Paul J. Lucassen: How does our brain adapt to a changing and often challenging environment? How can we conceptualize brain plasticity in relation to (early) stress, nutrition, exercise, inflammation, and diseases such as depression and dementia?
Paul Lucassen leads the Brain Plasticity group at the Swammerdam Institute for Life Sciences at the University of Amsterdam. Following his biomedical training, he completed his PhD with Dick Swaab at the Netherlands Institute for Neuroscience in 1995, followed by a postdoc with Ron De Kloet in Leiden, after which he joined Marian Joels at UvA in 1998, where he was appointed full professor in 2011. His Brain Plasticity group aims to understand how our brain adapts to a changing, and often challenging, environment, studying the hippocampus, amygdala, and hypothalamus, brain regions involved in cognition, stress, homeostasis, and in various disorders. Plasticity is approached from the molecular, structural, functional, and behavioural levels, focusing on how brain plasticity is modified by lifestyle factors, including early-life stress, nutrition, inflammation, physical exercise, enriched environment, and psychoactive drugs, and on how plasticity is involved in metabolic and brain disorders such as TBI, depression, and dementia. A key interest is adult neurogenesis, a unique form of structural plasticity in which stem cells continue to produce new neurons in the adult brains of various species, including humans, and are involved in various aspects of brain function. Lucassen's group combines molecular, cellular, and omics analyses with in vitro and rodent models, human brain imaging, human postmortem brain, and cohort studies. He serves as WP co-lead of the Alzheimer consortium MODEM, co-recipient of the Urban Mental Health grant, and the ME/CFS consortium on chronic fatigue, and co-recipient of a Gravitation grant for the Institute for Chemical Neuroscience on molecular mechanisms underlying psychiatric disorders.
Part 1: Paul Lucassen – Life and Career Paul Lucassen
Where were you born, and where do you live now?
I was born and now live in Amstelveen, close to Amsterdam, a city I love, where I received most of my training and lived for over 12 years previously.
Could you give us a glimpse into your personal history, emphasizing the pivotal moments that first kindled your passion for science?
I guess I was a curious child all along, with loving, very supportive parents who frequently took us on bike rides to the Amsterdamse Bos (Amsterdam Forest) and the Artis Zoo, which may have sparked my interest in biology. As a kid, I loved to play in the woods and roam near the water's edge, catching fish, frogs, and salamanders. Also, I had a great Biology teacher in high school who not only taught the obligatory material but also provided us with much extra info on evolution, philosophy, science, and many aspects of life in general, sparking formative discussions. This broadened my horizons and triggered my interest in studying medical biology in Amsterdam later. In parallel, I witnessed up close one of my uncles, who gradually developed dementia and started to change in personality and display inappropriate behaviours. That unfortunate sequence of events piqued my interest in the brain and led me to select internships and, later, my PhD in that direction.
Citation: Brain Medicine 2025; 10.61373/bm025k.0140
Please share with us what initially piqued your interest in your favourite research or professional focus area.
During my biomedical training, there were various inspirational classes and (public) lectures by endocrinology professors Joos Joosse, Wijnand Geraerds and Dick Swaab, along with books from and talks by a broad group of experts, including former Brain Research editor Dominque Purpura, Dutch biologist/author Midas Dekkers, stress researchers Robert Sapolsky, John Cidlowski, Mary Dallman, and Bruce McEwen, and primatologist Frans De Waal. They opened an inspiring world of neuroscience that truly fascinated me. Can there be anything more interesting than the brain?
I did my PhD with Dick Swaab on the hypothesis that, similar to muscle, training of brain cells is good for them and helps them withstand the deleterious consequences of aging and dementia, a concept paraphrased as; ‘use it or lose it’. It was a very stimulating and fun time for me as well, during which I worked a lot with human brain material and participated in the nightly autopsies of the Netherlands brain bank. Afterwards, I did my postdoc on stress and depression with Ron De Kloet. Cell death was a popular theme then; according to the ‘glucocorticoid cascade hypothesis’, excess stress was thought to kill hippocampal neurons, which we studied in animal models for stress and human brains of depressed cases using markers for pathology or cell death. However, we could not find much support for it. Apoptosis is a rapid process and inherently difficult to study in thin tissue sections; also, the many different (molecular) types of cell death that have been identified, including, among others, necroptosis and ferroptosis, made me lose interest in that topic.
This went together with the pivotal realization for me that the hippocampal shrinkage reported after chronic stress, and its normalization after recovery or treatment, did not necessarily have to be caused by cell loss, which would have been hard to reconcile anyway with the fact that one can recover from stress or depression. An alternative is that changes in cell birth are also involved. At the time, I only heard very late that Rusty Gage would give a talk on that new topic at a small meeting nearby, so I booked a flight and the next day I was in London listening to his talk, which completely blew me away. We met and talked, and I returned to Amsterdam knowing that instead of cell death, I wanted to work on cell birth in my new job at UvA with Marian. Marian was very supportive of this new topic in her lab, and together with our first PhD student, Vivi Heine, who has recently become a professor of stem cell biology, and later Karin Boekhoorn, Charlotte Oomen, and Mike Marlatt, we started to study adult neurogenesis in relation to (early) stress, depression, Alzheimer's disease, and aging and have been working on it ever since. This later led o.a. to our ‘Eurogenesis’ consortium with people like Gerd Kempermann, Nora Abrous, Georg Kuhn, Henriette van Praag, Sebastian Jessberger, Alejandro Schinder and Nico Toni.
We would like to know more about your career trajectory leading up to your most relevant leadership role. What defining moments channelled you toward that leadership responsibility?
Following my postdoc with Ron de Kloet in Leiden, Marian Joels invited me to come to Amsterdam, where I could start as an assistant professor, working with a PhD student and a technician, and also I had to teach. This developed well, and it was delightful to work with Marian, a bright and efficient mind, and we had a good team together with Harm Krugers, Henk Karst, and several PhDs and postdocs. I learned a lot from her, and due to the close connections between Marian and Ron. We had frequent joint meetings, which expanded my horizon on stress as well as my network, allowing me to connect with great people from Leiden, like Melly Oitzl, Onno Meijer, Menno Kruk, Marcel Schaaf, Roel De Rijk, Nicole Datson, Maarten van den Buuse, Mathias Schmidt, Erno Vreugdenhil, and international stress and dementia researchers like Stafford Lightman, Jonathan Seckl, Joszef Haller, John Cidlowski, Gig Levine, Carmen Sandi, and many others.
Around 2009, Marian left UvA to become scientific director of the Brain Centre Rudolf Magnus in Utrecht. At the time, I had two offers from other labs and was considering leaving as well. However, that would have had severe consequences for the remainder of her group and for our joint teaching efforts. I was asked to stay, and together with the support of Wytse Wadman, two new neuroscience professor positions were created; one was filled by Marten Smidt, who joined UvA with his molecular neuroscience group, and one for me. I was then able to start my Brain Plasticity group in 2011.
What is a decision or choice that seemed like a mistake at the time but ended up being valuable or transformative for your career or life?
We all fail, and I am no exception, but I do not recall specific ones that became transformative. However, if I have to pick one, I guess my time at UPenn taught me not only how different and dangerous that place was compared to the average European or Dutch city, but also that the science there was lonely, internally competitive, not attractive, and certainly not better than what I knew from Dutch or EU labs. In hindsight, I found my time in the US not useful at all and you could say, in that way, it was a mistake, yet; A) it ‘cured’ me from wanting to do a postdoc in the US, and B) I learned that the so-called ‘value’ of doing a postdoc in the US, at the time considered to be very important for your CV and future positions, is in fact highly overrated and I have opposed the concept that it is essential ever since.
What habits and values did you develop during your academic studies or subsequent postdoctoral experiences that you uphold within your research environment?
The only thing that keeps you going is a genuine interest in, preferably a passion for, the topic, combined with efficiency and hard work. During my PhD and postdoc, I learned the value of the larger concepts and the importance of (innovative) techniques. In Leiden and back at UvA, I learned that ‘the devil is in the details’ and that a proper experimental design, with the right time line, appropriate readouts and controls, and extensive method optimization, is critical.
The joint meetings with Ron and Marian in the local pub in their hometown were transformative for me; together with several PhD students and PIs working on one topic, discussing science for a full day, plenty of time to cover all relevant details, and importantly, we all could think along and contribute; everything was on the table. No interruptions, no phone calls; focus and fun. A traditional ‘uitsmijter’ (a meat sandwich with fried eggs) for lunch, followed by a walk in the beautiful outdoors and drinks afterwards; so, so valuable.
Ron also taught me the value of organizations and networks, which were much less present during my PhD, as the NIBR was much more self-centred, and I focused on my thesis. Currently, I find it important that our group is well embedded in (inter-)national networks, which is paying off in terms of new knowledge, collaborations, visibility, joint grants, and papers. I also keep the in-depth discussions during our weekly group meetings and in the more dedicated project meetings.
Please tell us more about your current scholarly focal points within your chosen field of science.
The field of adult neurogenesis is never dull, with yet another fierce debate on its role and existence in humans. Building on classic histological approaches, we now move to more molecular tools, such as single-nucleus sequencing and machine learning. At the same time, imaging approaches are also being developed for in vivo analysis. As such, a new vision of the role of adult neurogenesis is emerging, as we discussed in a joint perspective in Cell Stem Cell (DOI: 10.1016/j.stem.2023.01.002).
Second, ‘programming’ of adult plasticity starts during early life, where both negative (often stress-related) and positive events (like increased maternal care) interact and modify the risk for later psychopathology, and interestingly, now also for (resilience to) dementia, a field I have a long standing experience in, also as past chairman of the scientific advisory board of the Dutch charity Alzheimer Nederland (see our Biological Psychiatry 2025 paper (DOI: 10.1016/j.biopsych.2024.11.007) on this and https://modemproject.nl), which I find an exciting new development.
Third, being able nowadays to apply innovative molecular (multi-omic) approaches on human postmortem brain tissue and combine that with machine learning on the donor records and the fantastic new tools from the chemistry field, leads to truly novel insights into mechanisms for several brain disorders, which we now study with Inge Huitinga (Netherlands Brain Bank), Mario van der Stelt, Bart Eggen, Inge Holtman and others (https://i-cns.nl).
What impact do you hope to achieve in your field by focusing on specific research topics?
With an organ as complex as the brain, I have learned to be humble and will not overestimate what can be achieved. However, I hope we, as a group, can contribute to a better understanding of the mechanisms underlying brain function and disease, and test whether brain plasticity can be leveraged as a tool for potential future therapeutic or preventive approaches.
What do you most enjoy in your capacity as an academic or research leader?
Working with such an amazing group of thoughtful, pleasant, and driven people: Aniko Korosi, Harm Krugers, Carlos Fitzsimons, Joram Mul and Rixt van der Veen, Marten Smidt, Cyriel Pennartz, Helmut Kessels, Anouk Schrantee, Liesbeth Reneman, Evgenia Salta, Inge Huitinga and Anne-Marie van Dam. I learn from them every day.
Training/teaching the new generation of young scientists and seeing many of them develop into successful PhD, postdocs, and Principal Investigators (PIs). As examples, former students of mine like Floor Stam, who became CEO of the Alzheimer company Remind, while Ludo van der Pol, Vivi Heine and Maaike Kempes have by now become professors; it simply makes me proud to see them do so well.
Being part of the exciting and fast-paced field of brain plasticity and Alzheimer's disease. In both fields I have now worked for over 20 years, with its promising new developments, diverse mechanistic and functional aspects, intense debates, and broader societal implications.
At Genomic Press, we prioritize fostering research endeavours based solely on their inherent merit, uninfluenced by geography or the researchers' personal or demographic traits. Are there particular cultural facets within the scientific community that warrant transformative scrutiny, or is there a cause within science that you feel strongly devoted to?
Diversity could be improved at multiple levels in academia. The ‘glass ceiling’ for women at many Dutch universities is embarrassing. Diverse teams work better, in my opinion, and we should not leave out the best brains; we should give everyone, regardless of sex, background, SES, and other factors, the option to do what they do best.
Teaching should be a priority for all researchers, not just those at universities. All too often, teaching is seen as a low priority by some, in part because the criteria for their promotion set by employers often focus on scientific output and grants alone. A flaw in the system; we all have a responsibility to train the next generation well.
The maddening bureaucracy surrounding academia, and in particular animal experiments, in Europe represents a vast, unseen, and discouraging process in terms of money, time, and effort for many, which is slowing progress in important areas and, de facto, driving talent out of science. Most worrying is that senior management is often unaware or unsupportive, allowing this to get worse. While developing alternative models such as iPSCs and organoids is valuable, it comes at the cost of reducing animal experiments. However, studies on behaviour, memory, the immune system, the gut, side effects, and many other critical areas cannot be done on cells in a dish. For many neuroscience-related questions, we are not there yet. Both alternative AND animal models need to be supported.
The current anti-science movement (‘science is just another opinion’) is worrying, as is our failure as a scientific community to communicate and involve the general public more effectively, and, from there, to help promote and defend rational thought and data-based decisions on societal issues.
Finally, the current funding system has too strong a focus on promoting individuality rather than team science, even though almost all breakthroughs nowadays come from (large) groups and consortia, where individuals contribute their expertise, together making the whole greater than the sum of its parts. In a scientific ecosystem where individuals need to become their own ‘brand’, ego's emerge, as do claims on ‘what belongs to someone’ and silly arguments on authorship positions, etc.; it takes away the incentive to work together, which I think we cannot afford to miss in our future studies of ‘the big problems’ we face as society.
Outside professional confines, how do you prefer to allocate your leisure moments, or conversely, in what manner would you envision spending these moments given a choice?
My wife and I are blessed with two beautiful daughters, and we have a fun dog (Figure 2). Spending time with, and in our case, taking care of sick family members, is a priority; ‘first things first’.
I have also always been a big fan of graphic novels and comic art, which provide sufficient distraction and relaxation between my science. Cycling and running further help clear my mind, recharge, with space to think and reflect.
Citation: Brain Medicine 2025; 10.61373/bm025k.0140
Part 2: Paul Lucassen – Selected questions from the Proust Questionnaire
What is your most marked characteristic?1
Persistence, drive, interest in (neuro)science, I try to remain stable and help others where I can.
Among your talents, which one(s) give(s) you a competitive edge?
I do not know if I have, or want to have, a talent for competition. I am passionate about the brain, interested in people, and like working together to get things done. Furthermore, I am mild-tempered and do not judge or get angry easily, which, in many cases, helps move things forward.
If you could change one thing about yourself, what would it be?
Be more efficient in combining my activities in a day, knowing that there is obviously a limit to that, and that self-care, relaxation, and disconnecting are important too; 'If you cannot give your life more time, give your time more life’. And then try again next time.
What is your current state of mind?
Happy with my family and my group, stimulated and challenged by my work, yet concerned about its future, given the current scientific ecosystem, future demographics, upcoming budget cuts, and geopolitical developments.
What is your idea of perfect happiness?
Getting things done, the absence of health issues, and the satisfaction that comes from helping others and seeing them grow.
What is your greatest fear?
That something (brain or physical) health-related happens to your loved ones.
What are you most proud of?
My wife and daughters have shown persistence despite frequent and tough health-related setbacks. The fact that our brain plasticity group and neuroscience master track are doing quite well.
What do you consider your greatest achievement?
Aside from my family, the fact that after Marian's leave, our group has survived and now grown to 6 great PIs, two technicians, and over 12 PhD students, is well-embedded in several large consortia and grants, and is doing quite well.
What is your greatest extravagance?
Comic art.
What is your most treasured possession?
Pages by Jordi Lafebre, Franquin, and Eisner.
Where would you most like to live?
Over the years, I learned that many things are actually well arranged in Holland, despite our endemic grumbling and complaining. Amsterdam is great; I am happy here.
What is the quality you most admire in people?
Intelligence combined with generosity, kindness, persistence, and humility.
What is the trait you most dislike in people?
Ego, arrogance, dishonesty, manipulative behaviour, narcissism, and overconfidence.
What do you consider the most overrated virtue?
Modesty.
What do you most value in your friends?
Their support, the fun and openness when we are together, and our shared history.
Which living person do you most admire?
First, I realize I have been very fortunate to have been trained by Dick Swaab, Ron De Kloet, and Marian Joels. I admire them for their dedication and, each in their own way, their different approaches to life and to science, their humour, and the energy they maintain, career-long, in whatever they do. Second, perhaps David Attenborough and Barack Obama.
Who are your heroes in real life?
My wife Anne-Marie, our daughters Sofie and Eva, and the PIs of our group.
If you could have dinner with any historical figure, who would it be and why?
Charles Darwin, to learn how, in his time, he could, based on the specimens he collected and with the limited means available, develop such an overarching theory.
Who are your favourite writers?
In the Netherlands, Belcampo, Nescio, Marten Toonder, Midas Dekkers, Bert Keizer, WF Hermans, Leo Vroman, Hanco Kolk, Rutger Bregman, Frans De Waal.
Internationally, Steven Fry, Timothy Snyder, Oliver Sacks, Richard Dawkins, Robert Sapolsky, Charles Darwin, Michel Houellebecq, George Orwell, Murakami, Bill Watterson, Bourgeon, Tom Gauld, Cyril Pedrosa, Herge, and Will Eisner.
Who are your heroes of fiction?
Tom Poes (Toonder), Bras de Oliva Domingos (Ba & Moon), Jerry Spring (Jije), Bernard Prince (Hermann), Jimmy Corrigan (Ware), Asterios Polyp (Mazzucchelli), and Craig Thompson (Blankets).
What aphorism or motto best encapsulates your life philosophy?
Lose the ego. Be kind. Stay curious. And for the rest? Use it or lose it (Figure 3).
Citation: Brain Medicine 2025; 10.61373/bm025k.0140
Paul J. Lucassen, PhD, University of Amsterdam, The Netherlands.
Paul with his family enjoying the great outdoors in Croatia.
Cartoon by the Dutch graphic artist Joost Veerkamp, drawn after Paul Lucassen talked about his work and tried to explain the ‘use it or lose it’ hypothesis of brain aging.
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