ABEL, EDWIN G. (Ted), Ph.D.
Assistant Professor; Department of Biology, School of Arts and Sciences

Dr. Abel's laboratory examines the molecular basis and behavioral significance of synaptic plasticity in learning and memory, development of the nervous system, and in neurological and psychiatric disorders. Dr. Abel's laboratory examine deficits in long-term memory and synaptic plasticity in transgenic mice in which PKA activity in the hippocampus is reduced by the transgenic expression of R(AB), a dominant negative form of the regulatory subunit of PKA. New lines of transgenic mice are being developed in which expression of the R(AB) transgene is regulated temporally, quantitatively and spatially. Inducible systems that express different transgenes that enhance PKA activity will be used to determine if memory can be improved by altering this signaling pathway. Imaging approaches are being developed to follow th activation of PKA in neurons following the induction of long-term potentiation. Dr. Abel is the organizer of the Neurobehavioral Genetics Club (Mouse Club) and collaborates with Drs. Arnold, Blendy, Bucan, Gur, Klein, Thomas and Lucki.

Professor; Department of Psychiatry

Jay D. Amsterdam, M.D. is Professor of Psychiatry and Director of the The Depression Research Unit (DRU). The DRU is an internationally recognized clinical/research facility founded in 1966. The principal research focus of the DRU is: (i) development of new antidepressant therapies (including controlled clinical trials; (ii) bipolar disorders; (iii) treatment-resistant depression: (iv) psychoneuroendocrinology of depression; (v) psychoimmunovirology of depression; (vi) SPECT and PET brain imaging. The faculty of the DRU maintains active scientific and research collaborations with other investigators within the University Medical Center including the Departments of Medicine, Trauma Surgery, Radiology, Psychology, Pathology, and Bioethics. Collaborations have also been established with researchers at other Universities in the US and abroad, including Dr. Rickels.

Associate Professor; Department of Psychiatry

Dr. Arnold's laboratory investigates the cellular and molecular neuropathologic substrates of neuropsychiatric disorders. The principal areas of research are schizophrenia, Alzheimer's disease and related dementias, late life depression, and human fetal brain development. Dr. Arnold examines both neurodevelopmental and neurodegenerative aspects of these disorders. Tissue from cases that have been well-characterized with clinical research scales are used in the neuroanatomic studies which employ immunohistochemistry and in situ hybridization, along with novel quantitative microscopic image analysis. Current projects include studies of neuronal morphometry, specific and non-specific molecular markers of neurodegenerative diseases and cell death, cytoskeletal protein and mRNA expression, synapse related protein expression, and the integrity of excitatory-inhibitory neuron ensembles in limbic and frontal cortices. Dr. Arnold collaborates with Drs. Abel and Gur.

Professor; Department of Psychiatry

The Aston-Jones lab has 4 major research programs: (1) Drug abuse identify neural mechanisms for drug craving during protracted withdrawal using anatomical, pharmacological and neurophysiological methods. (2) Cognitive neuroscience specify the role of neuromodulatory systems of noradrenergic, dopaminergic and serotonergic neurons in cognitive function using neurophysiological, pharmacological and behavioral methods in waking primates. (3) Sleep & circadian regulation determine the roles of noradrenergic, dopaminergic and serotonergic neurons in regulation of sleep and waking using neurophysiological, pharmacological and behavioral methods in primates and rats. (4) Mood disorders Determine the role of noradrenergic brain systems in depression, and identify novel countermeasures to reverse behavioral and anatomical signs of depression using pharmacological and behavioral methods in rats. Dr. Aston-Jones collaborates with Drs. Dinges, Miselis, and Ross.

Associate Professor; Department of Pediatrics

The overall goal of Dr. Beck's research program is to elucidate how substrates of the stress response alter neural activity and are involved in the etiology and treatment of medical and psychiatric disorders, such as depression, anxiety, epilepsy, and stroke. The adrenal "stress" steroid hormones cortisol or corticosterone are important in maintaining homeostasis through interaction with their receptors in the CNS. In certain mood disorders the stress hormone levels are chronically elevated, and current hypotheses are that long term exposure to stressful stimuli and stress hormones leads to changes in neural activity that may underlie the development of pathological disease states such as depression and anxiety. We have found that adrenal steroids alter both basic cellular properties as well as responses mediated by the neurotransmitter receptor serotonin. Dr. Beck's laboratory is studying changes in neural activity in the 5-HT-limbic circuit due to chronic treatment with high corticosterone, different chronic stress paradigms, and chronic treatment with antidepressants. Our hypothesis is that there is a selective regulation of both basic cell characteristics as well as 5-HT receptor mediated effects by chronic treatment with corticosterone and/or antidepressants wihin this 5-HT-limbic circuit. Dr. Beck collaborates with Drs. Lucki and Valentino.

Professor; Departments of Psychiatry and Genetics

Dr. Berrettini's research interests concern the assessment of genetic contributions to normal behavior and to psychiatric disorders. Genetic studies in human populations are conducted to identify susceptibility genes for manic-depressive disorder, alcoholism, anorexia nervosa and heroin dependence. In addition, animal models for psychiatric disorders, especially for substance abuse, are being used to identify and study genes linked to special behavioral characteristics associated with abnormal behavior. In addition, studies are underway to identify genes involved in eating disorders, such as anorexia nervosa and obesity. Dr. Berrettini is Director of the Center for Neurobiology and Behavior. Dr. Berrettini collaborates with Drs. Blendy, Bucan, Ferraro, Lucki and O'Brien.

Assistant Professor; Department of Pharmacology

My laboratory is focused on establishing the functions of the CREB family of transcription factors (CREB and CREM) as modulators of CNS function. This family of proteins regulates the intracellular function of cAMP, an important signaling mechanism for a number of neurotransmitters. One major focus of the laboratory concerns the role of genomic regulation in the development and maintenance of addiction. A second focus involves identification of the role of CREB in mechanisms underlying reactivity to stress and the effects of antidepressant drugs. New mouse models currently under development in my lab will serve to delineate the regulatory pathways and targets that accompany the development of addiction and depression as well as the action of antidepressant and addictive drugs. This will involve the use of spatially and temporally restricted gene deletions (Cre/loxP system) as well as microarray analysis of CREB target genes. Bridging molecular techniques with behavioral phenotyping places us in a unique position to study complex neuropsychiatric disorders in a highly tractable mouse model system. Dr. Blendy is organizer of monthly meetings of the Drug Club. Dr.Blendy collaborates with Drs. Abel, Berretini, Lucki, Thomas, and Valentino.

Professor; Departments of Genetics and Psychiatry

Advances in the identification of genes causing complex disease, such as psychiatric disorders, have been modest. Current focus is on the identification of genes associated with specific endophenotypes - biochemical, physiological or behavioral components of a clinical syndrome. These traits are being used to increase resolution of human genetics studies. At the same time, efforts are underway to identify single gene mutations affecting corresponding traits in the mouse. We are currently identifying and characterizing behavioral mutations induced by ENU mutagenesis in the mouse. This project combines a whole genome screen for dominant behavioral mutations with a region-specific mutagenesis screen for mutations in the proximal portion of mouse chromosome 5. Research in the laboratory has focused on genes associated with circadian rest-activity cycles and a model of bipolar disease. Dr. Bucan collaborates with Drs. Abel, Berrettini, and Gur.

Professor; Department of Psychiatry, Division Chief and Laboratory Director

Dr. Dinges’ research program involves basic experiments in healthy humans and patient populations on the control of neurobehavioral, cognitive and physiological functions by sleep homeostasis and circadian rhythms. Experiments are directed at the dual goals of establishing the nature of the physiological and neurobehavioral changes engendered by sleep loss and circadian rhythmicity, and testing the effectiveness of interventions and countermeasures for sleepiness and fatigue. Techniques include intensive physiological monitoring of core body temperature, EEG, ECG, EOG, EMG, and actigraphy, over many days; EEG power spectral analysis; polysomnography; computerized and simulation-based neurobehavioral testing; time-series analyses of neuroendocrine and neuroimmune profiles; clinical trials of wake-promoting therapeutics and hypnotics; prolonged time-isolation and both acute and chronic sleep deprivation protocols; development of sensitive neurobehavioral assays of pharmacological effects; and statistical and biomathematical modeling. Current areas under investigation include: (1) establishing the effects in severely sleep-deprived humans of stimulant drugs and novel wake-promoting therapeutics on neurocognitive and physiological functions, relative to the temporal dynamics of sleep and circadian neurobiology; (2) biomathematical modeling of dose-dependent chronic sleep restriction and recovery sleep physiology on cumulative fatigue and cognitive functions; (3) investigation of novel sleep-promoting pharmacological agents; (4) experimentally deriving response surface models of cognitive and neuroendocrine functions of a result of chronic sleep-wake schedules; (5) investigation of the phenotypic basis for differential vulnerability of neurocognitive responses to sleep deprivation; (6) evaluation of behavioral, pharmacological and technological countermeasures to deficits from sleep loss and circadian rhythmicity in medical and occupational contexts. Dr. Dinges collaborates with Dr. Aston-Jones.

Professor; Departments of Pharmacology and Psychiatry

Dr. Eberwine's research interests focus on the genetic control of drug-induced tolerance and molecular mechanisms underlying control of circadian rhythmicity in the rat supra-chiasmatic nucleus. He utilizes the techniques of molecular biology and protein chemistry to isolate and charac-terize various components of opiate-regulated systems. His research involves efforts at cloning the D-opioid receptor and examining other presumed "tolerance factors" using transfection activity protocols. His research also studies the isolation and characterization of circadian-regulated mRNA transcripts using in situ transcription cloning and analysis strategies. To perform these studies, new subtraction hybridization protocols have been developed that easily permit the clon-ing of mRNA molecules from localized brain regions. Using these techniques, cDNA libraries can be made from single neuronal cells.

Professor and Chair; Department of Psychiatry

Dr. Evans' research examines how stress and depression may affect key parameters of cellular immunity in normal subjects, psychiatric patients and patients with HIV infection. Stress and depressive symptoms, especially when they occur jointly, are associated with decreased cellular immunity. In immunocompromised individuals, such as patients with HIV infection or cancer, stress and depressive symptoms may have clinical implications for the course of the disease. Underlying mechanisms with a specific focus on innate immunity are being studied as well as neuroendocrine and neuropeptide mechanisms. Dr. Evans collaborates with Dr. Lucki.

Research Associate Professor; Departments of Psychiatry and Pharmacology

Research in Dr. Ferraro's laboratory is focused on mapping and identifying genes for complex traits as they relate to the etiology and treatment of neurological and psychiatric disorders. The general strategy involves the identification of candidate genes in animal models and subsequent investigation of homologs of those genes in patient populations. Current projects focus strongly on seizure susceptibility genes mice as they relate to genetic susceptibility to epilepsy in humans. In associated projects, pharmacogenomic strategies are being applied to address individual variability in responsiveness to anticonvulsant drugs. These studies involve genetic mouse models of anticonvulsant action and subsequent clinical translation to patients with treatment-refractory epilepsy. Other projects address opioid action in mice as it relates to opioid addiction in humans. Studies focus on mapping and identifying genes in mice that influence the effects of morphine and the subsequent analysis of gene homologs in opioid-dependent humans. Dr. Ferraro collaborates with Drs. Berrettini and Lucki.

Professor; Department of Animal Biology, School of Veterinary Medicine

Dr. Fluharty's program encompasses two areas: 1) Studies of biochemical and physiological characteristics of catecholaminergic neurons in central and peripheral nervous systems. In live animals, Dr. Fluharty and his col-leagues manipulate or stimulate selected nerves and evaluate the consequent effects on tyrosine hydroxylase activity by relating enzyme measurements to the ability of such tissues as adrenal, heart and brain slices to release cate-cholamines. They are attempting to determine to what extent these presynaptic events influence postsynaptic receptor-effector systems for catecholamines; 2) Studies of the similarities between central and peripheral angio-tensin II receptors by examining their specificities for agonists and antagonists, their regulation by ions and gua-nine nucleotides and their coupling to such intracellular effector mechanisms as adenylate cyclase or phosphati-dylinositol hydrolysis. He and his co-workers are exploring the possibility that angiotensin II modulates catecholaminergic function by binding to presynaptic receptors that augment amine release and/or by binding to postsynaptic receptors sharing intracellular effector mechanisms with catecholaminergic receptors. Dr. Fluharty collaborates with Dr. Misselis.

Professor; Department of Psychiatry

The focus of Dr. Gur's research program is the evaluation of brain-behavior relationships in healthy control subjects and in psychiatric and neurological patients. Its purpose is to develop a neuropsychological perspective on psychiatric disorders (particularly schizophrenia(s) and affective disorders). Dr. Gur is Director of the Neuropsychiatry Research Training Program. Clinical, behavioral and neuropsy-chological data pertinent to regional brain function in psychiatric patients are obtained and are compared to findings in neurological patients with unilateral stroke, in patients with Parkinson's disease and in normal con-trols. Clinical data are derived from standardized neurological and psychiatric examinations. Behavioral data are obtained with a comprehensive neuropsychological battery that measures sensory-perceptive, motor, emotional and cognitive functions. Regional brain activity is determined by the 133-Xenon inhalation technique for measuring regional cerebral blood flow (rCBF) and by positron emission tomography (PET) for measuring glucose metabolism. The rCBF measurements are performed during rest and during activation with cognitive and emotional tasks. In order to confirm the relationship between the behavioral and physiological abnormalities and the clinical status, all mea-sures are obtained in a group of patients during the acute phase of illness and again after they are stable (3-5 months follow-up). Dr. Gur collaborates with Drs. Abel, Arnold, and Bucan.

Associate Professor, Departments of Medicine and Cell and Developmental Biology

Dr. Klein's laboratory studies the molecular mechanisms of lithium action in development and in the treatment of psychiatric disorders. The Klein lab has demonstrated that lithium directly and potently inhibits GSK-3, a negative regulator of the wnt and insulin signaling pathways. Inhibition of GSK-3 by lithium in turn activates wnt signaling and transcription of wnt regulated genes. While these findings show that the developmental effects of lithium are mediated through inhibition of GSK-3, the target of lithium in behavior and other settings remains unclear. My laboratory has developed multiple tools to validate GSK-3 as a target of lithium in these other settings, including pharmacological and genetic approaches. These include the identification of novel pharmacological inhibitors of GSK-3 and the use of gene knockouts and conditional transgene expression in mice. The lab has identified lithium sensitive behaviors in mice and demonstrated that mice lacking one copy of the GSK-3 gene exhibit similar behaviors as lithium treated animals. Molecular changes, including changes in neuronal gene expression and post-translational modifications are also similar in lithium treated and GSK-3 deficient mice. Alternative inhibitors of GSK-3 have been identified and genes encoding these novel GSK-3 inhibitors are currently being expressed using inducible promoters in transgenic mice to test whether they can mimic the behavioral effects of lithium and loss of GSK-3. The laboratory has also found that lithium reduces accumulation of -amyloid peptides in mice through direct inhibition of GSK-3alpha. Future work will address conditional disruption of GSK-3 alpha and beta in mice. Dr. Klein collaborates with Dr. Abel.

Professor; Departments of Radiology and Pharmacology

The laboratory of Dr. Kung is a multidisciplinary research and education group in the Department of Radiology. The focus of the group is the development of new radiopharmaceuticals that provide diagnostic information on various organs in normal and disease states. Current research interests include: 1) developing imaging agents for CNS receptors (dopamine, norepinephrine and serotonin neurotransmitter systems), 2) agents for imaging Alzheimer's disease, and 3) neuronal functional imaging of the heart. Major research activity comprises a wide spectrum of scientific disciplines: drug design, organic synthesis, radiochemistry, receptor pharmacology, pharmacokinetics, and physics and instrumentation of gamma imaging tomography devices. Dr. Kung collaborates with Drs. Lucki, Manning and O'Brien.

Trustee Professor; Departments of Neuroscience and Pharmacology

Dr. Lindstrom's laboratory investigates nicotinic acetylcholine receptors and the autoimmune response to muscle acetylcholine receptors which occurs in myasthenia gravis. He is studying the structures of the three branches of the ligand-gated ion channel gene family with nicotinic pharmacological properties: 1) acetylcholine receptors from muscles, 2) acetylcholine receptors from nerves, and 3) neuronal a-bungarotoxin binding proteins. All are formed from multiple homologous subunits and exist in multiple subtypes. Muscle type nicotinic receptors are the archetypic neurotransmitter receptor and their structure is known in the greatest detail. Subunit compositions of neuronal nicotinic receptors are being defined. Some subunit cDNAs of a- bungarotoxin binding proteins have been cloned, but their structures are the least well defined and their functions are unknown. Receptors from fish electric organs, mammalian muscles, and avian and mammalian neurons are being studied. Monoclonal antibodies and cDNAs are the major tools used in these studies. Goals are to determine the structures of these receptors, study how they function, how they are synthesized, where they are located and what their functional roles are. The clinical significance of neuronal nicotinic receptors and a-bungarotoxin binding proteins is not well characterized. They mediate the addictive response to tobacco in smokers, and their amount is upregulated in the brains of smokers. Their amount is reduced in the brains of those with Alzheimer's and Parkinson's diseases. It is hoped that structural studies of neuronal nicotinic receptors will lead to better understanding of some central neurological diseases, just as studies of muscle nicotinic receptors lead to better understanding of myasthenia gravis.

Professor; Departments of Psychiatry and Pharmacology, Director

Dr. Lucki's research program involves examination of the behavioral effects of antidepressant, antianxiety and antipsychotic medications in both preclinical and clinical settings. He and his colleagues develop and study func-tional models of CNS neurotransmission in rats to determine the behavioral effects caused by activating subtypes of serotonin and dopamine re-cep-tors. Behavioral models have been developed in his laboratory to study functional effects of monoamine receptors that are related to psychopathology, using techniques such as: elicitation of agonist-specific behaviors, drug discrimination, and animal models of psychopathology. Their studies examine the role of brain monoamine pathways and specific types of receptors responsible for the behavioral effects of antidepressant or antianxiety drugs. Behavioral effects of agonists and antagonists are examined on behavioral models of depression and anxiety in rodents. The contribution of genetic variables to psychopathology is being examined by measuring behavioral changes and drug effects in mice with genetic deletion of selected serotonin receptors. In addition, the effects of drugs and environmental stressors on the release of serotonin and dopamine are being studied using in vivo microdialysis. Dr. Lucki collaborates with Drs. Abel, Beck, Berrettini, Blendy, Evans, Ferraro, Kung, Manning, Rickels, Ross, Thomas, and Valentino.

Assistant Professor; Departments of Neurology and Pediatrics

Dr. Lynch's research has been directed toward understanding the pharmacological features of the NMDA receptor using molecular biological approaches. This glutamate receptor is a crucial component of excitotoxicity, a pathophysiological mechanism of acute and chronic neurologic disorders. Dr. Lynch's work has concentrated on defining the properties of specific subtypes of NMDA receptors in order to define therapeutic agents and approaches that ameliorate excitotoxicity without producing significant side effects. The initial studies from his lab used site directed mutagenesis to define the structural components of NMDA receptors that mediate subtype specific stimulation by polyamines and subtype specific inhibition by agents such as ifenprodil and haloperidol. Subsequent experiments have defined structural components of the receptor mediating subtype specific modulation of the NMDA receptor by protein kinase C. In these investigations, Dr. Lynch's lab also linked specific NMDA receptor subtypes to increased levels of cell death and reactive oxygen species production, connecting their cellular work with mechanisms of neuronal degeneration. The most recent work identifies the subtype specific NMDA receptor activation of calpain, and demonstrates that this enzyme may control turnover of NMDA receptors under excitotoxic conditions. Calpain, an enzyme activated selectively by NMDA receptors, also may play a crucial role in protein turnover of other disease causing proteins such as alpha synuclein, further associating Dr. Lynch's laboratory investigations with pathophysiological mechanisms of neurological and psychiatric disorders. Dr. Lynch collaborates with Dr. Robinson.

Professor; Department of Pharmacology

Dr. Manning's research program focuses on the mechanisms of hormonal and neurotransmitter action with emphasis on the involvement of guanine nucleotide-binding regulatory proteins (G proteins). In particular, the utilization of G proteins by growth factors is a current topic of study in Dr. Manning's laboratory. G proteins that interact with receptors for mitogenic and transforming growth factors are being defined, as are those subject to post-translational modification. Also, isoelectric focusing in conjunction with antibodies specific for primary structures is being used both to define cell complements of G proteins and to detect heterogeneity within seem-ingly homogeneous subunits. Finally, distributions of G proteins within the plasma membrane and among sub-cellular structures are being investigated by means of light and electron microscopy. The relationship of these distributions to those of receptors and target enzymes (or channels) is a likely determinant of hormonal specificity. Dr. Manning collaborates with Drs. Kung, Lucki and Pittman.

Professor; Department of Animal Biology, School of Veterinary Medicine

Dr. Miselis' research interests are on the neuroanatomical organization and function of the neural circuitry that mediates central control of visceral function. He is particularly interested in the precise neuroanatomical iden-tification of neural networks serving behavioral and physiological controls of homeostatic processes governing fluid balance and body weight control. Current topics are: circumventricular organs as sites of central receptors and their neural connections; the central organization of visceral afferent and efferent projections to the abdominal and thoracic viscera; hypothalamic and brainstem modulation of behavior; characterization of visceral neural networks by receptor autoradiography; in situ hybridization histochemistry for particular gene products. Dr. Miselis collaborates with Drs. Aston-Jones, Fluharty, and Valentino.

Professor, Department of Animal Biology, School of Veterinary Medicine

Dr. Morrison's group studies the amygdala's involvement in the regulation of sleep and wakefulness. A large body of literature supports the contention that the ability to attach emotional significance to sensory events resides in the amygdala. The amygdala is well connected anatomically to mediate aspects of attention dependent on reception of significant stimuli. Thus, the amygdala may be a key structure in deciding whether alerting stimuli are important enough to arouse an animal into full wakefulness. Using fear conditioning as a tool, the laboratory has found that manipulations of the amygdala appear to affect primarily REM sleep. The focus is primarily on the major sensory nucleus of the amygdala, the lateral nucleus, and serotonergic mechanisms operating within it. Dr. Morrison collaborates with Dr. Ross.

Professor; Department of Psychiatry

Dr. O'Brien's P60 NIH comprehensive research center investigates basic and clinical aspects of addiction to opiates, cocaine, alcohol and nicotine. Dr. O'Brien is Director of the Training Program in Substance Abuse. Work in his laboratory on the mechanisms of dependence involves both human and animal studies on conditioned effects of opioids and stimulants and their potential role in the persistence of drug self-administration. Physiologic and behavioral measures have been used to detect unconditioned and conditioned drug effects. Brain imaging in human subjects, both patients and normals, utilizes PET for studies of activation as measured by regional blood flow changes, measurement of neurotransmitter release using radio-labeled ligands and fMRI for studies of brain activation. Clinical studies are directly related to laboratory research and involve the testing of new medications such as cannabinoid antagonists for nicotine or alcohol dependence, GABA enhancing medications for reduction of drug craving, modafinil for cocaine dependence and pharmacogenetic studies of the treatment of alcoholism and cocaine addiction. Dr. O'Brien collaborates with Drs. Berrettini and Kung.

Professor; Department of Pharmacology

Cellular and molecular approaches are used to study signaling pathways controlling cell survival, cell death (apoptosis), and early nuclear events in polyglutamine neurodegenerative diseases. The two major projects in the lab are: 1) characterizing signaling pathways in the execution phase of apoptosis, and 2) investigating the relationship between CAG trinucleotide repeat proteins, the nuclear environment, the ubiquitin/proteasome machinery, and neuronal dysfunction/death. Apoptosis experiments are focused on understanding cellular events controlling signal transduction in the execution phase with particular emphasis on cytoskeletal changes associated with entry into the execution phase and dynamic membrane blebbing. Other studies on apoptosis are focused on kinase signaling at the interface of cell survival and cell death. Studies on the polyglutamine disease protein, ataxin-3, are currently focused on the relationship between the nuclear environment, transcriptional regulation, ubiquitination and proteasome system and neuronal dysfunction/death using cellular and animal models and reconstituted cellular and biochemical systems. Dr. Pittman collaborates with Dr. Manning.

Professor; Department of Psychiatry

Dr. Rickels' research program is involved in the assessment of the efficacy and safety of a variety of psychotropic agents in the Psychopharmacology Research and Treatment Clinic. Double-blind placebo-controlled trials focus on assessment of new and reference antidepressant, antianxiety and hyp-notic drugs, in particular. Working with Dr. Moira Rynn, the Clinic has also developed a program for assessment of pediatric psychopharmacology. Other issues examined in these studies include non-drug factors influencing the response to psychotropic drug treatment and the use of psychotropic agents in general practice settings. Dr. Rickels is particularly interested in the long-term treatment of GAD patients with medication. He just started a large NIMH supported study of the long-term treatment of GAD with venlafaxine XR. Dr. Rickels is also examining the efficacy and side effects associated with long-term use of benzodiazepines. Areas of concentration in this program include evaluation of the benefits of continuous, long-term benzodiazepine therapy for chronic anxiety states, problems of withdrawal from long-term treatment with various benzodiazepine compounds, treatment alternatives for benzodiazepines once they are withdrawn, psychological and cognitive assessments of patients on long-term benzodiazepine therapy and the ef-fects of anxiety and psychotropic drug treatment for anxiety on neuroendocrine function. Dr. Rickels collaborates with Drs. Amsterdam and Lucki.

Research Associate Professor; Departments of Pediatrics and Pharmacology

Glutamate and aspartate are the predominant excitatory neurotransmitters in the mammalian CNS. In addition to mediating rapid synaptic depolarization, these excitatory amino acids (EAAs) have been implicated in diverse processes, including synaptic plasticity and synapse formation. There is also evidence that prolonged and/or excessive activation of EAA receptors contributes to the neuronal death that occurs in many acute insults to the CNS, such as hypoxia/ischemia, hypoglycemia and head trauma. Dr. Robinson's research focuses on defining endogenous mechanisms that may normally protect the brain from this excitotoxicity. At this time, the primary emphasis of the laboratory is the family of sodium-dependent high affinity transport systems that directly regulate extracellular EAAs. We are studying both the transcriptional and post-translational regulation of these transporters. We have found that neurons actively participate in the regulation of the expression of the glial glutamate transporters. We are defining the signaling molecules involved in this regulation. We have also found that the activity and cell surface expression of many of these transporters can be regulated acutely (within min). We wish to understand the mechanisms involved in this regulation with the goal of defining the physiological relevance. The laboratory uses molecular biological, biochemical/cell biological, and other complimentary strategies to study these problems. Dr. Robinson collaborates with Drs. Lynch and Thomas.

Associate Professor; Department of Psychiatry

Dr. Ross conducts clinical and preclinical studies that measure sleep architecture. His clinical work focuses on post-traumatic stress disorder (PTSD), which is characterized by repetitive, stereotyped anxiety dreams and which is hypothesized to be a disorder of REM sleep mechanisms. Polysomnographic studies have revealed differences in tonic and phasic REM sleep measures between PTSD and healthy control subjects. Naturalistic and pharmacological "probes" of REM sleep behavior are used to further investigate the parameters of this REM sleep dysfunction. The eyeblink component of the startle response is also being measured in PTSD patients since startle is exaggerated in this disorder and REM sleep mechanisms may participate in the control of startle behavior. Dr. Ross' preclinical work involves the identification of monoaminergic systems that inhibit the generation of REM sleep and its phasic components in the cat. Acute and chronic studies of the effects of systemic anti-depressant drug administration have been carried out, and site-specific drug injections into brainstem regions thought to be involved in the initiation and maintenance of REM sleep are used to identify the anatomical substrates and pharmacological mechanisms of the monoaminergic inhibition of REM sleep. Dr. Ross collaborates with Drs. Aston-Jones, Lucki and Morrison.

Assistant Professor; Department of Pharmacology

Dr. Thomas studies the development and physiology of the adrenergic nervous system in which norepinephrine (NE) and epinephrine are the classic neurotransmitters. By genetically eliminating the biosynthetic enzyme for NE, dopamine-ß-hydroxylase (DBH), mutant mice (Dbh-/-) that completely lack NE and epinephrine have been created. These mice are conditional mutants in that NE can be restored to the adrenergic terminals by supplying a synthetic amino acid precursor of NE, L-DOPS. The lab is investigating the essential role of adrenergic signaling in several fundamental behavioral systems, including the role of NE in fetal development and maternal behavior, synaptic plasticity, learning and memory processes, and the mechanisms of antidepressant action. Because dopamine (DA) is the endogenous precursor of NE, the adrenergic terminals release dopamine instead of NE in the Dbh-/- mice. To address these questions, conditional mouse mutants are being created that have neither DA nor NE in their adrenergic terminals. Adrenergic signaling can also be defined as the release of any signaling molecule (co-transmitters as well as NE) from the adrenergic terminals. To study total signaling from the adrenergic terminals, we are creating genetic mouse models in which the adrenergic neurons can be turned off in a conditional manner. Dr. Thomas collaborates with Drs. Abel, Blendy, Lucki, and Robinson.

Professor; Department of Pediatrics

Dr. Valentino investigates how stress leads to psychiatric and medical disorders, as Director of the Laboratory of Stress Neurobiology. Specifically, her research centers on the stress-related neuropeptide, corticotropin-releasing factor (CRF). CRF targets and alters the activity of certain neuronal systems that have been implicated in depression and anxiety. Exposure to repeated stress or to a single severe stress produces long-term changes in the response of these neuronal systems and subsequent stressors. These changes may underlie some of the symptoms of a variety of stress-related medical and behavioral disorders, including attention disorders, anxiety, depression, substance abuse and functional bowel disorders. Ongoing studies in the laboratory are, also, designed to elucidate the neurobiological links between stress and substance abuse. An important aspect of her work involves treatment intervention, or determining how to manipulate brain neurochemicals using drugs to prevent the long-term impact of severe or repeated stress. Dr. Valentino and her colleagues are also mapping out and studying neuronal circuits that link the brain and pelvic viscera. Using neuroanatomical and electrophysiological approaches they identified a neural circuit that is positioned to coregulate pelvic (bladder and colon) functions with cortisol activity and thereby may underlie the comorbidity of pelvic viscera and psychiatric disorders. The pharmacological manipulation of components of this circuit may prove useful in treating incontinence as well as pelvic visceral disorders that are often accompanied by anxiety and depression. Dr. Valentino collaborates with Drs. Beck, Blendy, Lucki, and Miselis.