (function: anti-inflammation). Wait, what do you mean? Are you saying that I am not unique and this can also be done by macrophages? Yes, but I can act much faster and I am more effective in getting to the right place (better spatio-temporal regulation). And contrary to macrophages, I don’t need to be constantly replaced. Since I am privileged to be in the brain, the organism cannot afford to send new microglia constantly, because the blood-brain barrier is quite selective with who gets through and who doesn’t. So I am able to maintain my status quo and proliferate locally when necessary. I also help neurons choose their friends. When I see that the communication between two neurons is no longer what it used to be, I put an end to it (function: synapse stripping). In short, I am there to watch over the health of the neurons when things go wrong, and when things go a little better, I make sure that it stays that way (function: homeostasis). But I’ll stop talking about me. I leave you with Agnès Nadjar, who has been very interested in my life and my role in obesity.

Agnès Nadjar is a neurosciences professor at the University of Bordeaux and is interested in studying the effect of nutrition on the brain in the context of obesity. She focuses on microglia, the immune cell of the brain. Agnes did her thesis in Professor Robert Dantzer’s lab on the interactions between the immune system and the central nervous system, which sparked her passion for microglia. She did a postdoc on the process of pathological neuroinflammation in Parkinson’s disease, and then she was recruited as an university lecturer and researcher in Bordeaux. She also set up a project with Philip Haydon at Tufts University (Boston) on the role of interactions between microglia and astrocytes in the sleep response to inflammation. When she returned to Bordeaux she joined the NutriNeuro laboratory to add a nutritional component to her neuroimmunology studies. Last year she joined the Magendie neurocenter where she is working mainly on obesity and neuroinflammation.

JGR: What are the main dangers of obesity on our health?

AN: Obesity is a major risk factor for diabetes, cardiovascular disease, neurodegenerative diseases, depression and certain cognitive deficits. Moreover, obesity is often accompanied by a decrease in physical activity and apathy. So it is both a physical and a psychological problem.

JGR: Obesity has reached epidemic levels. Between 1995 and 2000 we went from 200 million obese people to 300 million. What do you think caused this increase?

AN: It can be considered a pandemic. It is estimated that 30% of the world’s population is overweight and 15 to 20% obese. Why is this? There are several things. First, there was a major nutritional shift a little less than a hundred years ago with the consumption of refined sugar, one of the most obesogenic nutrients. There is also the emergence of the western diet: fast food, pizza, sugary drinks. Associated with this, there has been an increase in sedentary lifestyle. People do less sport and walk less during the day. So overall we move less and we eat bad food in large quantities and at any moment of the day.

JGR: You study obesity on a much smaller scale: cellular and molecular. First of all, what is microglia?

AN: Microglia is the immune cell of the brain. Its role is to maintain an optimal environment for neurons by detecting normal and abnormal variations in the brain and responding to them. This cell is particularly sensitive to nutritional variations and can detect very small changes thanks to the extensions it has around the cell soma. Depending on what it senses, it modulates its activity to protect the neurons and keep them in good shape. The problem is that sometimes the attacks they undergo are too strong and they can no longer protect the neurons.

JGR: How is microglia related to obesity?

AN: Obesity is certainly a disease of the brain rather than a disease of the body. When you look at the susceptibility genes for obesity, they are all linked to brain processes. One of the first things that happens when you eat too much fat and too much sugar is inflammatory activation in the brain produced by microglia. We saw that if we could prevent this microglial inflammatory activation, we could prevent weight gain in animals (to be confirmed in humans).

JGR: In addition to microglia, you’ve been quite interested in omega-3. What is its role in this context?

AN: Omega-3 is a protective lipid that can prevent microglial inflammatory activity, so it’s pretty good for the brain. The problem with obesogenic diets is that there is a major deficit of omega-3s and they contain bad fatty acids and carbohydrates, so the microglia will combine all this information and will lead to inflammation. The Mediterranean diet is quite good in this sense, because it contains vegetables, fruits, olive oil and fish. It has very little saturated fatty acids and it contains omega-3.

JGR: What does omega-3 do in our cells?

AN: The omegas are incorporated into the phospholipids that make up the plasma membranes of every cell in the body. Most of the omega-3 goes to the brain, which is a real pump for this lipid. There is a theory that proposes that the brain of homo sapiens sapiens is what it is since we started eating omega-3 (fish, seafood, etc.). These omega-3s helped build the membranes of the brain cells and they may have roles related to their fluidity and the mobility of the receptors. But these molecules can also be cleaved from the membrane and become molecular signals in the cell, controlling different signaling pathways.

JGR: What are the latest discoveries made in your team?

AN: The last paper we published that I’m particularly proud of was on the role of omega-3s in brain development. In particular, we studied the effect of a lack of omega-3, which is the case for almost the entire world population. We have seen that when there is very little omega-3 during development, the brain will not develop very well. For example, there will be fewer synapses. Why is this? If the microglia detects this lack of omega-3 it will set up an activity that is detrimental to the synapses. I mentioned earlier that omega-3 can leave the membranes and act as molecular signals. When omega-3s are missing in microglia, they are cleaved and the resulting lipid fragment will activate a cascade of events in the cell and will lead to phagocytosis at the synaptic level. These omega-3s will be missing in the microglia and in the neuron, but what triggers phagocytosis is really the absence of this lipid in the microglia. The consequence is that the neurons end up with less ability to connect with their neighbors and these animals show cognitive deficits when they grow up.

JGR: You have set up a start-up in the past. So research and entrepreneurship are not incompatible. Would you have any advice for young researchers who also want to develop a project?

AN: You have to remain very open. I was the first to say: I will never work in the private sector. And here I am, starting a company. I had lost a little faith in research, even if it didn’t last long. So I set up a start-up at the same time as my work as a teacher-researcher. I found it extremely rewarding. If people have the idea of going into the private sector or setting up a start-up, I would advise them to get training. At the University of Bordeaux, there are now training courses for doctoral students where students are made aware of entrepreneurship. This training is called UBcreate. Any student at the University of Bordeaux who has an idea for a business can contact this structure to find support, help in setting up the project or financing. We have a whole network of incubators in the region. I would advise people to get trained to start building a small network in the field and understand the mechanisms. I’ve discovered with entrepreneurship that the goal is never to make money, but it’s an intellectual process first. So I advise people to be very open to that.

JGR: Do you remember any advice you were given in research?

AN: The first one I was given was: never put off until tomorrow what you can do the day before. In a thesis, this is the secret of success. Another piece of advice I was given, which was very important to me since I have a rather atypical background, is: do what you want! It doesn’t matter what your background is as long as you can justify it to a recruitment panel, as long as you can make sense of it. In fact, I now spend my time analyzing the files of young researchers and I have realized that there is no real classic path, there is no royal road.

JGR: Do you have any scientific reading to recommend?

AN: When I chose to do my thesis with Robert Dantzer it was because I had read his book The psychosomatic delusion. I thought it was great, the fact that our behavior could be controlled by our immune system and vice versa.

JGR: Any final message for readers?

AN: Never listen to the doomsayers, the people who tell you that you’re not going to make it. You just have to do things, you have to go for it when you have a passion!

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