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Neuroscience
J. John Mann, M.D., Chief of Psychiatric Research
Division of Neurochemistry
Beth Brodsky, Ph.D., Research Scientist II
Steven Ellis, Ph.D., Research Scientist V John Keilp, Ph.D., Research Scientist IV Shuhua Li, M.D., M.P.H., Dr.P.H., Research Scientist III Maria Oquendo, M.D., Psychiatrist (Research) II Stephen Rayport, M.D., Ph.D., Psychiatrist (Research) II Leo Sher, M.D., Psychiatrist I Barbara Stanley, Ph.D., Research Scientist VI David Sulzer, Ph.D., Research Scientist V Hadassah Tamir, Ph.D., Research Scientist VI Mark D. Underwood, Ph.D., Research Scientist V
Division of Neuropathology
Victoria Arango, Ph.D., Co-Director
Andrew Dwork, M.D., Co-Director Jonathan Javitch, M.D., Ph.D., Research Scientist V Claudia Schmauss, M.D., Research Scientist V
Division of Brain Imaging
Lawrence Kegeles, M.D., Ph.D., Psychiatrist (Research) II
Ramin V. Parsey, M.D., Ph.D., Research Scientist IV Malingham Pradhaban, M.S., Research Scientist II Norman Simpson, B.S., Research Scientist IV Ronald Van Heertum, M.D., Medical Specialist II
The Department of Neuroscience spans the research spectrum from basic cell biology to in vivo imaging, molecular genetics, and treatment trials. It emphasizes translational research and employs a multidisciplinary approach to psychiatric research to examine the biological substrate of mental illness at multiple levels. The department is comprised of three divisions that pursue postmortem and in vivo studies of psychiatric disorders. The Neurochemistry division develops laboratory probes for in vivo clinical and biological studies of the serotonergic and other monoamine systems, and organizes clinical treatment studies. It also conducts basic studies in single cells, rodents, and nonhuman primates. The Division of Neuropathology conducts neuroanatomical mapping and gene expression studies in human, nonhuman primate, and rodent brains, postmortem brain studies of psychiatric disorders, and provides neuropathology services to the OMH. The Division of Brain Imaging conducts functional and structural brain imaging studies in baboons and human subjects. Each division is involved with other departments at NYSPI and the Columbia-Presbyterian Medical Center. The Division of Neurochemistry works closely with the Center for Neurobiology and Behavior and the Columbia Genome Center on molecular genetics and with the Irving Center for Clinical Research in clinical inpatient research. The Division of Neuropathology is involved with the Department of Pathology and with the Alzheimer's Disease Research Center. The Division of Brain Imaging is closely involved with the Department of Radiology.
Division of Neurochemistry
The major areas of clinical investigation for the Division of Neurochemistry have been the biological basis of mood and psychotic disorders, the action of antidepressants and other psychotropics, and risk factors for suicidal behavior. Basic studies have involved studies of the serotonin and dopamine systems and the action of antipsychotics and antidepressants.
Dr. John Mann is the Director of the NIMH-funded Silvio O. Conte Center for the Neuroscience of Mental Disorders. The Center supports a range of studies into the risk factors for suicidal behavior in mood disorders, schizophrenia, and personality disorders. This work has defined a more comprehensive model of suicidal behavior that is now being tested in one of the largest prospective studies of suicidal patients ever conducted. This model is supported by a large set of clinical and biological findings reported by the investigators associated with the Center. The Center focuses on the neurobiological basis of suicidal behavior and utilizes translational approaches to its understanding.
Dr. Mann also heads the Stanley Center for the Applied Neuroscience of Bipolar Disorders. This Center uses PET scanning to study the neurochemistry of bipolar depression in vivo and the action of antidepressants. The Center also conducts neurochemical postmortem studies of bipolar disorder that inform the design and goals of the functional imaging studies. The ultimate goal of the Stanley Center is to develop treatment selection guidelines based on in vivo neurochemical testing of bipolar patients.
Dr. Maria Oquendo coordinates all the clinical/biological studies in the Division. Drs. Ramin Parsey, Michael Grunebaum, Leo Sher, and Lawrence Kegeles conduct psychobiological studies of mood and psychotic disorders. Dr. Beth Brodsky trains and supervises the clinical evaluation core research staff. The schizophrenia suicide studies component is directed by Dr. Jill Harkavy Friedman, who has an NIMH grant to support this work. The neurobiological studies in schizophrenia are supervised by Drs. Lawrence Kegeles and Roberto Gil. Neuropsychological studies of cognitive function and impulsivity are conducted by Dr. John Keilp. Dr. Barbara Stanley conducts neurochemical and psychological investigations in individuals who manifest impulsive self-injury. Recently she has commenced a study of the efficacy of a psychotherapy called dialectical behavior therapy versus an SSRI medication in the treatment of self injury in borderline personality disorder. Dr. Oquendo has also begun a treatment study to examine the effects of lithium and divalproex on suicidal behavior in bipolar disorder. Drs. John Mann, Maria Oquendo, and Ramin Parsey have developed methods using Positron Emission Tomography (PET) for visualizing regional brain responses to serotonin activation and serotonin receptors. These techniques allow study of mood disorders, the effect of treatment with medication or ECT, and identification of high-risk patients and the localization of regional brain abnormalities in high-risk patients. Other studies are in progress examining possible genetic influences on the manifestation of suicidal and self-harming behaviors. In collaboration with Drs. T. Conrad Gilliam of the Columbia Genome Center, René Hen of the Center for Neurobiology and Behavior, and Dr. David Brent of the University of Pittsburgh, a candidate gene approach has been adopted, focused on key serotonin-related genes. Several key genes have been found to be associated with mood disorders and others with major depression. A study of the familial transmission of depression, suicidal acts, and impulsive-aggressive traits is underway, funded by NIMH grants to Dr. Mann and Dr. Brent (in Pittsburgh). The studies are also supported by the NIMH funded Conte Center and three other NIH grants to Dr. Mann. The Conte Center is also supporting a microarray approach to the detection of altered gene expression.
Dr. Tamir and her associates are continuing their work on secretagogue-induced gating of chloride channels in the secretory vesicles of parafollicular cells (PF). They have shown that PF cells of the thyroid have features of both neurons and endocrine cells. Thyroid PF cells are neural crest-derived endocrine cells that secrete serotonin and calcitonin. The function of secretory vesicles in neurons is important for neurotransmission and, therefore, for disease and therapeutics. This work is supported by a NIH grant to Dr. Tamir.
Dr. Underwood conducts research into the regulation of serotonergic neurons in suicide and alcoholism. The studies examine serotonergic neurons in the brainstem and define their functional capacity using quantitative morphometric and receptor binding methods. Dr. Underwood is one of the few scientists studying serotonin neurons at the brainstem level in both humans and animals to further elucidate their role in normal brain function and in diseased states. This work is supported by the NIAAA, the NIMH Conte Center for the Neuroscience of Mental Disorders, and the Stanley Center.
In postnatal mesolimbic neuron cultures, Drs. Stephen Rayport and Myra P. Joyce have pursued studies of the synaptic physiology and psychopharmacology of mesolimbic neurons. Extending the laboratory's finding that glutamate may be a cotransmitter in mesolimbic dopamine neurons, they have now shown that dopamine neurons make glutamatergic connections with their expected postsynaptic targets in the nucleus accumbens. Strikingly, they have found that individual dopamine neurons may differentially target presynaptic D2 receptors to one synaptic connection and not to another. In nucleus accumbens culture, Dr. Rayport together with students J. Norris and I.G. Feldman have examined the distribution of dopamine receptors on individual accumbens neurons and shown that dopamine receptors potently modulate GABAergic synaptic transmission between accumbens neurons. Further, they have shown that dopamine receptors may be differentially targeted to the synapses of these neurons as well. This differential distribution suggests a novel substrate for drug-dependent synaptic modulation. In a collaboration with Dr. René Hen, Drs. Rayport and Justine Masson have initiated a transgenic strategy to knock out neurotransmitter glutamate synthesis in dopamine neurons to examine the behavioral impact of glutamate cotransmission. This work has been supported by grants from NIDA, NARSAD, Psychiatric Institute (PIRSG), and the Columbia University Department of Psychiatry Frontier Fund.
Dr. David Sulzer's laboratory is pursuing the modulation of dopamine release at the presynaptic level. They have recently identified a role for alpha-synuclein in activity-dependent presynaptic depression of release, and are elucidating the precise role for the D2 autoreceptor, and presynaptic metabotropic glutamate and GABA receptors. They have established the first direct recordings of quantal release in the central nervous system, showing the number of dopamine molecules and the temporal kinetics of the release. This approach has demonstrated the first direct evidence that quantal size can be changed in the CNS, and the lab has shown such effects by drugs including L-DOPA and amphetamine, and the growth factor GDNF; indeed, the mechanism of action of these two drugs is in large part explained by these effects. They are currently pursuing the role of antipsychotics drugs in presynaptic effects on dopamine terminals. They are now attempting to elucidate the effects of dopamine release on plasticity of the cortical-striatal synapse, that is thought to underlie the reward pathway, drug dependence, and motor control. They have been examining the effects of dopamine oxidation in neurodegeneration, which appears to underlie the neurotoxicity due to methamphetamine, the biosynthesis of neuromelanin, and possibly in Parkinson's disease. This work is supported by several NIH, NSF, and private foundation grants.
Division of Neuropathology
The Division of Neuropathology conducts basic and clinical research, participates in postgraduate medical education, and operates the New York State Office of Mental Hygiene (OMH) Central Reference Laboratory (CRL) in Neuropathology. The Neuropathology division examines the brains of OMH patients obtained at autopsy and it maintains an archival collection of these specimens.
Dr. Andrew Dwork and colleagues are searching for neuropathological features of schizophrenia and mood disorders, and for neuropathological correlates of the dementia that is common among elderly schizophrenics. Combining modern and classical neuropathological techniques, they have made several novel observations. They have also developed standardized procedures for the retrospective clinical review of psychiatric hospital records so that neuropathological findings can be compared with clinical data. These projects are supported by grants from NIH, NARSAD, the Theodore and Vada Stanley Foundation, the American Foundation for Suicide Prevention, and the US/Macedonian Joint Fund for Science and Technology.
Drs. Andrew Dwork, Gorazd Rosoklija, and colleagues recently reported structural abnormalities in subicular neurons of individuals with schizophrenia, which are shared by some individuals with mood disorders. In the brains of chronically institutionalized individuals with schizophrenia, the density of spines on apical dendrites of subicular pyramidal cells was severely reduced. This finding is consistent with current theories about synaptic dysfunction in schizophrenia and could be either the cause or the result of such dysfunction. If the loss of apical dendritic spines is primary, postsynaptic proteins that determine the size and shape of dendritic spines would be promising candidates for future biochemical and genetic studies. Dendritic spine density was similar to that of the worst of the schizophrenia subjects in institutionalized subjects with mood disorders who had numerous first-degree relatives with major psychiatric disorders (schizophrenia, mood disorder, or both), while mood disorders with higher spine density did not.
Dr. Victoria Arango, in collaboration with Drs. Mark Underwood, Hadassah Tamir, John Mann, Suham Kassir, and Yung-yu Huang, is conducting a program of postmortem studies of suicide victims utilizing a combination of quantitative receptor autoradiography, in situ hybridization histochemistry and morphometric analysis of forebrain and brainstem nuclei. Dr. Arango is the Director of the Brain Bank of the Conte Center for the Study of Suicidal Behavior. Psychological autopsies, conducted by the Clinical Evaluation and Treatment Core (Dr. Maria Oquendo, Director), are used to obtain detailed clinical information on each case in the Brain Bank. Brain toxicological screens on subjects in the Brain Bank are conducted by Tom Cooper of the Department of Analytical Psychopharmacology. Dr. Arango and colleagues demonstrated that the reported low serotonergic activity in suicide is not due to a loss of serotonergic neurons or processes in the dorsal raphe nucleus of suicide victims.
Dr. Arango and colleagues found that fewer serotonergic cells expressed the gene for the serotonin transporter in depressed suicide victims compared to controls. Less SERT gene expression may be interpreted as a homeostatic underexpression to compensate for lower intrasynaptic serotonin.
Dr. Arango and colleagues replicated their previous report that suicide victims had lower serotonin transporter binding in the orbital cortex and that females had lower binding than males. In this study, they also determined that subjects with major depression, independent of cause of death, had a widespread loss of serotonergic innervation in all the prefrontal areas studied.
A parallel set of postmortem studies is being conducted by the same investigators in alcoholics in order to determine the neurochemical and morphological consequences of acute and chronic alcohol consumption. A recent study of serotonin 5-HT2A receptors in the prefrontal cortex revealed that alcoholics with a positive family history of alcoholism had significantly lower 5-HT2A receptor binding throughout the prefrontal cortex than subjects without a positive family history of alcoholism, independent of whether the case was a control or an alcoholic. Alcoholics without a family history of alcoholism did not differ from controls without a family history of alcoholism in any brain region examined. Familial alcoholism may be associated with a prefrontal serotonergic abnormality.
These studies have identified areas in the brain that control impulsive behaviors such as suicide. They have also revealed fundamental neurochemical differences between suicide victims and mood disorder patients, important in enhancing our understanding as to why some patients are at higher risk for suicide, and indicating new diagnostic and screening possible tests for high suicide risk and new treatment targets. Drs. Arango, Underwood, and Mann are supported by the NIMH, the Stanley Foundation, and the NIAAA for postmortem human brain research.
Dr. Claudia Schmauss' research program uses molecular biological and biochemical approaches to study the expression and function of neurotransmitter receptors that are targets for drugs with antipsychotics potencies. During the past year, Dr. Schmauss' lab significantly extended the analysis of the posttranscriptional processing of the 5-HT2C-receptor-encoded pre-mRNA (known as RNA editing) in the prefrontal cortex of healthy controls and suicide victims with and without a history a major depressive disorders. These studies use RNA extracted from postmortem tissues of the Brain Bank of the Human Neurobiology Core of the Conte Center (directed by Dr. V. Arango). Results obtained from the analysis of additional samples identified significant alterations in the editing of 5-HT2C pre-mRNA in the prefrontal cortex of depressed suicide victims. Expression of one particular 5-HT2C mRNA isoform is significantly increased and the expression of other 5-HT2C mRNA isoforms that are abundantly expressed in control brains are significantly decreased. Results of additional studies also demonstrate that these alterations in editing are not due to altered substrate concentration, i.e., differences are not due to different expression levels of 5-HT2C mRNA. Thus, these studies (which are under currently under review for publication) provided new evidence for a significant role of alterations in the posttrancriptional regulation of gene expression in psychosis. These data have also supported a new NIH R01 grant proposal which has received a fundable score.
The other main project in Dr. Schmauss' laboratory focuses on elucidating the distinct functional properties of two members of the D2-class of dopamine receptors, named D2 and D3 (the main targets for neuroleptic drugs), by means of analyzing the behavioral and molecular/biochemical phenotypes of mutant mice lacking D2 and/or D3 receptors. The knockout mice were generated in Dr. Schmauss' lab, and four papers have now been published that report results of studies on these mutants. Most recent studies have shown that manipulations that selectively target one DA receptor subtype also produce changes in the functions of other DA receptors. For example, Dr. Schmauss' lab found that D1 receptor function is substantially impaired in brains of mice with a targeted disruption of D2, D3, and D2/D3 receptors. Importantly, these alterations occur in brain regions where DA is known to influence behaviors that are often found to be abnormal in schizophrenia. Specifically, mice deficient for D2 and D3 receptors exhibit a decreased agonist-stimulated D1-receptor activity in the entire neocortex, including the prefrontal cortex, a structure in which dopamine D1 receptor activity is a critical determinant for performance in working memory tasks. Moreover, D3 mutant mice show striking reductions in the expression of calbindin in the nucleus accumbens, a structure in which dopaminergic innervation is strongly implicated in the translation of cognitive processes into appropriate motor responses.
Dr. Schmauss is supported by research grants from the National Science Foundation, the National Institutes of Health, and NARSAD.
Dr. Jonathan Javitch and his colleagues have developed a systematic approach for identifying the residues in the membrane-spanning segments that form the surface of the D2 dopamine receptor binding site-crevice. The information obtained allows a comparison of the residues forming the surface of the binding site-crevice in related G-protein coupled receptors. Using these methods, Dr. Javitch and his colleagues have recently identified a cluster of four amino acids that are the structural determinants of the pharmacological specificity of a number of D4-selective drugs. In other work, his laboratory is identifying conformational changes in the membrane-spanning segments that are associated with receptor activation and is also exploring the role of receptor oligomerization in the function and possible dysfunction of dopamine D2 receptors.
Dr. Javitch's laboratory is also pursuing structure/function studies in the dopamine transporter, the molecular target of psychostimulants such as cocaine and amphetamine, and mapping the residues that form the surface of the transport pathway for dopamine and the binding site for cocaine. Such an approach will provide a unique view of the mechanisms of neurotransmitter transport and may allow the identification of a potential target region for a cocaine antagonist that would be without effect on transport itself.
Dr. Javitch is supported by a Scientist Development Award from NIMH, an R01 from the NIMH to study dopamine receptors, and an R01 and a P01 from NIDA to study the dopamine transporter. He recently was promoted to tenured Associate Professor of Psychiatry and Pharmacology in the Center for Molecular Recognition at Columbia University.
Dr. David Ruggiero's research findings predict a common central neurogenic etiology of stress-related behavioral and physical disorders in children and adults. His experimental design is focused on clarifying functional neural network responses to chronic stress, caused by mental illness and/or physical disease states and their neurochemical basis. Collaborative investigations, using animal models replicating human stress responses, have led to several key discoveries that are relevant to his unified, working hypothesis. (1) A critical period of increased vulnerability to stress was identified during the second postnatal week in the developing piglet. This period is characterized by paradoxical patterns of diminished cardiovascular and exaggerated central neural responses to hypoxia and CO2 stress. The immature response pattern may render the infant susceptible to risk factors for sudden infant death syndrome or life threatening episodes, that may trigger the genetic expression of inherited pediatric disorders (Downstate Medical Center, SUNY). A central finding is his discovery that a generalized chemoreceptor trigger zone, the area postrema, is essential in protecting the newborn infants' systemic and cerebral circulations against upper airway obstruction during sleep, a major risk factor for sudden cardiac death in infants with respiratory and gastrointestinal infections, and in babies exposed, in utero, to nicotine and to passive smoke, postnatally. (2) Coping responses to chronic stress were found to engage the visceral thalamus and its prefrontal/temporal cortical domains, which exhibited sustained responses to chronic intermittent hypoxia (CIH). Preliminary studies are implicating the same parallel networks in coping with persistent mental stress and chronic pain and inflammation, triggering a cascade of mal-adaptive signaling mechanisms underlying their behavioral and neuroendocrinological manifestations. Sustained expression of late genetic transcriptional regulators were restricted to sympathetic control regions of cerebral cortex, thalamus, and medulla oblongata in rats exposed to chronic hypoxia, including a tonically inhibited cardiovascular control region of midline thalamus that was discovered in collaboration with Dr. Benarroch from the Department of Neurology of the Mayo Clinic. The time course of the long term network response to chronic hypoxia strongly correlated with the pathogenesis of neurogenic hypertension, discovered in an animal model for obstructive sleep apnea that was developed in collaboration with the Long Island Jewish/Albert Einstein Medical Center.
Division of Brain Imaging
On July 1, 2000, the Division of Brain Imaging had a major reorganization. Ronald Van Heertum, M.D. has been named as the Director of the Brain Imaging Core, and Ramin Parsey M.D., Ph.D. has been named Associate Director for the Stanley Center for the Applied Neuroscience of Bipolar Disorders and the Conte Center for the Neurobiological Studies of Suicidal Behavior. The division supports both these cores. These Centers were newly refunded this year. The image analysis group was expanded through the hiring of new staff as well as staff necessary for the routine conduct of the PET studies were added and trained. We hired Dr. Marie-Jose Belanger who has a Ph.D. in biomechanical engineering and did her dissertation in brain imaging at MIT. She has added valuable expertise in PET physics and signal processing.
The division is continuing to study unipolar and bipolar depressed subjects before and after treatment with an SSRI or ECT, bipolar depressed subjects, suicide attempters and non-attempters, and healthy volunteers. We completed a total of 47 human PET studies in 2000, nearly one per week. In addition we are continuing our non-human primate PET studies focusing on new ligand development and evaluation, endogenous competition studies, and blocking studies. We also have continued our structural brain studies with quantitative MRIs of subjects enrolled in the PET studies. Our efforts have been greatly assisted by collaborations with the Department of Radiology (Ronald van Heertum, M.D. and Peter Esser, Ph.D.). In collaboration with Dr. De La Paz, Dr. John Keilp has an AFSP grant to study cognitive function with fMR.
During 2000, we continued providing technical support for ongoing imaging studies for Dr. Devanand in the Department of Biological Psychiatry. We are commencing in 2001 support for a study by Drs. Attia and Walsh in eating disorders.
New grants in brain imaging in 2000 were
obtained by Drs. Mann, Parsey, Attia, Van Heertum, and Oquendo. Ongoing
funding from NIMH and foundations include two center grants, RO1s, a KO1
award, AFSP, Clinical Trials, and NARSAD grants.
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