In a recent open-access interview, Dr. Eric J. Nestler, the Anne and Joel Ehrenkranz Dean of the Icahn School of Medicine at Mount Sinai, looks back on nearly four decades of research into how stress and drugs reshape brain function. He highlights the transcription factor ΔFosB’s role in long-lasting behavioral change and argues that understanding natural resilience could shift mental health care toward strengthening protective mechanisms, not just correcting damage.
Dr. Eric J. Nestler traces his scientific journey back to an improvised laboratory in the basement of his family’s home in Nassau County, Long Island, where his father, a high school biology teacher in the New York City public school system, supervised his earliest experiments. According to a recent Genomic Press interview published in Brain Medicine, those projects evolved into award‑winning science fair entries and laid the groundwork for an academic path through Yale University, where Nestler earned BA, PhD and MD degrees while training with Nobel laureate Paul Greengard.
At Yale School of Medicine, Nestler and colleague Ron Duman chose the forward‑looking name “Laboratory of Molecular Psychiatry” for their research group at a time when applying molecular biology to psychiatric illness was still considered bold. As recounted in the Brain Medicine profile, Nestler was subsequently appointed founding director of Yale’s Division of Molecular Psychiatry after then‑director Dr. George Heninger voluntarily stepped aside, a gesture Nestler cites as a model for how senior scientists can support younger colleagues.
One of the most influential lines of work from Nestler’s laboratory centers on the transcription factor ΔFosB. The Brain Medicine article explains that ΔFosB accumulates in the brain’s reward circuitry during prolonged exposure to drugs of abuse and sustained stress, where it alters patterns of gene expression in affected neurons. Unlike many proteins that are rapidly degraded, ΔFosB can persist for weeks or even months, providing a biological explanation for how relatively brief experiences can produce enduring changes in mood, motivation and behavior. Researchers worldwide now regard ΔFosB as a key contributor to vulnerability to addiction, according to Genomic Press.
Over roughly four decades, Nestler’s research program has broadened from early work on intracellular signaling pathways to studies of transcription factors and wider gene networks that influence behavior in specific brain regions. Around 20 years ago, his group began investigating epigenetic regulation — chromatin modifications through which environmental conditions can leave lasting marks on brain function — and has since moved toward increasingly granular approaches. As described in the interview, the lab’s current efforts use cell‑type‑specific and single‑cell analyses, raising the prospect that, in the future, treatments might be tailored to particular populations of neurons in individual patients.
A defining feature of Nestler’s work has been a pivot from focusing only on pathology to systematically studying resilience. His laboratory has identified molecular, cellular and circuit‑level signatures that distinguish animals that maintain normal behavior despite repeated stress or drug exposure from those that become vulnerable. “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,” Nestler says in the Brain Medicine interview. Genomic Press reports that several resilience‑based strategies inspired by this work are now in clinical testing for depression.
Findings from animal models have been reinforced by analyses of postmortem human brain tissue from people with addiction and stress‑related disorders, providing cross‑species support that the mechanisms uncovered in the lab are relevant to human disease. The ScienceDaily summary of the Brain Medicine article notes that Nestler has authored more than 800 publications and major textbooks on the neurobiology of mental illness and molecular neuropharmacology, with over 177,000 citations and an h‑index of 210 placing him among the most widely cited scientists in his field.
The interview also situates this scientific trajectory within a broader push for open, independent research. Genomic Press, which published the profile, is described as an open‑access platform aimed at removing barriers to medical science. Nestler voices concern about the risks of political interference, 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 comments underscore a view that safeguarding scientific integrity is essential if advances in areas such as stress, addiction and resilience are to benefit people regardless of geography or political affiliation.
The Brain Medicine feature closes by noting the personal and professional influences that have shaped Nestler’s career, from his family and early mentors to the colleagues and trainees he has supported. While he has received major honors, including election to the National Academy of Sciences and the National Academy of Medicine, the article emphasizes that he takes particular pride in the achievements of former students and postdoctoral fellows whose work continues to expand the field of molecular psychiatry.
