Yue, Luo, and colleagues discovered that adenosine signalling is the common underlying mechanism of rapid acting antidepressant therapies, unifying the effects of ketamine, ECT and acute intermittent hypoxia. They use genetically encoded sensors, along with extensive mechanistic dissection, to show that all three induce adenosine surges in mood-regulatory circuits via A1 and A2A receptor activation. The mechanism of action of ketamine primarily involves modulation of mitochondrial metabolism as opposed to NMDA receptor antagonism, thereby presenting the possibility for improvements in derivative products with better therapeutic indices. These outcomes offers a rational framework for gauging therapeutic benefit for depression and raise vexing questions about patterns of caffeine consumption in treatment resistant depression, specifically whether the chronic use has a protective effect or whether the acute use impedes treatment response.

Sleep is a fundamental physiological process essential for maintaining both physical and mental health. While significant advances have been made in understanding the central nervous system mechanisms that regulate sleep-wake cycles, emerging evidence reveals the crucial role of peripheral organs, particularly the digestive system, in modulating brain function and behavior through the microbiota-gut-brain axis. This bidirectional communication network between the gut and the central nervous system directly and indirectly impacts sleep regulation. Disruptions in gut microbiota composition are closely linked to sleep disturbances, and alterations in the microbiota-gut-brain axis have been observed in several sleep disorders and illnesses with comorbid sleep disturbances. This review synthesizes current insights into the interplay between gut microbiota and sleep-wake regulation, highlighting potential routes of the microbiota-gut-brain axis in sleep and gut microbiome interactions and their health implications. Modulating gut microbiota may present a promising strategy for developing novel therapeutic approaches to address sleep disorders.

Dr Alex Tsompanidis emerges as a rising star in autism research at the University of Cambridge, where his pioneering work on the placenta-brain axis may revolutionize our understanding of neurodevelopment and human brain evolution. Named among the world’s top 40 under 40 autism researchers by Spectrum magazine and recipient of the International Society for Autism Research (INSAR) Best Dissertation Award, Dr Tsompanidis has established himself as an influential figure in developmental neuroscience. His research, now supported by a collaborative multi-million-pound grant from the Simons Foundation, explores how prenatal steroid hormones and placental function influence brain development and predict the likelihood of autism. In this exclusive Genomic Press Interview, Dr Tsompanidis reveals his journey from discovering his passion through childhood microscopy experiments to coordinating international research consortia spanning three continents. His recent evolutionary hypothesis, published in journal Evolutionary Anthropology, proposes that the placenta and its hormonal production may have played a crucial role in human brain evolution, positioning pregnancy at the heart of our species’ cognitive development. As Assistant Research Professor at Cambridge’s Department of Psychiatry and Honorary Research Associate at Peterhouse College, Dr Tsompanidis continues to bridge disciplines from genetics to evolutionary anthropology, advancing translational approaches that could enable early autism screening after birth through placental biomarkers. His commitment to inclusivity in science and dedication to mentoring the next generation of researchers exemplify the collaborative spirit driving modern neuroscience forward.

In this vignette, Dr. Esther Sternberg contributes to Dr. Seymour Reichlin's Festschrift, describing how he has influenced her career for over 35 years, first as a reviewer of her National Institutes of Health (NIH) research program, then as a mentor, and now as a friend. She explores the elements that have made him a role model for thriving through the decades, and which have kept Dr. Reichlin vibrant beyond his 100th year. She concludes that Reichlin embodies many elements known to contribute to healthy aging and long health spans: many friends and positive intergenerational relationships; a deep sense of meaning and purpose in life; an abiding wonder in the world around him; a great sense of humor and ability to laugh; and, in later years, his own brand of spiritual pursuit.

Professor Alexei Verkhratsky revolutionizes our understanding of neuroglia through groundbreaking research that transforms how we view brain disorders and therapeutic possibilities. This illuminating Genomic Press Interview reveals the extraordinary journey of an internationally acclaimed neurophysiologist whose pioneering discoveries in neuroglial pathophysiology have fundamentally reshaped neuroscience. Born in Ukraine and now at the University of Manchester, Verkhratsky stands as a towering figure with over 600 publications, including landmark articles on glial ionic excitability, astroglial sodium signalling, and pathophysiology of neuroglia that fundamentally changed our understanding of brain function in health and disease. His election to prestigious academies, including the German National Academy of Sciences Leopoldina, Academia Europaea, and multiple European academies, underscores his profound scientific impact. Verkhratsky's revolutionary work discovered that while neurons communicate through electrical impulses, glial cells possess specific form of intracellular excitability mediated by dynamic changes in ions and second messengers, demonstrating that glia actively participate in brain information processing through neurotransmitter receptors and calcium waves rather than being passive support cells. This paradigm-shifting concept of glial calcium excitability revealed an entirely new dimension of brain communication. His groundbreaking research on neuroglial ionic signalling, including sodium and chloride mechanisms, provides crucial insights for developing therapeutic strategies. As Professor of Neurophysiology in Manchester and through distinguished professorships worldwide, he champions the view that neuroglial malfunction drives brain disorders including neuropsychiatric and neurodegenerative diseases. His comprehensive 730-page reference book on neuroglia, published in 2023 with Arthur Butt, represents the culmination of decades of transformative research. Through extensive international collaborations and mentorship, Verkhratsky continues advancing neurogliopathology, offering hope for treating depression, Alzheimer's disease, multiple sclerosis, and other devastating brain disorders by targeting neuroglial homeostatic support and neuroprotection mechanisms.

Professor David Rubinsztein stands as a pioneering force in neurodegeneration research, revolutionizing our understanding of autophagy's critical role in combating diseases like Huntington's, Parkinson's, and Alzheimer's. This exclusive Genomic Press Interview reveals the journey of the Cambridge-based scientist whose groundbreaking discovery that autophagy regulates the clearance of toxic aggregate-prone proteins has transformed therapeutic approaches to neurodegenerative diseases worldwide. As Professor of Molecular Neurogenetics at the University of Cambridge and UK Dementia Research Institute Group Leader, Rubinsztein has authored over 400 scientific papers and ranks among the world's most highly cited researchers, with over 134,000 citations demonstrating his extraordinary impact. His laboratory's pioneering work identifying autophagy upregulation as a therapeutic strategy has opened unprecedented avenues for drug development, earning him exceptional recognition, as exemplified by Fellowship of the Academy of Medical Sciences, EMBO membership, and Fellowship of the Royal Society. His transformative contributions have been honoured with prestigious awards, including the Roger de Spoelberch Prize, the Thudichum Medal, and the Movement Disorders Research Award from the American Academy of Neurology, alongside consistent recognition as a Clarivate Analytics Highly Cited Researcher. Beyond his scientific achievements, this intimate portrait reveals Rubinsztein's dedication to mentoring the next generation of scientists, his passion for classical music, and his philosophy of pursuing curiosity-driven research. From his early days in Cape Town to becoming the first UK-trained genetic pathologist, his remarkable career exemplifies how fundamental discoveries in cellular biology can translate into hope for millions affected by neurodegenerative diseases, positioning autophagy modulation at the forefront of therapeutic innovation.

Professor Philip Hyland stands as a transformative figure in trauma psychology research, with his groundbreaking work on PTSD and Complex PTSD fundamentally reshaping global understanding of trauma-related disorders. As Professor of Psychology at Maynooth University and Chair of the International Trauma Consortium, Hyland has amassed an extraordinary 19,898 citations across over 340 publications, establishing himself as one of the world's leading authorities on posttraumatic stress. His pioneering research proved integral to the World Health Organization's landmark decision to include Complex PTSD as a distinct diagnosis in ICD-11, revolutionizing how clinicians worldwide assess and treat trauma survivors. The Genomic Press Interview reveals Hyland's remarkable journey from personal struggles with anxiety in his youth to becoming the 2023 Early Career Achievement Award winner at Maynooth University, showcasing how his innovative development of the International Trauma Questionnaire—now the gold standard measurement tool used globally—emerged from his commitment to improving trauma assessment accuracy. As Deputy Statistical Editor for the Journal of Traumatic Stress, Hyland champions revolutionary approaches to measuring psychological symptoms, challenging conventional clinical wisdom by prioritizing self-report measures over clinician judgments. His recent co-leadership of Ireland's first major sexual violence prevalence study since 2002 demonstrates his dedication to addressing critical societal issues, while his expansion into grief research, including validating prolonged grief disorder following pet loss, illustrates his compassionate approach to understanding human suffering. With research funded by prestigious organizations, including the European Commission, and published in elite journals, Hyland continues to advance trauma science through innovative theoretical models and measurement tools that directly improve lives globally.

Dr. Camilo de la Fuente-Sandoval, honored with the Schizophrenia International Research Society's prestigious 2024 Global Schizophrenia Award, has transformed early psychosis research through groundbreaking neuroimaging studies at Mexico's Instituto Nacional de Neurología y Neurocirugía (INNN). His pioneering MRI spectroscopy investigations in antipsychotic-naïve individuals experiencing their first episode of psychosis have profoundly influenced our current understanding of the neurochemical alterations linked to psychosis onset and subsequent antipsychotic treatment. His Laboratory of Experimental Psychiatry has become a beacon for innovative schizophrenia research in Latin America, supported by prestigious funding from the U.S. National Institutes of Health, the Secretariat of Science, Humanities, Technology, and Innovation, UC MEXUS-CONACyT, and multiple Mexican scientific agencies. The Genomic Press Interview reveals how this distinguished scientist channeled personal experiences into scientific excellence, establishing comprehensive clinical programs that provide free care while advancing personalized medicine approaches. His seminal discoveries demonstrating elevated glutamate levels in the associative striatum of first-episode psychosis patients, which normalize after effective treatment, have opened new avenues for biomarker development and targeted interventions. Leading international collaborations including the ENIGMA Clinical High Risk for Psychosis Working Group, Dr. de la Fuente-Sandoval bridges translational neuroscience and global mental health, offering unprecedented insights into schizophrenia within resource-limited contexts. His visionary work combining neuroimaging, electrophysiology, cognition, and inflammation markers represents a paradigm shift toward precision psychiatry, inspiring a new generation of researchers across the Global South while fundamentally advancing our understanding of psychosis mechanisms and treatment response prediction.

This Genomic Press Interview explores Dr. David R. Rubinow's transformative contributions to reproductive psychiatry through his journey from a major in philosophy and history to becoming a leading researcher. Rubinow fundamentally changed how we understand mood disorders linked to hormonal changes by discovering that women with conditions like premenstrual dysphoric disorder (PMDD), postpartum depression, and perimenopausal depression have normal hormone levels but respond differently to hormonal fluctuations, a concept he termed “differential sensitivity.” This breakthrough shifted treatment approaches from attempting to normalize hormones to targeting the abnormal responses themselves. His research directly contributed to the development of brexanolone (Zulresso), the first FDA-approved medication specifically for postpartum depression, which works through novel neurosteroid mechanisms rather than traditional antidepressant pathways. After 27 years at the National Institutes of Health (NIH), where he served as National Institute of Mental Health (NIMH) Clinical Director and founding Chief of the Behavioral Endocrinology Branch, Rubinow joined UNC-Chapel Hill in 2006 as Chair of Psychiatry, a position he held until 2019. During his tenure, he founded the UNC Center for Women's Mood Disorders, established the nation's first peripartum inpatient unit and first NIH-sponsored fellowship in women's mood disorders, and led the department to consistently top-10 national rankings in NIH funding. A member of the National Academy of Medicine since 2012, Rubinow has authored over 400 scientific publications and served as president of both the Society of Biological Psychiatry and the American College of Neuropsychopharmacology. The interview reveals how serendipity shaped his career trajectory, from an unexpected fellowship with Bob Post to leadership positions while maintaining parallel passions for music and woodworking. His philosophy of “bringing the chisel when sent for the hammer” reflects the thoughtful approach that has characterized his research. Rubinow's work has validated the experiences of millions of women whose hormone-related mood symptoms were previously dismissed, establishing reproductive psychiatry as a legitimate subspecialty with evidence-based treatments.

Randy Nelson studies sleep and circadian rhythms in health and illness. For the past 15 years, his lab has focused on the role of disrupted circadian rhythms on physiology and behavior. He studies the effects of these disrupted circadian rhythms on several parameters including immune function, neuroinflammation, metabolism, sleep, and mood. He has published nearly 500 papers and more than 12 books during his career describing studies in biological rhythms, behavioral neuroendocrinology, stress, immune function, and aggressive behavior. He has been elected to Fellow status in several scientific societies. Nelson earned his AB and MA degrees in Psychology at the University of California, Berkeley. He earned a PhD in Psychology, as well as a second PhD in Endocrinology, both from UC Berkeley; he was the first in the US to simultaneously earn two PhDs. Dr. Nelson then completed a postdoctoral fellowship at the University of Texas, Austin, after which he joined the faculty at The Johns Hopkins University, where he became professor of Psychology, Neuroscience, Biochemistry, and Molecular Biology. He then served on the faculty at The Ohio State University from 2000–2018, during which time he served as Distinguished University Professor and Chair of Neuroscience, as well as the co-director of the Neurological Institute. Dr. Nelson was recruited to WVU in 2018 to serve as professor and inaugural chair for the new Department of Neuroscience. In addition to his NIH funding, he is Co-I of the NSF Track 1 award, ‘West Virginia Network for Functional Neuroscience and Transcriptomics’. He has directly mentored 25 PhD and 16 postdoctoral colleagues. In this Genomic Press Interview Dr. Nelson shares insights into his personal and professional trajectories.

This Genomic Press Interview features Dr. Danielle Beckman, a pioneering neuroscientist at the University of California, Davis, whose groundbreaking research bridges virology and neuroscience to uncover how viral infections trigger lasting neurological damage and accelerate neurodegenerative diseases. Dr. Beckman's remarkable journey from Rio de Janeiro, Brazil, to becoming a leading expert in neurovirology showcases her innovative approach to developing translational animal models that illuminate the cellular mechanisms underlying Alzheimer's disease, Long Covid, and viral-induced brain pathology. Working under the mentorship of renowned neurobiologist John Morrison at the California National Primate Research Center, she has revolutionized our understanding of how viruses like SARS-CoV-2, Zika, and HIV disrupt brain homeostasis, leading to neuroinflammation and cognitive decline that affects millions of patients worldwide. Her pioneering work includes developing novel rhesus monkey models for Alzheimer's disease research, investigating the propagation of tau and amyloid pathology, and establishing critical connections between viral infections and neurodegenerative processes that contribute to conditions such as brain fog and memory impairment. As an active member of the World Health Network's Long Covid advisory group, Dr. Beckman combines her expertise in advanced microscopy techniques with her passion for science outreach to advance therapeutic development and provide hope for patients suffering from post-viral neurological symptoms. Her research, published in prestigious journals, represents a paradigm shift in understanding viral neuroimmunology and offers crucial insights for developing targeted treatments for neurodegenerative diseases and Long Covid. At the same time, her commitment to mentoring Latin American scientists and advocating for diversity in STEM fields demonstrates her dedication to fostering the next generation of neuroscience researchers.

The Genomic Press Interview with Sara Poletti, PhD, senior researcher at IRCCS Ospedale San Raffaele Milan, reveals how childhood trauma shapes adult mental health through neuroinflammation pathways. Project Leader at San Raffaele Hospital's Psychiatry and Clinical Psychobiology Unit, Poletti illuminates connections between early adversity, immune dysregulation, and mood disorders including depression and bipolar disorder. Her pioneering neuroimaging research demonstrates lasting neurobiological changes from childhood experiences, fundamentally altering brain-immune interactions throughout life. As the only tenure-track psychologist in psychiatry at her institute, Poletti bridges experimental psychology with clinical neuroscience through multidisciplinary approaches combining neuroimaging, genetic analysis, immunological markers, and neuropsychological assessments. Her European Research Area Network (ERA-NET) Neuron project coordination exemplifies innovative leadership advancing inflammation's role in psychiatric disorders. Poletti envisions precision psychiatry where individual biological signatures guide personalized treatments, offering new therapeutic targets focused on immune-brain interactions and prevention strategies. Beyond scientific achievements, she shares personal insights including her passion for Italian mountain hiking and life philosophy embracing present-moment happiness, revealing a researcher whose dedication transforms how we conceptualize psychiatric disorders.

Stanford Chemistry PhD graduate Sophia Shi reveals her pioneering journey decoding how sugar molecules protect aging brains in this Genomic Press Interview. Working under the mentorship of Nobel laureate Carolyn Bertozzi and renowned neurobiologist Tony Wyss-Coray, Dr. Shi has uncovered groundbreaking evidence that the brain's protective glycocalyx, a complex sugar coating on blood-brain barrier endothelial cells, deteriorates dramatically with age, contributing to cognitive decline and neurodegenerative diseases. Her recent Nature publication demonstrates that this “forest” of sugar molecules becomes sparse and degraded in aging brains, leading to blood-brain barrier dysfunction and neuroinflammation. Remarkably, her team demonstrated that restoring these critical mucin-type O-glycans in aged mice significantly improves barrier integrity and cognitive function, thereby opening up unprecedented therapeutic avenues for Alzheimer's disease and related conditions. Now launching her independent laboratory at Harvard's prestigious Rowland Institute directly from doctoral training, a rare achievement that speaks to her exceptional promise, Dr. Shi represents a new generation of interdisciplinary scientists seamlessly bridging glycobiology and neuroscience. From solving childhood puzzles in New Jersey to decoding molecular mysteries at Stanford, she shares candid insights on navigating scientific challenges, the transformative impact of supportive mentorship, building inclusive research environments, and her ambitious vision for developing glycan-based therapies to combat brain aging. Her recognition with the David S. Miller Young Scientist Award at the Cerebral Vascular Biology Conference underscores her emergence as a leading voice in understanding how post-translational modifications, particularly glycosylation, shape brain health, and resilience throughout the lifespan, offering tangible hope for millions affected by age-related cognitive decline and neurodegenerative diseases worldwide.

Professor Francesco Benedetti emerges in this Genomic Press Interview as a passionate scientist-clinician whose career has been dedicated to reclaiming psychiatry's place within medical science through rigorous research and compassionate practice. As founder and leader of the Psychiatry & Clinical Psychobiology research unit at IRCCS Ospedale San Raffaele in Milano, Italy, Dr. Benedetti has spent decades bridging the gap between neuroscience and behavioral disorders while maintaining an active clinical practice treating patients with mood disorders. His scientific journey began with a profound awareness of mental illness suffering during childhood and was shaped by his conviction that psychiatric conditions are fundamentally biological rather than merely “functional”—a controversial stance in Italian academia during his early career. Despite facing rejection from traditional psychiatric training programs, Dr. Benedetti persevered through an alternate path that ultimately led him to groundbreaking work in chronotherapeutics, immuno-psychiatry, and psychiatric genomics. Direct clinical observations have driven his research: noticing patterns of infection and inflammation in depressed patients sparked his exploration of immuno-inflammatory mechanisms; witnessing the suffering of suicidal bipolar patients unresponsive to standard treatments led to innovative chronotherapeutic protocols. Dr. Benedetti has maintained throughout his career that scientific research and clinical practice are inseparable, stating, “I see no boundaries between science and everyday clinical work.” His current focus on how gene variants, immune responses, and life experiences interact to affect brain homeostasis reflects his commitment to understanding mood disorders as legitimate medical conditions rather than the “horrible abyss of pain, stigma, misery that they are now.” When not conducting research, Professor Benedetti satisfies his “voracious curiosity” through reading, music, museum visits, and outdoor activities, approaching both his professional and personal life with the philosophical depth captured in his guiding motto from Ecclesiastes: “Whatever your hand finds to do, do it with all your might.”

In this personal tribute, Leonard P. Kapcala, M.D., a former Endocrine Fellow who trained with Seymour “Si” Reichlin, M.D., Ph.D. for 4 years at Tufts New England Medical Center (TNEMC), recounts his experiences and interactions with Dr. Reichlin spanning nearly five decades. These recollections begin with his pursuit of an Endocrine Fellowship, continue through his training years, and extend to his ongoing relationship with Dr. Reichlin up through the celebration of Si's 100th birthday in June 2024 and, most recently, as of January 2025. After training with Dr. Reichlin, Dr. Kapcala went on to a distinguished career in academic medicine, research, biotechnology, and regulatory science. Through intimate vignettes and personal stories, Dr. Kapcala portrays Dr. Reichlin as a scientific maven with unparalleled expertise in neuroendocrinology, a dedicated mentor who provided invaluable guidance and a genuine mensch whose kindness and humanity touched all those around him. This tribute offers a unique window into the remarkable character and profound influence of one of the most distinguished figures in the field of neuroendocrinology.

Mental health and substance use disorders represent a major public health burden worldwide, and current diagnostic methods rarely include objective, quantifiable metrics. In this Genomic Press Interview, Dr. Romina Mizrahi, Professor at McGill University Department of Psychiatry and Principal Investigator, Clinical & Translational Sciences (CaTS) lab at the Douglas Research Center, discusses how positron emission tomography (PET) imaging provides transformative opportunities to study the molecular mechanisms underlying psychiatric disorders. Dr. Mizrahi uses PET to study the pathophysiology of schizophrenia, clinical high risk (CHR) for psychosis, and addiction with a focus on cannabis use. She was the first to investigate in-vivo dopamine response to stress in CHR, schizophrenia, and cannabis users. Importantly, Dr. Mizrahi pioneered PET studies with novel radiotracers, including [¹¹C]-(+)-PHNO, [¹⁸F]-FEPPA, [¹¹C]-CURB, [¹¹C]-NOP, [¹¹C]SL25.1188 and [¹⁸F]SynVesT-1 to image dopamine, neuroinflammation, endocannabinoid, nociceptin expression, monoaminoxidase B (MAO-B) and synaptic density (respectively) in psychosis spectrum, cannabis use, and more recently in suicide phenotypes. These molecular imaging techniques allow for identifying biomarkers related to specific disorders, discovering new treatment targets, early behavioral intervention, and assessing real-time treatment responses. Dr. Mizrahi's research aims to improve individualized treatment decisions and predictions of treatment response in psychiatry by integrating PET data with genetic, clinical, and environmental data. Dr. Mizrahi is a champion for interdisciplinary collaborations aimed at improving the science of mental health, and she has published over 160 papers in high-impact journals. She is highly involved with public health, including extensive media engagement and testimony as a witness at the Canadian House of Commons standing committee on youth marijuana use, an important global priority in the context of cannabis legalization.

Since Rudolf Heidenhain first identified neuroendocrine cells in 1870, our understanding of neuroendocrine tumors (NETs) has advanced significantly. The increasing incidence and prevalence of NETs, combined with complete tumor resection being the only curative option, has driven the search for effective treatments. Peptide receptor radionuclide therapy, which combines radioactive elements with octreotide derivatives, has emerged as a promising therapeutic approach. While β-particle emitters are currently used in clinical practice, targeted alpha-particle therapy (TAT) shows particular potential for NET treatment. This review examines the physical and radiobiological characteristics of α- and β-particles, evaluates preclinical and clinical evidence for TAT in somatostatin receptor–expressing NETs, and explores both challenges and future developments in α-particle therapy for NETs.

In this engaging Genomic Press Interview, Dr. Guy A. Rouleau, OC, OQ, FRCPC, FRSC, FAAN, opens up about his remarkable journey from a young boy conducting chemistry experiments in his basement to becoming Director of The Neuro (Montreal Neurological Institute-Hospital) and Chair of McGill University's Department of Neurology and Neurosurgery. A world-renowned clinician and neurogenetics researcher, Dr. Rouleau has dedicated 35 years to uncovering the genetic foundations of devastating neurological conditions, identifying dozens of disease-causing genes in ALS, hereditary neuropathies, epilepsy, schizophrenia, and autism. His scientific impact is reflected in nearly 1,000 peer-reviewed publications cited over 110,000 times, but his vision for transforming research methodology may be his most lasting legacy. As co-founder of the Tanenbaum Open Science Institute and First Vice-President of the World Federation of Neurology, he is pioneering a revolution in scientific collaboration by establishing The Neuro as the world's first academic institution fully committed to open science principles. Through personal anecdotes and professional insights, Dr. Rouleau shares his passion for sailing, commitment to mentoring the next generation, and unwavering belief that open, collaborative science will accelerate discoveries to benefit patients worldwide.

The influence of gonadal hormones on neurological health and disease is a rapidly developing domain in fundamental and clinical neuroscience. Sex hormones, directly or via their neurosteroid metabolites, impact monoaminergic, cholinergic, and peptidergic neurotransmission and play essential roles in shaping brain organization and function under normal and pathological conditions. The clinical expression of various neurological disorders may be modified by hormonal fluctuations related to the menstrual cycle, pregnancy, menopause, and oral contraceptive use. Understanding these interactions could lead to targeted hormonal and antihormonal therapies for diverse neurological conditions, including but not limited to catamenial epilepsy, Parkinson disease, and acute intermittent porphyria.

Joseph B. Martin, MD, PhD, Edward R. and Anne G. Lefler Professor of Neurobiology, Emeritus, former Dean of Harvard Medical School (1997–2007), and former Dean of the School of Medicine (1989–1993) and Chancellor (1993–1997) of the University of California, San Francisco (UCSF), presents the second guest editorial in this Festschrift issue honoring Dr. Seymour Reichlin's centennial. Drawing from his experience as one of Dr. Reichlin's earliest fellows in 1967 at the University of Rochester, where he completed his PhD in anatomy, Martin provides a personal account of his scientific journey under Reichlin's mentorship. He details their groundbreaking work on hypothalamic-pituitary regulation, which laid the foundation for Martin's distinguished career in neurology and academic medicine. Martin describes Reichlin as the “quintessential physician-scientist,” highlighting his mentor's exceptional breadth of knowledge and innovative approach to neuroendocrine research. Their decades-long collaboration culminated in co-authoring the definitive 1987 textbook Clinical Neuroendocrinology and numerous influential publications. The guest editorial offers unique insights into Reichlin's lasting impact on the field from one of academic medicine's most accomplished leaders, including observations of his mentor's continued scientific contributions at age 100, exploring novel applications of neuroendocrine regulators in cognition and sensory function.

The physiologic experiments of the 1950s and 1960s that established the hypothalamic regulation of pituitary function led to the biochemical characterization of the various release and inhibiting hormones and their receptors over the next two decades and ultimately to the development of medical therapies for the various pituitary adenoma types. The paradigm of medical therapy is the extremely successful use of dopamine agonists (DA) for the treatment of prolactinomas, which built upon the basic knowledge that dopamine is the physiologic prolactin (PRL) inhibitor factor. The discovery of somatostatin and its receptors led to the development of somatostatin receptor ligands (SRLs) for the treatment of acromegaly and thyrotropin (TSH)-secreting adenomas, Knowledge of how growth hormone (GH) interacts with its receptor led to the development of pegvisomant, which blocks the binding of GH to its receptor. Early clinical observations of patients with acromegaly have led to the use of estrogens and selective estrogen receptor modulators to aid in its treatment. DAs and SRLs have only modest activity in Cushing's disease and most therapies involve enzymatic blockade of the various steps in cortisol synthesis, the two most recent being osilodrostat and levoketoconazole. Blockade of the cortisol receptor by mifepristone was found accidentally but then was established as a good treatment for Cushing's syndrome. The finding that clinically nonfunctioning adenomas had dopamine receptors led to the use of DA in these patients as well. Finally, an understanding of some of the abnormal molecular pathways underlying the rare aggressiveness of some adenomas and carcinomas has led to the use of temozolomide and now other chemotherapies and immunotherapies in such patients.

Depression, according to the World Health Organization, stands as one of the most impactful disabilities worldwide. Its toll reaches beyond mood and thought, extending into physical health risks like coronary artery disease, diabetes, osteoporosis, and stroke, leading to a lifespan reduction of approximately 7 to 10 years in those affected. This paper explores the view of depression as a neuroendocrine disorder, especially focusing on the subtype of melancholic depression. Structural and functional disruptions in brain areas—such as the prefrontal cortex and hippocampus—reveal a misalignment in the stress response system that might drive depressive symptoms. Specifically, the roles of corticotropin-releasing hormone, norepinephrine hyperactivity, glucocorticoid levels, and inflammation-related mechanisms are investigated here. These insights point to promising new treatments targeting these neuroendocrine pathways that may enhance therapeutic responses.

This overview, part of a special Festschrift issue celebrating Dr. Seymour Reichlin’s centennial year, honors the remarkable life and enduring scientific legacy of a researcher whose journey has fundamentally shaped our understanding of neuroendocrinology. From his early insights into stress responses during World War II to his groundbreaking work on hypothalamic control of pituitary function, Dr. Reichlin’s research has bridged the gap between brain function and hormonal regulation. His discovery of multiple glucocorticoid receptor isoforms in the placenta and pioneering work on somatostatin exemplify his innovative approach to understanding complex neuroendocrine systems. Beyond his scientific achievements, Dr. Reichlin’s influence as a mentor has touched generations of endocrinologists, with his trainees leading major medical institutions worldwide. Now at 100 years old, he continues to contribute actively to the field, writing books on the neuroendocrinology of Alzheimer’s disease and exploring the biological basis of ecstatic mysticism. This paper traces his journey from a young medical student fascinated by Hans Selye’s work to becoming a foundational figure in modern neuroendocrinology, highlighting how his personal experiences, including his military service and clinical observations, shaped his unique perspective on the interaction between emotional states and physiological responses.