Interview with Sonia Garel
Sonia Garel is a neurobiologist. Her work focuses on the interactions between the immune system and neural circuits, in a disciplinary field that has been booming in recent years, at the interface between neuroscience and immunology.
Since 2020, Sonia Garel has been Professor of Neurobiology and the Immune System at the Collège de France.
Your work on brain plasticity has led you to study, among other things, microglia - our brain's immune cells. What are their roles ?
Sonia Garel :When we think of the brain, we inevitably think of neurons. These very important cells convey information, enable it to be processed and ultimately do everything we're capable of doing. But the brain is home to a host of other cells, collectively known as glial cells. Among them, microglia are special because of their small size. Their origin is also very different from that of their neighbors, since they originate from the immune system and colonize the brain very early in embryonic development, around the fourth week of gestation in humans. For a long time, these immune cells have been the focus of much attention, in the context of neurodegenerative pathologies and inflammatory diseases. By attacking the brain, the immune system can cause or contribute to the development of diseases such as multiple sclerosis. However, when we looked at the development of brain circuits, we realized that microglia were involved in their construction. Microglia were discovered at the beginning of the 20th century. By observing them, the Spaniard Pío del Río Hortega, a pioneer in the field, realized their capacity for transformation. In the context of injury, inflammation or diseases such as Alzheimer's, these cells can transform themselves to protect and cleanse brain tissue against damage or accumulation, for example of amyloid plaques[1] in the case of Alzheimer's disease. For a very long time, these cells were thought to be all-purpose cells, and their change in activity a relatively uninteresting consequence of a pathological situation. Recently, however, at the beginning of the 21st century, it was noticed that mutations - in genes that only affected microglia in the brain - contributed to the risk of developing Alzheimer's disease. The potential role of these cells, or at least their dysfunction, in the development of pathologies was thus recognized. The field of investigation into microglia was re-launched.
This renewed interest in microglia and the understanding of their role in certain diseases is therefore at the origin of neuroimmunology, a new discipline at the interface between two disciplines, neuroscience and immunology, previously separated by a watertight partition ?
In fact, a number of factors came together. First, we understood that microglia were important in pathological contexts. Then, advances in imaging enabled us to show that they were constantly scanning the brain in physiological conditions, i.e. in the absence of disease. This incredible permanent basal activity of these cells is accompanied by an enormous energy cost, suggesting a real monitoring role. At the same time, other researchers were interested in what is known as the " immune privilege of the brain ". As this organ lies behind the blood-brain barrier, which regulates the passage of substances and cells between the bloodstream and brain tissue, circulating immune cells - which produce antibodies and are capable of an adaptive immune response[2], such as B or T lymphocytes - do not normally enter the brain. At the same time as they were working on microglia, a whole group of researchers were looking at what was going on in the meninges, the structures around the brain. There, they identified a multitude of resident immune cells producing molecules capable of acting on the brain and detecting what was going on there. Neuroimmunology - the interactions between the immune and nervous systems - has thus really taken off, thanks to a convergence of studies and projects. On a broader level, more and more studies are showing that physiological body signals can alter the functioning of brain circuits. In recent years, for example, there has been a lot of talk about the interactions between intestinal flora and the brain, which can be direct or via the immune system. These immune cells are like gateways to the modulation, functioning and construction of brain circuits.
How does the immune system influence brain development ?
Microglia influence the very early stages of brain circuit construction, for example by acting on certain neurons, known as inhibitors, which orchestrate circuit activity. More recently, we have understood that they are very important in maintaining tissue integrity in certain border regions between developing structures. They maintain cohesion in the brain during development. So, in their absence, we see lesions. A little later, they are also essential for modulating the formation, dynamics, activity and refinement of synapses - the brain structure that underpins learning. Initially, synaptic connections are made in very large numbers, then pruned, allowing circuits to be built and refined according to the electrical activity of the circuits. We always imagine that the brain follows a construction plan that will result in a functional organ in adulthood. In reality, as we can see from observing infants and children, the brain goes through several stages during which it functions in slightly different ways. In psychology, we speak of developmental phases, but physiologically, these also correspond to different wiring, maturation and circuitry. During these different phases, microglia are associated with different aspects : maturation and inhibition, then pruning of synapses. Thus, pathological inflammation during pregnancy or around birth could be a risk factor for various neurodevelopmental pathologies, in particular autism spectrum disorders. It's essential to remember that these disorders have primarily multifactorial genetic origins, but there may also be contributions from environmental factors. It is important to determine how these factors may act in combination with genetic factors. While this causality is difficult to establish, it is currently fuelling new avenues of research.
And conversely, does the brain influence the immune system ?
The question of the brain's role in modulating the immune system is a fascinating subject. Exceptional work is being done in this area. We're talking here about modulating factors that have nothing to do with consciousness ; just because you're strong-willed doesn't mean you won't get sick, or that you'll be able to stimulate your immune system in a controlled way. We need to understand this if we are to avoid potentially misleading interpretations of all this work. Today, we know that by stimulating certain brain regions, we can reinforce the immune response in peripheral cells, and there is a mapping of potential inflammatory responses. So, our brain knows what's going on when we're ill. This is part of its role in controlling, to a certain extent, all body functions.
How does the microbiota fit into this equation ?
It's quite complicated. There are direct modulations between the brain and the microbiota via the vagus nerve. There are also factors originating from the intestinal microbiota, which can act in the bloodstream or on the local immune system, which in turn can act at a distance on the global immune system, which in turn acts on neurons. So we have several entry points. We have observed changes in microglial activity linked to this microbiota, but there is still a lot to be clarified. This subject is of interest to everyone, as it echoes things we experience in everyday life, and which affect pathologies - neurodevelopmental, psychiatric - that affect a large number of people. Depression, for example, is associated with, and correlated with, immune disturbances. When you're ill, you're de facto in a state that's close to depression : you're apathetic, you don't seek out social interaction, you sleep a lot, you withdraw into yourself... This set of symptoms is what lets us know that someone is ill. So there are neuro-immune links in many psychiatric and neurodegenerative diseases. These neuro-immune interactions are therefore a source of hope that we need to cultivate. Above all, we need to put causal or correlative factors in their proper place. We're trying to understand what happens under different conditions, and then develop potential therapeutic approaches.
You originally obtained your PhD in developmental biology. What drew you to the emerging discipline of neuroimmunology ?
As is often the case in science, it was by following experiments and results - and - that I got here. I've always been fascinated by these subjects. Embryonic development is an exceptional process of self-organization. From a single cell, an entire organism is built, with all its complexity and multiple functions ! In the brain, this is particularly impressive, as cells transform, extend, connect at a distance and form circuits that relay information... Then, by looking at how these circuits self-organize, we realized that we had to look at all the cells present, not just the neurons. And quite naturally, we ended up looking at microglia, because this population of glial cells is present very early on in the brain. So it was through the developmental approach that we became aware of the importance of these neuro-immune interactions.
How is research evolving in a nascent disciplinary field, situated at the interface between two fields whose rich interactivity was previously little suspected ?
You have to be constantly renewing yourself, which is part of being a researcher. I particularly enjoy exploring new disciplinary fields, new techniques and new approaches. To do that, you have to collaborate, which is part of the richness of this profession. I quickly managed to find some remarkable collaborators from different fields, like Florent Ginhoux who is a developmental immunologist. We are fortunate to be tackling these issues at a time of flourishing technology, with cutting-edge imaging, the ability to see how a cell's genes are modified in vivo and to manipulate this genetic heritage directly in the cell to try and understand its role in the brain. These interactions are important at every level of fundamental and applied biological research. Without them, we couldn't move forward. Take the example of GFP (Green Fluorescent Protein), discovered in jellyfish. When inserted into brain cells, the fluorescence it generates enables them to be observed very specifically. This pure product of marine biology research has spin-offs that are not initially targeted and has applications in a wide range of fields. This cross-disciplinary approach to discoveries is vital for a frontier discipline like ours. It nourishes the breeding ground for scientific advances.
Since 2020, you have been teaching these concepts at the Neurobiology and the Immune System Chair at the Collège de France. What do you draw from this experience ?
Lectures at the Collège de France are an exceptional mission. Our lectures are free, and anyone can attend them or consult them on the Internet. It's also a challenge for the professors, because they have to prepare lectures that are representative of current research. They have to be cutting-edge, summarizing the latest articles published in the field and, at the same time, be as accessible as possible to a fairly wide audience. When I started talking about neuro-immune interactions at the Collège, I met a fairly diverse audience interested in this disciplinary field, with students in biology and medicine, but also former teachers and the curious who are interested in the brain, the immune system or pathologies... Teaching this knowledge at the frontier of different fields creates interactions between these communities, while disseminating this knowledge to a wider and more diverse audience. It's been as hard as it has been rewarding, because as teachers, it's up to us to find the right tone to convey notions in an intelligible way.
Interview by William Rowe-Pirra
Glossary
[1] Amyloid plaques : these aggregates of proteins and other substances form and accumulate around neurons in neurodegenerative diseases such as Alzheimer's.
[2] Adaptive immune response : when a pathogen (bacteria, virus) infects the body, the adaptive immune response is one which, based on the memory of past infections, is specifically directed against the intruder and is therefore more effective in eliminating it.
