The brain switch that could rewrite how we treat mental illness
In a recent Genomic Press Interview published in Brain Medicine, Dr. Eric J. Nestler reflects on how an early
In a recent Genomic Press Interview published in Brain Medicine, Dr. Eric J. Nestler reflects on how an early fascination with brain chemistry helped shape a worldwide transformation in psychiatric research. As the Anne and Joel Ehrenkranz Dean of the Icahn School of Medicine at Mount Sinai, he describes nearly four decades spent unraveling the molecular processes that explain why drugs and stress influence human behavior. What started as an effort to study basic protein signaling in the laboratory of Nobel laureate Paul Greengard eventually grew into a broad understanding of how life experiences can alter the brain’s genetic activity over time.
Dr. Nestler traces his interest in science back to an unusual home laboratory in the basement of his family’s house in Nassau County, Long Island. Guided by his father, a high school biology teacher in the New York City public school system, he learned how to design and carry out experiments. These projects later became award-winning science fair entries and set the stage for an academic path through Yale University, where he earned BA, PhD, and MD degrees while training under Dr. Greengard.
Building a New Field in Molecular Psychiatry
His decision to name his research group at Yale Medical School “The Laboratory of Molecular Psychiatry” turned out to be remarkably forward-thinking. At a time when applying molecular biology to psychiatric questions was still considered bold, Dr. Nestler and colleague Dr. Ron Duman recognized that the field was ready for a new scientific direction. The name reflected genuine ambition. Within a few years, he was appointed Founding Director of the Division of Molecular Psychiatry at Yale, a role made possible when the sitting Director, Dr. George Heninger, voluntarily stepped aside. Dr. Nestler often recalls this moment as an example of generosity that he has tried to extend to younger scientists throughout his career.
Breakthrough Insights Into Brain Adaptation
One of the most influential discoveries associated with his work involves the transcription factor ΔFosB. This protein accumulates in the brain’s reward circuits during prolonged drug exposure and sustained stress, altering patterns of gene expression in affected neurons. While most proteins break down quickly, ΔFosB remains active for weeks or months. This unusually long lifespan provides a biological explanation for how relatively brief experiences can produce long-lasting changes in mood, motivation, and behavior. Researchers around the world now view ΔFosB as a key contributor to vulnerability to addiction.
The interview highlights the type of forward-looking scientific dialogue that characterizes Genomic Press’s open-access publications, which make cutting-edge findings accessible to researchers globally. The organization’s commitment to broad, barrier-free dissemination has helped accelerate progress across multiple branches of medical science.
From Signaling Pathways to Single-Cell Biology
Over roughly forty years, the direction of this research has shifted in notable ways. Early work focused on intracellular signaling cascades, then expanded into the study of transcription factors and gene networks that shape behavior in specific parts of the brain. Approximately twenty years ago, Dr. Nestler’s team began exploring epigenetic regulation, the chromatin modifications that allow environmental conditions to produce lasting changes in brain function. Improvements in scientific tools have since enabled increasingly detailed studies: first at the level of whole brain regions, then individual cell types, and now single-cell analyses that reveal subtle differences unseen in earlier studies. These advances raise an important question: could these insights eventually lead to personalized treatments tailored to select neuron populations within a single patient?
Resilience as a New Direction in Mental Health Science
A defining aspect of this research program is the emphasis on resilience rather than solely on pathology. His laboratory identified specific molecular, cellular, and circuit-level signatures in animals that maintain normal behavior despite exposure to stress or drugs. These animals show natural protective features that are absent in more susceptible individuals. The idea that some brains possess built-in defenses has far-reaching implications, suggesting new ways to develop treatments that strengthen resilience instead of only repairing damage.
“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 of these resilience-based approaches are now in clinical testing for depression, offering one of the clearest examples of basic research informing new therapeutic possibilities. The potential success of these treatments prompts important questions about how psychiatric care may evolve in the coming decade.
Cross-Species Evidence and the Need to Protect Scientific Integrity
Key discoveries from animal research have been supported by findings in postmortem human brain tissue from individuals with addiction and stress disorders, providing strong evidence that the principles uncovered in the laboratory translate to humans. Dr. Nestler’s publication record includes more than 800 papers and major textbooks on the neurobiology of mental illness and molecular neuropharmacology. His work has been cited more than 177,000 times, and his h-index of 210 places him among the most influential scientists worldwide.
When asked about his greatest concern for the future of science, he offers a clear warning: “My greatest fear is that science becomes politicized, whereas science must never be political. People in blue and red states get the same illnesses.” His message emphasizes the need to safeguard scientific independence at a time when political pressures threaten evidence-based research in many regions. The mission of Genomic Press to advance open-access medical science aligns strongly with this vision of science serving people everywhere.
A Life Shaped by Family, Mentorship, and Service
Outside of his research, Dr. Nestler values time spent with his wife Susan of 45 years, their three children David, Matt, and Jane, their spouses, and their five grandchildren, who range in age from eighteen months to four years. He describes his defining traits as hard work and generosity and considers organization and discipline to be his strongest skills. He also shares a desire to cultivate more patience and to become more willing to challenge unkind behavior.
When asked what brings him the most pride, he points not to the major honors he has received, including the Julius Axelrod Prize for Mentorship, the Gold Medal Award from the Society of Biological Psychiatry, election to the National Academy of Sciences and the National Academy of Medicine, and honorary doctorates from Uppsala University and Concordia University. Instead, he cites the achievements of his former students and postdoctoral fellows. Additional information about Dr. Nestler and other leaders in science can be found on the Genomic Press website: https://genomicpress.kglmeridian.com/.
His guiding philosophy comes from Theodore Roosevelt, who wrote that credit belongs 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 remained in that arena, contributing discoveries that continue to shape how the world understands the brain and its response to adversity.
