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Biomedical subjects

S E Hyman

Publications and source records attributed to S E Hyman.

At least 19 recordsLinked to original sources
PubMed2001

Dopamine and glutamate induce distinct striatal splice forms of Ania-6, an RNA polymerase II-associated cyclin.

Control of neuronal gene expression by drugs or neurotransmitters is a critical step in long-term neural plasticity. Here, we show that a gene induced in the striatum by cocaine or direct dopamine stimulation, ania-6, is a member of a novel family of cyclins with homology to cyclins K/T/H/C. Further, different types of neurotransmitter stimulation cause selective induction of distinct ania-6 isoforms, through alternative splicing. The longer Ania-6 protein colocalizes with nuclear speckles and is associated with key elements of the RNA elongation/processing complex, including the hyperphosphorylated form of RNA polymerase II, the splicing factor SC-35, and the p110 PITSLRE cyclin-dependent kinase. Distinct types of neuronal stimulation may therefore differentially modulate nuclear RNA processing, through altered transcription and splicing of ania-6.

Alternative Splicing↗
PubMed2001

Addiction and the brain: the neurobiology of compulsion and its persistence.

People take addictive drugs to elevate mood, but with repeated use these drugs produce serious unwanted effects, which can include tolerance to some drug effects, sensitization to others, and an adapted state - dependence - which sets the stage for withdrawal symptoms when drug use stops. The most serious consequence of repetitive drug taking, however, is addiction: a persistent state in which compulsive drug use escapes control, even when serious negative consequences ensue. Addiction is characterized by a long-lasting risk of relapse, which is often initiated by exposure to drug-related cues. Substantial progress has been made in understanding the molecular and cellular mechanisms of tolerance, dependence and withdrawal, but as yet we understand little of the neural substrates of compulsive drug use and its remarkable persistence. Here we review evidence for the possibility that compulsion and its persistence are based on a pathological usurpation of molecular mechanisms that are normally involved in memory.

Animals↗
PubMed2000

Goals for research on bipolar disorder: the view from NIMH.

We have much yet to accomplish in research on bipolar disorder. We must find vulnerability genes. We must identify the circuits that regulate mood, emotion, energy, and other relevant functions that are affected in bipolar disorder, and we must determine what goes wrong in those circuits during mania, depression, and other aspects of this illness. We will need to translate findings in basic neuroscience, genetics, and basic behavioral science into diverse clinical applications: novel treatments, diagnostic tools, epidemiologic approaches that could lead to preventive interventions, and surrogate markers for clinical trials. We must develop improved psychosocial interventions and test both pharmacologic and psychosocial treatments in trials that, simultaneously, improve the quality of care available and convince insurers and employers that these treatments are of substantial benefit and cost effective. The agenda is ambitious, but entirely feasible, given the scientific tools and technologies that are currently available or on the horizon. The National Institute of Mental Health is newly recommitted to harnessing these tools and technologies for the benefit of people with bipolar disorder.

Animals↗
PubMed2000

The millennium of mind, brain, and behavior.

Psychiatry enters the new millennium poised to answer many of its central questions. Given the complexity of the human brain and its interactions with our world, these questions are among the most difficult ever addressed by human science. How is the human brain built? How does it change over the life span? What are the precise genetic and environmental risk factors for mental illnesses? What are the pathophysiologic processes that produce the symptoms and disabilities? How do our treatments, including psychotherapy, work? What objective markers can we discover to monitor the progression of the pathogenic processes and the effects of treatment? How will we discover preventive measures and cures that will be effective in diverse populations and settings? Parallel to the pursuit of its public health agenda, psychiatry will grow closer to neuroscience, behavioral science, and neurology. In so doing, those who practice these disciplines will be better positioned to ask meaningful questions about the relationship among mind, brain, and behavior, and to finally overcome the pervasive Cartesianism that continues to incubate stigma and ignorance about mental illness.

Biological Psychiatry↗
PubMed2000

National Institute of Mental Health goals for behavioral science.

Because all health conditions for which the National Institute of Mental Health (NIMH) is responsible manifest at the level of behavior, and all interventions must have an impact at the behavioral level, NIMH is firmly committed to the support of behavioral science. In an era in which research in areas that some view as reductionist--for example, genomics, genetics, functional genomics and proteomics, and molecular science--is especially promising, NIMH is striving to maintain a balance in its portfolio with studies that explore integrative aspects of biology, including behavior. Without this perspective, new information about fundamental processes will prove ultimately to be shallow. This commentary discusses how understanding of brain and behavior in mental illness and health calls for integrating bottom-up research that studies brain and behavior through genes and molecules, with top-down research that examines the impact of environment.

Behavioral Sciences↗
PubMed2000

The genetics of mental illness: implications for practice.

Many of the comfortable and relatively simple models of the nature of mental disorders, their causes and their neural substrates now appear quite frayed. Gone is the idea that symptom clusters, course of illness, family history and treatment response would coalesce in a simple way to yield valid diagnoses. Also too simple was the concept, born of early pharmacological successes, that abnormal levels of one or more neurotransmitters would satisfactorily explain the pathogenesis of depression or schizophrenia. Gone is the notion that there is a single gene that causes any mental disorder or determines any behavioural variant. The concept of the causative gene has been replaced by that of genetic complexity, in which multiple genes act in concert with non-genetic factors to produce a risk of mental disorder. Discoveries in genetics and neuroscience can be expected to lead to better models that provide improved representation of the complexity of the brain and behaviour and the development of both. There are likely to be profound implications for clinical practice. The complex genetics of risk should reinvigorate research on the epidemiology and classification of mental disorders and explain the complex patterns of disease transmission within families. Knowledge of the timing of the expression of risk genes during brain development and of their function should not only contribute to an understanding of gene action and the pathophysiology of disease but should also help to direct the search for modifiable environmental risk factors that convert risk into illness. The function of risk genes can only become comprehensible in the context of advances at the molecular, cellular and systems levels in neuroscience and the behavioural sciences. Genetics should yield new therapies aimed not just at symptoms but also at pathogenic processes, thus permitting the targeting of specific therapies to individual patients.

Genetic Predisposition to Disease↗
PubMed1999

Proenkephalin transgene regulation in the paraventricular nucleus of the hypothalamus by lipopolysaccharide and interleukin-1beta.

Immunologic challenge with lipopolysaccharide (LPS) or interleukin-1beta (IL-1beta) produces a functional response within the paraventricular nucleus of the hypothalamus (PVN) and leads to changes in gene expression within PVN neurons. Regulated expression of neuropeptide genes within neurons of the PVN is a potential mechanism by which an organism can adapt to stressful challenges. Here, the authors used a transgenic mouse model in which expression of a readily measurable beta-galactosidase reporter was driven in PVN neurons by human proenkephalin regulatory sequences. This proenkephalin-beta-galactosidase transgene has been demonstrated previously to respond appropriately to a variety of stressors. It is demonstrated that expression of the proenkephalin transgene product was up-regulated significantly in a subset of PVN neurons 6 hours following intraperitoneal LPS (16-400 microg/kg) administration, remained elevated at 12 hours, and fell below basal levels by 24 hours. A more rapid and transient pattern of transgene up-regulation in the PVN followed administration of intraperitoneal IL-1beta (10 microg/kg) with significant induction by 2 hours, peak levels reached by 4 hours, and a return toward basal levels by 6 hours. IL-1beta (10-50 ng/mouse) administered intracerebroventricularly also led to up-regulation of the transgene 6 hours following infusion. Transgene expression was not up-regulated in hypothalamic slice cultures treated directly with IL-1beta (5-10 ng/ml media). Up-regulation of transgene expression does not appear to result from local action of IL-1beta at the level of the PVN but, rather, through as yet unidentified intermediates. The authors demonstrate phosphorylation of the cyclic amino-3-hydroxy-5-methyl-4-isoxazolepropionate response element binding protein, a transcription factor known to interact with proenkephalin regulatory sequences within the transgene, in the PVN following LPS administration. LPS induced up-regulation of the transgene was blocked by pretreatment with naltrexone, indicating an additional role for endogenous opioid systems in regulation of the PVN response to immune challenge.

Animals↗