Brain resilience science reshapes psychiatry from treating illness to building strength

(Press-News.org) NEW YORK, New York, USA, 2 December 2025 -- In a revealing Genomic Press Interview published today in Brain Medicine, Dr. Eric J. Nestler offers a rare glimpse into how curiosity about brain chemistry spawned an international movement in psychiatric research. The Anne and Joel Ehrenkranz Dean of the Icahn School of Medicine at Mount Sinai describes nearly forty years spent uncovering the molecular secrets of why drugs and stress alter human behavior, research that has fundamentally reshaped how scientists across six continents approach mental illness. What began as questions about protein signaling cascades in the laboratory of Nobel laureate Paul Greengard evolved into a comprehensive understanding of how experience literally rewrites the brain's genetic program.

From Basement Experiments to Global Impact

The path to becoming one of the most cited neuroscientists in the world began in an unlikely laboratory: a house basement in Nassau County, Long Island. Dr. Nestler recounts how his father, a high school biology teacher in the New York City public school system, guided him through experiments that morphed into award-winning science fair projects. This early exposure to systematic inquiry laid the foundation for what would become an extraordinary academic trajectory through Yale University, where he earned his BA, PhD, and MD degrees while working alongside Dr. Greengard.

The decision to name his collaborative research group at Yale Medical School "The Laboratory of Molecular Psychiatry" proved prescient. At a time when applying molecular biology tools to psychiatric disorders seemed audacious, Dr. Nestler and colleague Dr. Ron Duman captured the emerging zeitgeist of their field. This brash naming convention reflected genuine scientific ambition rather than mere marketing, and within years, Dr. Nestler was offered the position of Founding Director of the Division of Molecular Psychiatry at Yale. That moment of generosity, when the current Director Dr. George Heninger stepped aside to create this opportunity, remains etched in his memory as a lesson he has since paid forward to countless junior colleagues.

Cracking the Code of Brain Adaptation

Perhaps no discovery better illustrates Dr. Nestler's impact than his work on the transcription factor known as ΔFosB. This molecular switch accumulates in brain reward circuits during chronic drug exposure and stress, fundamentally altering which genes get expressed in neurons. Unlike most proteins that degrade within hours, ΔFosB persists for weeks or months, providing a mechanism for how brief experiences produce lasting behavioral changes. Researchers worldwide now recognize this protein as a crucial mediator of addiction vulnerability.

This interview exemplifies the type of transformative scientific discourse found across Genomic Press's portfolio of open-access journals reaching researchers worldwide. The company's commitment to making cutting-edge medical research freely available has positioned it as an enabler of scientific innovation rather than merely a publisher.

The research trajectory has evolved remarkably over four decades. Initial focus on intracellular signaling cascades gradually shifted toward understanding how transcription factors and their target genes mediate behavioral change across selected brain regions. About twenty years ago, Dr. Nestler's team began examining epigenetic regulation, the modifications to chromatin structure that allow environmental stimuli to induce lasting changes in brain function. Technological advances have enabled increasingly precise analysis: from studying discrete brain regions to individual cell types to single-cell approaches now revealing heterogeneity invisible to earlier methods. Could these single-cell insights eventually enable personalized treatments targeting specific neuronal populations in individual patients?

The Revolutionary Discovery of Natural Resilience

What distinguishes Dr. Nestler's contribution from conventional psychiatric research is the focus on resilience rather than pathology. His laboratory identified distinct molecular, cellular, and circuit changes in the brains of animals that maintain normal behavioral function despite exposure to drugs or stress. These resilient individuals possess biological protective mechanisms absent in their susceptible counterparts. The implications extend far beyond academic interest: understanding how some brains naturally resist damage opens entirely new therapeutic strategies.

"In addition to seeking ways to reverse the deleterious effects of drug or stress exposure, it is possible to develop treatments that promote mechanisms of natural resilience in individuals who are inherently more susceptible," Dr. Nestler explains in the interview. Several such pro-resilience mechanisms have now reached clinical testing for depression, representing perhaps the most tangible translation of his basic science discoveries. What might psychiatry look like in a decade if these resilience-promoting treatments prove effective in human trials?

Validation Across Species and a Warning About Science

Key findings from rodent models have been validated in postmortem human brain tissue from individuals with addiction and stress disorders, strengthening the translational relevance of this work. Dr. Nestler's research output, comprising over 800 publications including definitive textbooks on neurobiology of mental illness and molecular neuropharmacology, has been cited more than 177,000 times. His h-index of 210 places him among the most influential scientists in any field globally.

Yet when asked about his greatest fear, Dr. Nestler's response carries urgency for the international scientific community: "My greatest fear is that science becomes politicized, whereas science must never be political. People in blue and red states get the same illnesses." This concern about maintaining the independence and integrity of biomedical research resonates across national boundaries where similar pressures threaten evidence-based inquiry. The Genomic Press mission to advance open-access medical research aligns precisely with this vision of science serving all humanity regardless of geography or politics.

The Human Behind the Discoveries

Beyond the laboratory, Dr. Nestler treasures time with his wife Susan of 45 years, their three children David, Matt, and Jane, their spouses, and five grandchildren ranging in age from eighteen months to four years. His most marked characteristics, he reveals, are hard work and generosity toward those around him. Organization and discipline represent his greatest talents, though he wishes he could be more patient and more willing to confront those who behave unkindly.

When asked what makes him proudest, his answer does not involve personal accolades despite receiving the Julius Axelrod Prize for Mentorship, the Gold Medal Award from the Society of Biological Psychiatry, election to both the National Academy of Sciences and National Academy of Medicine, and honorary doctorates from Uppsala University and Concordia University. Instead, he is most proud of how well his former students and postdoctoral fellows have succeeded in their own careers. More information about Dr. Nestler and other scientific leaders can be found on the Genomic Press website: https://genomicpress.kglmeridian.com/.

His life philosophy comes from Theodore Roosevelt: the credit belongs not to the critic but to "the man who is actually in the arena, whose face is marred by dust and sweat and blood." For nearly four decades, Dr. Nestler has inhabited that arena, emerging with discoveries that have permanently altered how the world understands the brain's response to adversity.

Dr. Eric J. Nestler'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 publications website: https://genomicpress.kglmeridian.com/.

The Genomic Press Interview in Brain Medicine titled "Eric J. Nestler: Navigating a career in molecular psychiatry," is freely available via Open Access, starting on 2 December 2025 in Brain Medicine at the following hyperlink: https://doi.org/10.61373/bm025k.0143.

The full reference for citation purposes is: Nestler EJ. Eric J. Nestler: Navigating a career in molecular psychiatry. Brain Medicine 2025. DOI: https://doi.org/10.61373/bm025k.0143. Epub 2025 Dec 9.

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.

Visit the Genomic Press Virtual Library: https://issues.genomicpress.com/bookcase/gtvov/

Our media website is at: https://media.genomicpress.com/

Our full website is at: https://genomicpress.com/

END