Carmen Sandi: “There is a causal link between mitochondrial function and rank in social hierarchy”

Can brain biology negatively affect an individual’s position in society? The answer seems to be yes – and the mitochondria (the cell’s batteries) appear to be an important player. Could this negative impact be reduced with drugs?

It has been shown that stress causes anxiety in anxiety-prone rats, making them less dominant, less competitive, than those that are, by nature, less prone to anxiety. But why is this so? Carmen Sandi set out to study the neurobiological basis of the link between anxiety and social hierarchy.

Born in Santander, Spain, Sandi trained in her home country and did her postdoctoral research both in France and the UK. She then worked in Spain for a few years, studying the relationship between stress and memory. In the mid-2000’s, she started her current line of research at the Brain Mind Institute of the École Polytechnique Fédérale de Lausanne, where she still works today.

When, a few years ago, this soft-spoken and rather shy woman first presented her work, showing that the link between anxiety and social rank lies in the way mitochondria (the cells’ batteries) function in a specific region of the brain, the result was received with scepticism. Today, it has become a well-established idea.

Sandi was in Lisbon a few weeks ago to give a talk at the Champalimaud Centre for the Unknown. We asked her a few questions about her work.

You study the way an individual’s propension to anxiety can affect his social status. How does this work?

Social dominance is a trait about which we know very little, and the way I have got into this topic is by trying to understand whether differences in anxiety could affect social dominance.

We found that individuals with low-anxiety personalities will normally continue to fight longer for themselves in a context of social competition, maybe because they are not so impaired by stress – whereas stress makes highly anxious individuals retract earlier. So yes, we think that anxiety as a personality trait can have an acute impact on where individuals place themselves in society.

Is anxiety as a personality trait reflected in the individual’s brain biology?

At the level of the brain, we have done many experiments in rats, now also some experiments in mice and a few experiments in humans. And what we see are differences in the nucleus accumbens, a very important structure for decision-making.

More specifically, there are differences in the function and the structure of the mitochondria of neurons in the nucleus accumbens depending on the anxious nature of individuals. We found that, in rats with low-anxiety personalities, the mitochondria work better, that they are capable of producing more energy.

We also showed there is a causal link between mitochondrial function and rank in social hierarchy. Indeed, when we pharmacologically inhibited the activity of the mitochondria, the animals lost in social competitions. But when we then boosted the function of the mitochondria with nicotinamide, which is a form of vitamin B3, this reduced or even abolished the disadvantage individuals with high anxiety have when they are competing. It made them more similar to the low-anxiety individuals.

What you are saying is that poor social achievement in competition may be due to an energy deficit in neurons of the nucleus accumbens?

That’s what we think. We are trying to understand why, so we identified some molecules that are important for the dynamics of mitochondria and that are expressed in lower levels. This also fits with differences in the structure, in the aspect of the mitochondria, which are mainly indicative of poor function.

And it might actually be possible to give some sort of vitamin to humans to make them, if not less anxious, at least less prone to suffer from stressful situations?

Yes, maybe to make them more self-confident. This is the way I see it. I think it’s a bit about how you compare with others in self-confidence, about how much you believe in yourself when you have to compete.

What are you currently studying?

Now I’m more interested in something beyond social dominance. We started looking at depressive-like behaviors, that are related to coping (when one has to make efforts on the face of adversity).

I am very interested in individuality. How is it that even if you started with the same genetics, you always end up with variability in behavior and traits that are very relevant not only for social organization, but also for everything else?

Mitochondrial function could be involved in some of the negative symptoms of depression?

Yes, in motivation and depression. We know already that mitochondria are affected in depression. There are also a few studies that suggest that anti-depressants have an impact on mitochondria.

Mitochondria seem to be at the center of many important neural processes…

Yes, they are becoming very important to understand these processes. But many neuroscientists are “synapse-centric” – that is, they tend to explain everything through [synaptic] plasticity, so they don’t like this idea.

The first time I presented our work – two years ago, maybe two years and a half – people were a bit angry at me, because they thought mitochondria are at the service of the synapse, and they couldn’t accept that there could be also differences in mitochondria that affect how synapses works. It’s not only one-way. But I think now the evidence is strong.

Were you interested in this topic right from the beginning of your career?

No, no. Before 2003, I was in Spain working on how stress affects memory. Then I moved to Switzerland and we started looking at how early-life stress could induce psychopathology or depression later in life.

We were using a predator odor to stress the animals, and we were a bit concerned that the odor would stay in the stressed animals’ fur and stress the other animals in the same cage.

We did some experiments to exclude this possibility, and what we  concluded was that maybe the reaction of other animals to a stressed one was not related to the odor, but to the strange social behavior we observed in the stressed animal.

This made me think that stress could make us behave so differently that this affected our social environment – a concept that had not been reported in the literature.

From there, we started a small project and slowly got into this stress and social behavior thing. In fact, it was a bit of a serendipity finding.



Ana Gerschenfeld works as a Science Writer at the Science Communication Office at the Champalimaud Neuroscience Programme



Edited by: Catarina Ramos (Science Communication Office).


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