Natalie Ness is a 1st year PhD student working in Marco Brancaccio's group on her project "Glial interplay in the specification of circadian function and its dysregulation in Alzheimer’s Disease". Natalie has joined the lab under the prestigious Imperial College President PhD Scholarship.

 

February 2021

Dr Mathieu Nollet is a UK DRI Research Associate specialising in sleep and circadian rhythm. He is currently working in the lab of Professor Bill Wisden. 

Natalie: To start off, could you just tell me a bit about your career background and research?

Mathieu: Yes, of course. I did my PhD in France. So yes, I'm French. And I did my PhD in a medium-sized town called Tours. It’s in the middle of France, south of Paris.  I did my PhD in neuroscience and studied major depression using an animal model, and so very early in my career I was very interested by neuroscience and everything that is at the interface between psychology and biology. So working on major depression and in psychiatry was really interesting for me. 

After defending my PhD, I moved to the UK, this was in 2012. I started as a young Postdoc in the pharmaceutical company Eli Lilly and Company. This was a fellowship, so I wrote my own project. I worked with this company in partnership with the University of Surrey for four years. There, I continued to work on major depression using an animal model, the same animal model I was using in France, but this time I was working on sleep more specifically, studying sleep disturbances and whether we can reproduce some of the sleep changes that are observed in depressed patients.

After that, I moved to the Francis Crick Institute, where I worked for two years, investigating the link between circadian rhythm and sleep. In 2018 I moved to Imperial College and I am still working on sleep now but this time in relation to dementia. 

Basically, what we are trying to do is to understand if sleep disturbances can affect and predict some of the symptoms of dementia and the other way around. patients with dementia often complain about sleep disturbances and we want to understand: Why and how they develop sleep changes. 

Natalie: Are you working with human patients at all? Or are you mainly working with animal models?

Mathieu: I always worked with animal models. I'm not a clinician, and I think it's also a choice for me because I really like to understand the basic neuroscience of the disease and that is something that you cannot do in humans. Working with animals, you have drawbacks. I mean, you are working with animal models, so you never work with the actual disease and you always need to keep in mind that this is just a model. So what you are trying to understand is some specific mechanisms. But this is really what I like: to look into the details that are not available in human studies. 

Natalie: Have you found any interesting links between sleep disturbance and dementia symptoms so far?

Mathieu: Yeah, we are starting to have interesting results. It's a very time-consuming process, it's not an experiment in which after a few months you get the result. You need to wait until the animal gets older, so it's actually a long process, but we are now getting to an interesting stage. In the next few months, what we will try to do is to get a better understanding of the detailed mechanisms that explain why patients with Alzheimer’s Disease in particular, but in dementia in general, develop sleep disturbances. More precisely, which brain regions are responsible for these changes and how? And we also want to understand why some patients have sleep disturbances and other patients don't. This is really uncharted territory and we are here to try to get a better understanding of all the underlying mechanisms.

Natalie: Great, do you already have an idea what kind of pathways are involved in this relationship?

Mathieu: We have some good ideas about which brain region could be involved in the sleep changes. This is very complex because there's not only one pathway that is involved in sleep regulation. There's not only one region that is disturbed by dementia. There is a lot of biomarkers for dementia, so it's certainly not a single mechanism in one precise region that is involved, it's the interaction between many, many different processes. I think it will take a very, very long time to figure this out and what we really want to do here is to start to understand these mechanisms. I would say it will require many more people working on this subject and a lot of time to get a good understanding of what is going wrong in terms of sleep, and if treating sleep can actually prevent some of the symptoms. And if we observe sleep changes early in the development of the disease, can we also predict the symptoms that the patient will develop? This would help to provide a better diagnosis of patients, but it will take a long time.

Natalie: That's very exciting. You have recently published a review paper called ‘Sleep Deprivation and Stress: a reciprocal relationship’. Could you tell me a bit about this relationship?

Mathieu: Yes, so the gold standard method to study sleep is to use sleep deprivation in your experiment and to study the sleep recovery. Basically, because there's a sleep pressure that builds up when an animal or human is sleep deprived, there's sleep rebound after. So then, the mouse or the patient sleeps more and we can study the different aspects of this sleep recovery and it gives us some tools to understand sleep homeostasis and sleep in general. It’s very common to use sleep deprivation in sleep studies. But when you sleep deprive an animal or patient, it is difficult to avoid the stress associated with this sleep deprivation. It's easier to avoid this stress in humans compared to animals because for animals, the sleep-deprivation method itself can be stressful. We have different gentle strategies for depriving sleep in animals. Basically, when you see that the animal is starting to sleep, you can gently touch the animal or just move the cage a bit to wake the animal up. You also have automated systems, for instance with a moving bar at the bottom of the cage. All these methods can be stressful and that is something we really want to avoid because stress and sleep are linked and because it can interfere with your result. It is well documented that when we are stressed, we also have more difficulty falling asleep and sleeping, so I think it's really important to be aware of this connection between sleep, stress and sleep deprivation. And this is why we reviewed the literature and proposed some ways to avoid stress during sleep deprivation. In our laboratory, we developed a gentle way to sleep deprive an animal by introducing some novel objects in the cage. The animal is often interested in the novel objects and will naturally stay awake. You need to regularly replace the item to avoid any habituation. This review of the literature is the starting point of an additional aspect of my project that aims to make sure that when we are doing sleep deprivation, we avoid stress as much as possible.

Natalie: Yes, that sounds very important. So if stress affects our sleep, is there also an effect of sleep loss on stress or susceptibility to stress?

Mathieu: Yes, when you experience poor sleep then you are more susceptible to stress. It's bidirectional, stress can affect your sleep and bad sleep can affect your stress level. There is also an overlap between some of the mechanisms that regulate sleep and stress, especially in the hypothalamus. This is also interesting because in dementia, we also have this component of stress. In patients suffering from Alzheimer's disease or Parkinson's disease, there is commonly higher levels of stress, which could have different origins. For example, experiencing the disease can be stressful, but brain damages could also have an effect on the mechanisms that control stress. Studying stress in relation to sleep and in relation to dementia is something that we also study because it's very important.

Natalie: You just mentioned that you are in the process of developing a better mechanism for sleep deprivation that will reduce the stress component. Are there any other technological innovations that have aided the advancement of your field in recent years?

Mathieu: I would say many. I'm not a specialist in all of these new technologies, but I can mention optogenetics, chemogenetics and what can be done in terms of genome sequencing, for instance single cell sequencing. All of these new tools are just amazing. You can study a mechanism and find some pathological pathways in the brain and after that, you can really go deep into it, looking at very precise molecular mechanisms. All these new tools we are trying to use in our project by collaborating with other labs and people who are specialists in these techniques. It is really helpful to get a broad understanding of specific mechanisms. We are using a lot of these genetic tools in our lab. For example, we are developing what is called adeno associated viruses that can target very specific types of cells in the brain that you want to study. It is very effective and useful for deciphering and comprehending mechanisms that would have been impossible to understand without these new technologies.

Natalie: That’s fascinating. So what do you think are the biggest current limitations in sleep research or even in linking neurodegeneration and sleep disturbances?

Mathieu:  Well, there's many limitations, but in sleep research, one in particular is the scoring of sleep. Using electrodes we can record the electroencephalogram of the animal, which is the electrical activity at the surface of the brain. We also record the electromyogram, which is the muscle activity. You then have signals that you need to interpret and score to know whether the animal is awake or is entering different stages of sleep. At the moment, the gold standard to do this is to do it manually. Therefore, you need to spend hours and hours just scoring the electroencephalogram that you divide in small episodes of 5 or 10 seconds. For each episode, you need to decide if it’s non-REM or REM sleep or if the animal is awake, one-by-one for several days of recording. The time this takes is extremely long when you have a lot of animals and when you are doing multiple recordings per animal. There is no effective algorithm to automate this process at the moment. This is also something that we are trying to work on in our lab, to develop an automated system to score the sleep. But it is difficult so I would say that this is still a major limit for sleep research, it is extremely time consuming. 

Natalie: Yeah, I see, that is very complicated. Great to hear that you are working on this too.  You said that before joining the UK DRI, you did some research on sleep and mental health disorders, specifically depression. Could you tell us a little bit about how these are linked to sleep?

Mathieu: It’s amazing that actually sleep is everywhere. I mean, sleep is a very important biological mechanism and we sleep almost a third of our life, so it's not very surprising that lots of diseases have an effect on sleep and vice versa because when you have bad sleep, it has an effect on your health. It’s well known that patients suffering from major depression have very bad sleep. They have a very specific sleep pattern that is well described. And it’s also amazing that some research shows that by sleep depriving a depressed patient you can actually alleviate their mood and improve some symptoms of depression. So, again, we still don't really understand how it works and there is still some mystery there. We also know that most of the antidepressants affect sleep, and that some of the drugs used to treat sleep problems can improve some of the symptoms of depression. 

More specifically what I studied during my PhD was a particular type of neuron in the hypothalamus that secretes orexin, a neuropeptide that is mainly involved in sleep regulation. It is also involved in stress regulation, which is quite interesting. What we observed in our animal model of depression is that there is a major change in the activity of these neurons. Our lab and other labs as well discovered that by blocking the release of orexin by these neurons you can also improve the depressive-like symptoms of the animal. There are also some papers in humans now that show that by improving sleep you can also improve the health and mood of the patient. It’s not something that is well understood yet, but even if we don't understand it, the link is clear.

Natalie: That's very interesting. Is there any research pharmacologically targeting the orexin pathway? 

Mathieu: Yes, there are some drugs that directly target the orexinergic system and I think some of them have been tested on depressed patients. They were not tested as new antidepressants though. These pills are now prescribed for people suffering from insomnia. 

There's a lot of research about this neuropeptidergic system. They were discovered relatively recently, in 1998, and it appears that they play a major role in sleep regulation. They are not like other types of drugs like benzodiazepines or other drugs that act on the GABAergic system in the whole brain. These drugs only alter the functioning of a discrete population of neurons in the hypothalamus that expresses orexin. This is a more refined way to improve sleep, that's why researchers are very interested in this particular system.

Natalie: That sounds like it may be very promising for a lot of sleep-related diseases.

Mathieu: Yes it is, I would love to be able to have a look at this orexinergic system. If we can demonstrate that there is a clear mechanism linking sleep and dementia, then I would be very interested to see how improving or modifying sleep through this orexinergic system would affect cognitive symptoms and other symptoms of dementia. That could really offer new avenues of research. If by improving sleep you can also alleviate the symptoms of dementia, that could really improve the life of the patients and their carers.

Natalie: Yeah, that certainly sounds very promising. Finally, can I ask you what drives your passion for research?

Mathieu: Well, to be honest it's very exciting to be able to discover and work on something that has never been studied before. You are doing something that is new and nobody has ever looked at it before.  I think this is what keeps my passion alive. I can say that I still have a burning fire inside me which helps me continue to do research. But at the same time it's also very challenging because it's a lot of pressure. There is some competition and you also need to have a bit of luck. That’s also very important to acknowledge because you can be extremely bright and have a very interesting research project but if you don't get any positive results, it’s currently a problem. Unfortunately, in science, negative results are not as sexy as positive results. So, yeah, you work hard on your research project because it is interesting but you are not sure what you will get at the end. Hopefully you find something amazing and you are able to publish it. I'm still extremely interested by scientific research. It's a fantastic job. At the same time, I'm also aware that it's very difficult and very competitive. I am trying not to think about the long-term future, and try to do the best I can with the time I have for this particular research project. I think that it is my way to do it if I don't want to lose my motivation to do research, because it is a difficult job. 

Natalie: Yes, that's a very good point. Thank you very much for taking the time to do this interview. It was very interesting.

Mathieu: Thank you very much.