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Biomedical subjects

Steven E Hyman

Publications and source records attributed to Steven E Hyman.

At least 19 recordsLinked to original sources
PubMed2026

Schizophrenia Spectrum Biomarkers Consortium: Establishment of a Biorepository for the Discovery of Quantitative Fluid Biomarkers.

BACKGROUND AND HYPOTHESIS: Schizophrenia spectrum disorders (SSDs) produce severe symptoms, disability, and premature mortality, but only partially effective symptomatic treatments exist. Treatment development is impeded by lack of insight into disease mechanisms or objective biomarkers for clinical trials. Advances in genetics and neurobiology have converged on strong pathogenic hypotheses for SSDs centered on synapse dysfunction and excessive pruning, pathogenic processes that may produce measurable proteomic evidence in cerebrospinal fluid (CSF). Leveraging design precedents from successful fluid biomarkers discovery for Alzheimer's disease, we undertook a pilot study to test the feasibility of repeated CSF and blood samples collection from individuals with SSDs. Here we report on successful implementation of longitudinal bio-behavioral phenotyping in SSDs and establishment of a repository to permit broad sample and data sharing. STUDY DESIGN: The Schizophrenia Spectrum Biomarkers Consortium (SSBC) study principles included longitudinal study design, paired CSF and plasma collection associated with robust phenotypic characterization, at 3 academic sites and the establishment of a biorepository. Participants underwent clinical and cognitive assessments, neuroimaging, blood draws, and CSF collection via lumbar puncture (LP) every 6 months. STUDY RESULTS: SSBC successfully enrolled 48 SSD and 41 Healthy Controls with a 73% longitudinal retention. Clinical, cognitive, and neuroimaging results were consistent across sites and with existing studies. Study procedures were well tolerated, and almost all LPs (99%) resulted in either no or minor headache/backache that resolved without medical interventions. CONCLUSIONS: The pilot SSBC study demonstrates that a multi-site, longitudinal study with repeat CSF collection is feasible, with excellent participant acceptability and retention.

Humans↗
PubMed2006

The Homer-1 protein Ania-3 interacts with the plasma membrane calcium pump.

The Homer family of scaffold proteins couples NMDA receptors to metabotropic glutamate receptors and links extracellular signals to calcium release from intracellular stores. Ania-3 is a member of the Homer family and is rapidly inducible in brain in response to diverse stimuli. Here, we report the identification of the plasma membrane Ca2+ ATPase (PMCA) as a novel Ania-3/Homer-associated protein. Ania-3/Homer interacts with the b-splice forms of all PMCAs (PMCA1b, 2b, 3b, and 4b) via their PDZ domain-binding COOH-terminal tail. Ectopically expressed Ania-3 colocalized with the PMCA at the plasma membrane of polarized MDCK epithelial cells, and endogenous Ania-3/Homer and PMCA2 are co-expressed in the soma and dendrites of primary rat hippocampal neurons. The interaction between Ania-3/Homer and PMCAs may represent a novel mechanism by which local calcium signaling and hence synaptic function can be modulated in neurons.

Animals↗
PubMed2006

Neural mechanisms of addiction: the role of reward-related learning and memory.

Addiction is a state of compulsive drug use; despite treatment and other attempts to control drug taking, addiction tends to persist. Clinical and laboratory observations have converged on the hypothesis that addiction represents the pathological usurpation of neural processes that normally serve reward-related learning. The major substrates of persistent compulsive drug use are hypothesized to be molecular and cellular mechanisms that underlie long-term associative memories in several forebrain circuits (involving the ventral and dorsal striatum and prefrontal cortex) that receive input from midbrain dopamine neurons. Here we review progress in identifying candidate mechanisms of addiction.

Animals↗
PubMed2005

Metabotropic glutamate receptors and dopamine receptors cooperate to enhance extracellular signal-regulated kinase phosphorylation in striatal neurons.

Striatal medium spiny neurons are an important site of convergence for signaling mediated by the neurotransmitters dopamine and glutamate. We report that in striatal neurons in primary culture, signaling through group I metabotropic glutamate receptors (mGluRs) 1/5 and the D1 class of dopamine receptors (DRs) 1/5 converges to increase phosphorylation of the mitogen-activated protein kinase ERK2 (extracellular signal-regulated kinase 2). Induction of mitogen-activated protein kinase kinase-dependent signaling cascades by either mGluR1/5 or DR1/5 gave rise to increases in phosphorylation of ERK2. Coactivation of mGluR1/5 and DR1/5 with (S)-3,5-dihydroxyphenylglycine and (+)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride enhanced the phosphorylation of ERK2. This interaction between mGluR1/5 and DR1/5 required protein kinase C (PKC), because the PKC inhibitors calphostin C, bisindolylmaleimide I, and Gö6976 blocked DR1/5-enhanced phosphorylation of ERK2. Use of the phosphatase inhibitors calyculin and okadaic acid indicated that inhibition of protein phosphatases 1 and 2A dramatically enhanced ERK2 phosphorylation by mGluR1/5. Coactivation of mGluR1/5 and DR1/5 also enhanced cAMP-response element binding protein (CREB) phosphorylation (compared with each receptor agonist alone) but did not enhance CREB-mediated transcriptional activity. Thus, signal transduction pathways activated by DR1/5 and mGluR5 interact to modify downstream events in striatal neurons while retaining numerous regulatory checkpoints.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2005

The impact of terrorism on brain, and behavior: what we know and what we need to know.

Following the recent US experience with terrorism, including bioterrorism, significant biomedical research resources have been appropriately focused on bioterror weapons. Far less research attention has been focused on the behavioral and psychobiological effects of terrorism. Yet, the psychological responses to terrorism exert significant effects on mental and physical health and on society. We present a research agenda, based on a comprehensive review of the literature, to address the troubling gaps in our knowledge about the long-term effects of terrorism on brain, behavior, and physical health, the risk factors for predicting who will be most affected by terrorism, and interventions that might promote resilience at an individual and population level.

Behavior↗
PubMed2005

Addiction: a disease of learning and memory.

If neurobiology is ultimately to contribute to the development of successful treatments for drug addiction, researchers must discover the molecular mechanisms by which drug-seeking behaviors are consolidated into compulsive use, the mechanisms that underlie the long persistence of relapse risk, and the mechanisms by which drug-associated cues come to control behavior. Evidence at the molecular, cellular, systems, behavioral, and computational levels of analysis is converging to suggest the view that addiction represents a pathological usurpation of the neural mechanisms of learning and memory that under normal circumstances serve to shape survival behaviors related to the pursuit of rewards and the cues that predict them. The author summarizes the converging evidence in this area and highlights key questions that remain.

Animals↗
PubMed2004

Decreased absolute amygdala volume in cocaine addicts.

The amygdala is instrumental to a set of brain processes that lead to cocaine consumption, including those that mediate reward and drug craving. This study examined the volumes of the amygdala and hippocampus in cocaine-addicted subjects and matched healthy controls and determined that the amygdala but not the hippocampus was significantly reduced in volume. The right-left amygdala asymmetry in control subjects was absent in the cocaine addicts. Topological analysis of amygdala isosurfaces (population averages) revealed that the isosurface of the cocaine-dependent group undercut the anterior and superior surfaces of the control group, implicating a difference in the corticomedial and basolateral nuclei. In cocaine addicts, amygdala volume did not correlate with any measure of cocaine use. The amygdala symmetry coefficient did correlate with baseline but not cocaine-primed craving. These findings argue for a condition that predisposes the individual to cocaine dependence by affecting the amygdala, or a primary event early in the course of cocaine use.

Adult↗
PubMed2004

Computational roles for dopamine in behavioural control.

Neuromodulators such as dopamine have a central role in cognitive disorders. In the past decade, biological findings on dopamine function have been infused with concepts taken from computational theories of reinforcement learning. These more abstract approaches have now been applied to describe the biological algorithms at play in our brains when we form value judgements and make choices. The application of such quantitative models has opened up new fields, ripe for attack by young synthesizers and theoreticians.

Animals↗
PubMed2003

Regulation of ania-6 splice variants by distinct signaling pathways in striatal neurons.

The striatum is a brain region involved in motor control and in diverse forms of implicit memory. It is also involved in the pathogenesis of many significant human disorders, including drug addiction, that are thought to involve adaptive changes in gene expression. We have previously shown that the cyclin L, ania-6, is expressed as at least two splice forms, which are differentially regulated in striatal neurons by different neurotransmitters. Here, we report that ania-6 transcription is mostly regulated via cAMP response element binding protein (CREB), but that signaling pathways that converge on CREB at the transcriptional level produce different effects on splicing and neuronal gene expression. Glutamate induced a long ania-6 mRNA that encodes a truncated form of the cyclin. This effect depended on the activation of NMDA receptors but was independent of both calcium/calmodulin-dependent protein kinases (CaMK) and extracellular regulated kinase (ERK). Forskolin or brain-derived neurotropic factor (BDNF) induced a short ania-6 mRNA, that encodes the full-length cyclin, and this induction depended on ERK. However, KCl-mediated induction of ania-6 short mRNA, which required activation of L-type calcium channels, was independent of ERK but depended on CaMK. These data suggest that different neuronal signals can differentially regulate splicing and that different intracellular pathways can be recruited to yield a given splice variant.

Alternative Splicing↗
PubMed2002

The human genome project and its impact on psychiatry.

There has been substantial evidence for more than three decades that the major psychiatric illnesses such as schizophrenia, bipolar disorder, autism, and alcoholism have a strong genetic basis. During the past 15 years considerable effort has been expended in trying to establish the genetic loci associated with susceptibility to these and other mental disorders using principally linkage analysis. Despite this, only a handful of specific genes have been identified, and it is now generally recognized that further advances along these lines will require the analysis of literally hundreds of affected individuals and their families. Fortunately, the emergence in the past three years of a number of new approaches and more effective tools has given new hope to those engaged in the search for the underlying genetic and environmental factors involved in causing these illnesses, which collectively are among the most serious in all societies. Chief among these new tools is the availability of the entire human genome sequence and the prospect that within the next several years the entire complement of human genes will be known and the functions of most of their protein products elucidated. In the meantime the search for susceptibility loci is being facilitated by the availability of single nucleotide polymorphisms (SNPs) and by the beginning of haplotype mapping, which tracks the distribution of clusters of SNPs that segregate as a group. Together with high throughput DNA sequencing, microarrays for whole genome scanning, advances in proteomics, and the development of more sophisticated computer programs for analyzing sequence and association data, these advances hold promise of greatly accelerating the search for the genetic basis of most mental illnesses while, at the same time, providing molecular targets for the development of new and more effective therapies.

Chromosome Mapping↗