Does the "use it or lose it" principle determine brain plasticity and shape how we age?

AMSTERDAM, The Netherlands, 2 December 2025 -- In a revelatory Genomic Press Interview published today in Brain Medicine, Dr. Paul Lucassen, full professor at the University of Amsterdam and leader of the Brain Plasticity group, shares his scientific journey that helped transform our understanding of how adult brains adapt to challenge and change. His research, spanning topics like apoptosis, neurogenesis, (early life) stress, rodent work, human brain tissue and diseases like depression and dementia, carries implications for those affected by these disorders globally.

From Dementia Bedside to Neurogenesis Discovery

The spark for Dr. Lucassen's career came from an unexpected source: watching an uncle gradually succumb to dementia. "That unfortunate sequence of events piqued my interest in the brain," he recalls. What followed was doctoral research with Dick Swaab at the Netherlands Institute for Neuroscience, investigating a deceptively simple hypothesis.

"I did my PhD with Dick Swaab on the hypothesis that, similar to muscle, activation and ‘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'," Dr. Lucassen explains. Those years proved formative, involving animal studies and work on human brain material including participation in the nightly autopsies of the Netherlands Brain Bank in Amsterdam. The question of whether neurons could be protected through activity would shape everything that followed.

A pivotal moment arrived during his postdoctoral work on stress and depression. The prevailing theory held that chronic stress could kill hippocampal neurons through glucocorticoid toxicity. But the evidence refused to cooperate. "We could not find much support for it," Dr. Lucassen admits. The realization that hippocampal shrinkage after stress could normalize with recovery suggested something else entirely: perhaps also changes in cell birth, not just cell death, were involved.

A Flight to London That Changed Everything

Learning almost too late about a talk by Rusty Gage on adult neurogenesis, Dr. Lucassen booked a flight and found himself in London the next day. "It completely blew me away," he recounts. ‘The discovery that stem cells continue producing new neurons in adult brains represented a paradigm shift for me’. He returned to Amsterdam determined to abandon his cell death research and pursue (adult) cell birth instead.

With colleague Marian Joels and their then first PhD student Vivi Heine, who has since become a professor of stem cell biology, the team began investigating adult neurogenesis in relation to stress, depression, Alzheimer's disease and aging. This work eventually led to the Eurogenesis consortium, connecting researchers like Gerd Kempermann, Nora Abrous, Georg Kuhn, Henriette van Praag, Sebastian Jessberger, Alejandro Schinder, Nico Toni and others. With Liesbeth Reneman, Anouk Schrantee and Mirjana Maletic-Savetic, he works on detecting neurogenesis in vivo, and another topic, as discussed with Evgenia Salta in Cell Stem Cell in 2023, is whether factors that promote neurogenesis can offer protection against neurodegenerative conditions, like Alzheimer’s.

This interview exemplifies the transformative scientific discourse found across Genomic Press's portfolio of open-access journals, enabling researchers worldwide to share discoveries that reshape how we understand brain health. More information is available at: https://genomicpress.kglmeridian.com/

Early Life Programming and Later Resilience

Dr. Lucassen's current work focuses on understanding how adult plasticity is involved in human disease and how it is "programmed" during the period of early life. Both negative events, often stress-related, and positive experiences, like increased maternal care, interact to modify risk for later psychopathology. Intriguingly, early life programming may also extend to dementia resilience, a finding his team discussed in Biological Psychiatry in 2025.

"With an organ as complex as the brain, I have learned to be humble," Dr. Lucassen reflects. Nevertheless, he hopes to contribute to a better understanding of the mechanisms underlying brain function and disease, testing whether brain plasticity can be leveraged for therapeutic or preventive approaches. In the MODEM consortium on dementia, and via collaborations through the Institute for Chemical Neuroscience, innovative molecular and multi-omic approaches are tested in rodent models and applied to human postmortem brain tissue where they will be combined with machine learning of the patient data, which he hopes will yield novel insights into the mechanisms underlying neuropsychiatric symptoms.

Beyond the Laboratory: Comic Art and Scientific Culture

The interview reveals a scientist who finds balance through graphic novels and comic art, with treasured original pages by Lafebre, Franquin and Will Eisner. Cycling and running help clear his mind, providing space for reflection. His life philosophy crystallizes into four phrases: "Lose the ego. Be kind. Stay curious." And of course, the principle that launched his career: "For the rest; use it or lose it."

Dr. Lucassen voices concerns about challenges facing science: the glass ceiling for women in Dutch academia, bureaucracy surrounding animal experiments that drives talent away, the anti-science movement dismissing research as "just another opinion," and funding systems that promote individuality over the team science necessary for tackling complex problems. "Almost all major breakthroughs nowadays come from large groups and muti-disciplinary consortia," he observes.

Training the Next Generation of Brain Scientists

What gives Dr. Lucassen greatest satisfaction? Working with his team and watching young scientists develop. In their successful master track on brain disorders, that he coordinates with Aniko Korosi for the past 15 years, many students went on to do a PhD, and also his own (PhD) students Mike Marlatt and Floor Stam, obtained leading roles in Daiichi Sankyo Pharma US, and the Belgian Alzheimer company Remynd, resp., while Ludo van der Pol, Vivi Heine and Maaike Kempes became full professors. "It simply makes me happy and proud to see them do so well, working at the basis of implementing novel treatments for patients." Currently, Lucassen his Brain Plasticity group has grown to six principal investigators, two technicians, and over 15 PhD students, and is embedded in major consortia including Urban Mental Health, ZonMW-ME/CFS and the Institute for Chemical Neuroscience.

Asked which living person he most admires, Dr. Lucassen names his mentors: Dick Swaab, Ron De Kloet, and Marian Joels, admiring "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." His real-life heroes? His wife Anne-Marie, daughters Sofie and Eva, and the principal investigators of his group.

Dr. Paul Lucassen's Genomic Press interview is part of a larger series called Innovators & Ideas that highlights the people behind today's most influential scientific breakthroughs. Each interview in the series offers a blend of cutting-edge research and personal reflections, providing readers with a comprehensive view of the scientists shaping the future. By combining a focus on professional achievements with personal insights, this interview style invites a richer narrative that both engages and educates readers. This format provides an ideal starting point for profiles that explore the scientist's impact on the field, while also touching on broader human themes. More information on the research leaders and rising stars featured in our Innovators & Ideas -- Genomic Press Interview series can be found on our interview website: https://interviews.genomicpress.com/.

The Genomic Press Interview in Brain Medicine titled "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?" is freely available via Open Access starting on 2 December 2025 in Brain Medicine at the following hyperlink: https://doi.org/10.61373/bm025k.0140.

About Brain Medicine: Brain Medicine (ISSN: 2997-2639, online and 2997-2647, print) is a peer-reviewed medical research journal published by Genomic Press, New York. Brain Medicine is a new home for the cross-disciplinary pathway from innovation in fundamental neuroscience to translational initiatives in brain medicine. The journal's scope includes the underlying science, causes, outcomes, treatments, and societal impact of brain disorders, across all clinical disciplines and their interface.

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