Carmen Sandi is a professor of neuroscience at the Swiss Federal Institute of Technology Lausanne (EPFL), where she heads the Laboratory of Behavioural Genetics at the Brain Mind Institute. On 3 October 2021, Carmen Sandi will present her plenary lecture at the 34th ECNP Congress entitled “A metabolic nexus between anxiety and low motivation”.
ECNP Press Officer Tom Parkhill caught up with her to discuss why we respond differently to challenges.
Notre humeur met le prix à tout ce qui nous vient de la fortune. Our temperament decides the value of everything fortune bestows on us.
La Rochefoucauld, Maximes 47 (1665)
The first question is inevitably about COVID. What’s changed?
The travelling, and working from home. I had COVID at the beginning of the pandemic, in March last year. I wasn’t badly affected, but I had a high temperature and fatigue. Better not to get it!
You are Spanish, but you work in Switzerland, how did this come about?
My partner is Swiss. I had a position in Madrid, but when I could take a sabbatical I was able to take a position in Berne. While I was there I learned that they were setting up a new institute in Lausanne. So I came for a kick-off meeting, and some colleagues invited me to give a seminar. It turned out that they were recruiting and, eventually, I was offered a position. This was in 2003, so I’ve been here more than 17 years. I’m settled here now, and I’ve taken Swiss nationality.
Your presentation at the ECNP Congress is entitled “A metabolic nexus between anxiety and low motivation”. How did you end up in this field?
I had a feeling that there would be a metabolic basis to problems in motivation or differences in motivated behaviour. Motivation is a reflection of the energy that one puts into working towards something one wants. It’s the vigour of the response, a decision between not investing resources or “going for it”. Of course, in neuroscience now we are dissecting the circuitry of motivation, emotions, etc., and we are interested in understanding individual differences, not just what is the circuitry, but why we sometimes engage the circuitry and sometimes not. What can explain these individual differences, and what can make it malfunction when there is psychopathology? When we look at how individuals relate to motivated behaviour, one of the factors that we have seen the importance of is anxiety. We all have different levels of anxiety, and those who tend to be more anxious are more vulnerable when faced with a challenge – they tend to give up earlier. When stressed they tend to develop more passive coping mechanisms, instead of more active.
I thought that perhaps if we looked at differences in mitochondrial function in the neural circuits that are involved in motivated behaviours, we might find differences. It was difficult to tackle this, because it’s technically very challenging; people who were looking at mitochondrial function normally looked at the liver or similar organs where you can get a lot of tissue. Of course, these circuits we are investigating are tiny, you get very little tissue, very little protein, and of course few mitochondria. In fact, when we approached possible collaborators, they were a bit sceptical and gave us the protocols for liver! So we had to adapt the protocols to tiny amounts, and this took us some time.
There were also sceptics who said that, in order to see differences at that level, you would need a genetic knock-out. We started with rats which were classified as either high anxious or non-anxious, and we found that highly anxious rats were more sensitive to stress and showed deficits in motivated behaviours. We probed mitochondria in the nucleus accumbens – a brain region critical for motivation and effort exertion – of anxious and non-anxious rats, using different substrates to look at the maximal respiratory capacity. Those that were highly anxious had lower maximal respiratory capacity, which meant that there are indeed differences; this gave us a first sign that we could look for possible mechanisms. We began to manipulate the activity of mitochondria in the nucleus accumbens and found this could impact the outcome of social competition, for example, or tests related to motivated behaviour. This gave us the impetus to go forward.
So manipulating mitochondria produced a behavioural result?
Yes, but we needed to work with care and use low doses of inhibitors, otherwise you can produce cell damage. Of course, now we have gone much further, but that takes us away from your question on how we got started.
Indeed. So where are you now, what will you talk about when you come to the ECNP?
Neuroscience is my field, but the ECNP has a greater clinical emphasis.
So are you a scientist or a clinician?
I’m a neuroscientist. Of course, I’m interested in finding treatments, but I work more at a basic level. And now we have started combining animal and human studies, so we can go from the molecular level in animals, to metabolic levels, and imaging, in humans.
And then, of course, we use the intermediate step of using imaging in animals. What we’d like to do is to discover key targets, and I think we are quite close to that. We have some nutritional treatments which we believe can have some impact on improving motivated behaviour, but also the capacity to endure and the capacity to reduce fatigue. I’m hoping that these pathways are going to reveal mechanisms and also targets for all these disturbing situations and conditions.
So you see it as being very practical work. It’s not completely blue-sky research.
Yes that’s right. Nowadays it’s very difficult to do blue-sky research. This is a new field, and I’m very curious to look at brain metabolites – we can do this. We also need to look at metabolites in other brain regions, that will allow us to discover new links.
I find it interesting that you are talking about nutritional, rather than pharmacological treatments.
Nutrition has advantages from a clinical trial viewpoint. I’m not against looking for pharmaceutical treatments, it’s just that it’s more difficult.
What’s the scale of the issue, who do you think your work might be able to help?
Motivated behaviour has different components. There’s an active component, trying to approach rewards, and another component, which is when we go through adverse conditions, and when we need to keep trying to get out of that adversity. These situations can be demanding, and some individuals give up, even if they are trapped. They just don’t try to get out. Motivation is one aspect, but we also have those individuals who simply get tired very quickly, or who get very anxious and stressed.
A lot of work we are doing in animals is to give them tasks, and then rather than just analysing traditional task parameters, such as, for example, how many responses are needed to get a reward, we apply computational modelling, so that from the task data we can extract critical functions, such as sensitivity to incentives, sensitivity to costs, or fatigue. We can see individual differences in effort and endurance, and we can map these back to the metabolites we are measuring in the brain. We’re still finding out how far we can go in mapping metabolism to specific functions. With humans, in addition to experimental tasks, we use a lot of questionnaires. We can see if a person is highly energetic – some people have always been active, others less so. Fatigue is another factor; many have conditions leading to high fatigue.
You’ve been President of FENS. What were the difficulties and challenges, and how do you see FENS working with other organisations – like the ECNP?
FENS and ECNP are very complementary, and I always thought we could do more together; for example, something like back-to-back meetings. I’m very committed to the climate, and this would mean that we could travel less – I often go to both meetings, and this would mean that I’d only travel once. And it would be good to have a dialogue between delegates attending each of these conferences. There is some overlap, but the meetings are very complementary, with more clinicians in the ECNP and more basic scientists in FENS. It would be good for the ECNP to interact with basic scientists, and what FENS needs is a greater translational component, where ECNP can help. I became FENS President in 2018, following our Berlin meeting. The society was booming, the quality and critical mass was very positive. It was a pleasure. The problem is how we evolve, especially the FENS Forum, which is a main focus for FENS. For the 2020 Forum, we invited FENS member societies to hold mini-conferences at the Forum, which brought important “bottom-up” contributions. The main challenge in 2020 of course was the pandemic, which meant that we couldn’t go to Glasgow last year.
I’m from Glasgow myself, so I can share the disappointment a little. If you could plot a way forward for your work, what would the plan include?
I’d love to have some clinical impact, which is perhaps possible with our current focus on nutritional approaches. But at the same time, the scientist in me wants to understand how it would work: to combine the application with the basic science.
PL.01 – A metabolic nexus between anxiety and low motivation
Sunday 3 October 2021
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