Celebrating the legacy of the Institute of Psychiatric Research (IPR), and moving brain research forward In 2013-2015, the Institute of Psychiatric Research building (IPR) on the IUPUI campus was demolished and a new Neuroscience Research Building was constructed as part of the Neuroscience Center of Excellence on West 16th Street. The city lost the address that housed the IPR as Eskenazi Hospital expanded to fill that space. The IPR building was a testament to the scientific prowess and creativity found among those who studied mental disorders at Indiana University. It was a center for outstanding research and teaching in the service of improved patient care for persons suffering with brain disorders. We review brain research done at the IPR and highlight its future at Indiana University Medical Center. The Institute of Psychiatric Research was a free-standing center developed by the State of Indiana in 1957 to investigate the causes of mental illness. Everything reflects its time and place. Sixty three years ago, the US was led by President Dwight Eisenhower, Elvis Presley emerged as the world's major musical star, and the discovery of the DNA double helical structure was just three years old. Governor George Craig and Mental Health Commissioner Margaret Morgan saw a need for research on the underlying physical causes of psychiatric disorders, such as schizophrenia, mood and anxiety disorders, autism, dementia, and addiction. At the time, many believed that these were individual spiritual problems or moral failings, although newer theories assigned blame to poor parenting and childhood mistreatment. Indeed, the medical paradigm, including commonly used current psychiatric drugs was just coming into clinical use during the 1950’s (Table 1). With a far-sighted approach, the State of Indiana and the IU School of Medicine embraced the fledgling field of biological psychiatry, instead. While not neglecting interpersonal and social causes, the emphasis of biological psychiatry is on understanding brain function and on firmly embedding psychiatry within the realm of medicine. The vision of the Governor, the State Legislature, and the Mental Health Commissioner to put a major focus on neuropsychiatric research was bold and forward-looking. With the exception of the New York State Psychiatric Institute and the Institute of Living (Hartford), there were few free-standing centers for biological studies of psychiatric disorders (though there were a number of psychoanalytically-oriented institutions). At that time, specific psychiatric disorders were not substantially represented in the scientific literature. For example, during 1950-1955, articles published globally in autism and Alzheimer's disease came to no more than 19 and 74 articles, respectively (Table 2). The following fifty years witnessed increasing research activity, and during 2000-2005 articles published in autism and Alzheimer's disease rose to 3,270 and 18,800, respectively (Table 2). Over the past sixty years, biological psychiatry has received support from three sets of data: 1) the undeniable response of severely ill patients to treatment with psychotropic medications, 2) imaging studies revealing abnormal brain function associated with many psychiatric disorders, and 3) the burgeoning knowledge of human genetics and its role in all of the major brain disorders. The Institute of Psychiatric Research (IPR) at the Indiana University School of Medicine was built by the state in 1956 and opened in 1957 with a nationally known Board of Directors. IPR was to combine the best and brightest in the fields of not only psychiatry and psychology, but also biochemistry, neurochemistry, neurophysiology, classical genetics, and the new field of molecular biology. IPR took the lead in several vital threads of neurological and psychiatric research over the ensuing decades. In the 1960s, IPR researchers discovered that glycine was a neurotransmitter. They also established general principles for the confirmation of neurotransmitters. Since that time, glycine (initially known as an inhibitory transmitter) has been identified as a key modulator of excitatory pathways in the human brain. In the 1970s, IPR faculty contributed to our understanding of the brain chemical serotonin, and the ways in which serotonin affects behavior. We now know that serotonin contributes to the action of most commonly used antidepressant drugs. In the late 1980s, groundwork was laid at IPR for the study of psychiatric genetics, or the understanding of brain biological differences that lead to vulnerability to depression or addiction. Recently this work has expanded to consider the genetic basis of drug response, which have led to the modern realization that drug effects are not “one-size-fits-all”. Different people have different responses to the same dose of the same drug, and these differences can come from genetic variations. In addition, during this decade, evidence that has helped demonstrate the fundamentally biological nature of “mental” disorders such as schizophrenia was found in magnetic resonance imaging scans of the brain by a group at IPR. In the 1990s Indiana University scientists led groundbreaking research demonstrating that addiction is biologically tied to some of the same pathways (serotonin and dopamine) that are used to treat depression and other psychiatric disorders. The genetic regulation of Alzheimer’s disease and the molecular basis of the drugs used to treat Alzheimer’s (primarily drug effects on the messenger chemical acetylcholine) have also been successfully explored at the IPR. The first decade and a half of the 21st century saw additional expansion at IPR. In addition to strictly biological studies, the interaction of environment with health history, genes, and drug treatments became a matter of important study. A whole-system approach has become important at IPR, where more traditional “single-focus” studies are now expanded and complemented by models that explicitly incorporate environmental and genetic risk factors for a disorder, such as the “Latent Early-life Associated Regulation” (LEARn) model, which proposes specific mechanisms by which environment and genetics interact within a person to produce effects that appear years to decades after an initial exposure to a toxin. The concept of early-life exposure having effects in later stages of life may have relevance for social problems such as crime and poverty as well as specific brain disorders such as bipolar disorder and attention deficit disorder. Another recent pioneering study being conducted by IPR investigators relates to the development of novel and specific protein biomarkers, which may be useful in understanding and diagnosing autism, bipolar disorder, and Alzheimer’s disease. In each decade, IPR has changed its focus and has remained fundamentally useful. Our faculty and staff are now experiencing a significant development. IPR is no longer a stand-alone physical institution. Science now progresses as a team effort, especially in complex fields like neuroscience and psychiatry. The faculty and research staff of IPR have moved to new facilities that are intermingled with faculty from Neurology, Neurosurgery, and other Departments of the Indiana University School of Medicine and IU Health. Throughout its history, IPR contributed heavily to training neuroscientists and psychiatrists in the Hoosier state and beyond, and to other scholarly activities. It became the home of Editors of internationally-respected journals, such as Current Alzheimer Research (Bentham) and Psychiatric Genetics (Wolters Kluwers). In addition, IPR served as a magnet for many highly competitive federal and corporate grants, providing jobs and economic stimulus to the state. Over $20.7 million in grants (primarily from the National Institutes of Health) were awarded to IPR investigators during 2009-2014. This reminds us that public and private investments in scientific research always pay off to the society in large as evident from the IPR’s significant contributions in research, teaching and training. Notably, IPR initiated the first graduate program in Medical Neurobiology at IUSM, and had been the home of this successful program until 2000. The Institute’s mission continues vigorously in its new home in the Neuroscience Center of Excellence at 16th and Senate near the IU Health Methodist campus, by the NIH-funded researchers in the area of alcohol, addiction, Alzheimer’s disease, bipolar disorder, schizophrenia, suicide and panic disorders. Other scholarly activities, such as grand rounds and neuropsychiatry group meetings, enrich the mission. Indianapolis has made a significant imprint on neuropsychiatry. Eli Lilly developed the antidepressants Aventyl in the 1960s and Prozac in the 1980s and has continued with agents such as Zyprexa and Strattera and Cymbalta in recent years. The city of Indianapolis has also supported scientific/industrial advances from the Dow, Beckman, and Alison companies. The building development on the IUPUI campus, even for those working there, has been a continual surprise over the last several decades. With the full demolition of the IPR building and the surrounding area as well as the construction of the massive Eskenazi hospital, geography of that area has changed forever. Neither the Union building, Wishard drive, nor “791 Union Drive”, the address that made in numerous pages of so many international journals, exist anymore. Demolition of the IPR building, nevertheless, did not dampen psychiatric research