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Faculty and Research
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One of the cornerstones of the undergraduate program in Neuroscience is the provision for laboratory experience. Such an experience gives the student a chance to see how neuroscientists study the brain and provides training in laboratory techniques that are used in neuroscience research. The laboratory experience can come from laboratory courses offered in the Departments of Biology and Psychology or from the undergraduate research courses offered under the auspices of the Neuroscience Program. Students are particularly encouraged to consider utilizing undergraduate research courses to satisfy the requirement for laboratory experience. In these courses, students actually participate in the laboratory research of one of the Neuroscience faculty on the Vanderbilt Campus. This provides a unique opportunity for the individual student to discover what research "is really like" and to learn "one-on-one" from some of the top neuroscientists in the world. In the laboratories of Vanderbilt neuroscientists, researchers utilize state-of-the art equipment and techniques to study fundamental questions about how the nervous system works and how that knowledge can be applied to the treatment and prevention of brain disease and injury. Brief sketches of the research interests of the faculty that are available to train students are presented below. Students should feel free to contact any of the faculty members for more information on their research program and to discuss the possibility of having them serve as a mentor for a course in independent research. Registration for one of the research courses requires the approval of the Director of Honors and Independent Study who can also provide information about various research programs and help with identifying an appropriate laboratory. Students are strongly encouraged to initiate contact at the end of their Sophomore year or early in their Junior year.
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Developmental Neurobiology
Bruce Appel
Department of Biological Sciences
U7215 BSB/MRB III
322-2003
bruce.appel@vanderbilt.edu
The Appel lab investigates the molecular genetic mechanisms that regulate cell fate specification, migration and differentiation in the vertebrate nervous system using zebrafish as a model system. Much of the lab's current work focuses on the development of oligodendrocytes, the myelinating cell type of the central nervous system. Lab members investigate the temporal and spatial patterning of the zebrafish spinal cord by producing transgenic zebrafish that express fluorescent reporter proteins in subsets of neural precursors and their daughter cells and by labeling single precursor cells with vital dyes to analyze the role of cell lineage in neural cell fate specification. Subsequently, they test hypotheses addressing the roles of particular signal transduction pathways using mutants, transgenics that allow conditional manipulation of gene function, and small molecular weight compounds that inhibit activity of pathway components. Trainees in the Appel lab analyze oligodendrocyte migration and differentiation using a similar combination of gene function tests together with extensive time-lapse confocal imaging. Most lab members also participate in a screen for mutations that disrupt oligodendrocyte specification and migration and are also involved in genetic mapping and positional cloning projects.
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Neurobiology of astrocytes, blood-brain barrier transport, and heavy metal neurotoxicology
Michael Aschner
Department of Pediatrics
B-3307 Medical Center North
322-8024
michael.aschner@vanderbilt.edu
Within the broad area of astrocytic biochemistry and physiology, the laboratory focuses on the role of astrocytes in brain physiology and pathology. Specifically, on-going studies address (1) the mechanisms and consequences of astrocytic swelling, (2) the role of astrocytes in heavy metal (mercury, manganese, and uranium) neurotoxicity, (3) the functional importance of astrocytic metallothioneins in attenuating neurotoxicity, and (4) the responses of astrocytes to chronic exposure to ethanol (EtOH). An important process in the toxic outcome of metals is their transport from plasma into the brain across the capillary endothelial cells that comprise the blood-brain barrier (BBB). In order to cross this barrier, metal complexes must be either highly lipid soluble, or possess affinity for specific carrier-mediated transport systems within the endothelial cell plasma membrane. Little is known about the transport of various metals, and virtually no experimental data exist regarding the transport mechanisms of manganese and uranium across the BBB, a crucial step in the central nervous systems (CNS). Ongoing studies in the lab assess the substrate specificity of manganese and uranium transport into the CNS, testing the hypothesis that the divalent metal cation 1 (DMT1), which has an unusually broad substrate range that includes Fe2+, Zn2+, Mn2+, Co2+, Cd2+, Cu2+, Ni2+ and Pb2+, is mediating their transport into the CNS. The study of these metals is timely, given potential exposure of Gulf War Veterans to depleted uranium, and concern about potential exposure to manganese in the population at large.
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Production and perception of nonlinguistic acoustic cues
Jo-Anne Bachorowski
Department of Psychology
307 Wilson Hall
343-5915
j.a.bachorowski@vanderbilt.edu
Bachorowski’s research broadly concerns the production and perception of nonlinguistic acoustic cues, with attention given to social and other contextual influences on signal production as well as the impact of vocal acoustics on listener emotional responding. Towards these ends, empirical work variously involves studying laughter, vocal expression of emotion, indexical cueing in speech, and infant-directed speech. Despite the diversity of signals being studied, the work is anchored by two core themes: understanding the linkages between vocal acoustics and affect-related responding, and developing an empirically based approach to vocal signaling that is defensible from principles associated with the selfish-gene theory of evolution. Research methods used in this research include detailed analysis of vocal signals using state-of-the-art unix-based software, perceptual testing, and structural and functional imaging studies.
Neuroscience students working in lab for research credit will be involved in acoustic analysis of vocal signals and will gain exposure to imaging techniques and analysis. These students will also be involved in data collection, which typically involves collecting audio-recordings of both children and college-aged adults participating in socially interactive paradigms. Depending on their interests, these students can also be highly involved in perceptual testing, including stimulus selection, subject testing, and data analysis. Some current questions of interest in perceptual work include listener responsive to various kinds of laugh sounds and listener judgments of talker body size from very short speech sounds.
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Neural Bases of Human Visual Perception
Randolph Blake
Department of Psychology
Vanderbilt Vision Research Center
511 Wilson Hall
343-7010
randolph.blake@vanderbilt.edu
My research concerns the neural bases of human visual perception, with an emphasis on binocular vision, motion perception and perceptual grouping. I utilize psychophysical techniques to study the abilities of people to make judgments about the 3D structure and layout of objects in visual space, with an eye toward developing neural models to account for those abilities. The psychophysical work uses computer generated animation sequences viewed stereoscopically to simulate 3D objects undergoing transformations associated with motion. The theoretical work relies heavily on extant physiological and neurological data A major theme running throughout my work is the establishment of "sites" of visual information processing based on perceptual data In recent years, my colleagues and I have developed several fruitful localization strategies, including ones that utilize binocular rivalry as a neural "reference" for localizing other sites of action. The inferential strength of this so-called "psychoanatomical" technique will continue to grow as more is learned about the actual neural concomitants of visual information processing. To supplement this strategy, I use functional MRI as a complementary localization technique. This work is carried out in collaboration with scientists in the Vanderbilt Medical School as well as with investigators at other universities. In recent years, I have also studied visual imagery, visual memory and the role of knowledge in putatively early visual processes (e.g. binocular vision; motion). My work, which is supported by a grant from the NIH, is carried out in a modern laboratory that includes Macintosh computers, an eye-tracker, image processing hardware and optical components including mirror stereoscopes.
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Genes that Control Responses to Cocaine and Antidepressants in the Brain
Randy Blakely
Department of Pharmacology
Center for Molecular Neuroscience
419A Medical Research Building-II
936-3037
randy.blakely@mcmail.vanderbilt.edu
Cocaine and antidepressants block the ability of the brain to inactivate neurotransmitters such as dopamine, serotonin and norepinephrine. My lab has cloned the targets for these drugs and is actively involved in studying how the genes and their encoded proteins regulate chemical signaling in the brain. We also are seeking to understand how these genes might participate in brain diseases such as depression and autism. Students with a good background or strong interest in neurochemistry, molecular biology or cell biology should consider opportunities in my lab.
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Molecular Regulation of Lymphocyte Function in Inflammatory Demyelinating Disorder
Mark Boothby, MD, PhD
Department of Microbiology and Immunology
AA-4214 MCN
343-1699 (office)
mark.boothby@vanderbilt.edu
Our lab studies molecular mechanisms of signal transduction and gene transcription regulation as a part of immune-mediated inflammation, including studies in mouse models such as EAE, a model of multiple sclerosis.
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Huntington Disease, Movement Disorders, Neurodevelopment and Neurodegeneration
Aaron Bowman
Department of Neurology
465 21st Avenue South, MRB III U-9228 Learned Lab
322-2651 (office)
322-0486 (Fax)
aaron.bowman@mcmail.vanderbilt.edu
The long-term objective of my lab is to understand how environmental and genetic factors interact to cause neuropathology. Despite burgeoning knowledge of genetic and environmental factors that hasten neurological disease, there is a dearth of information about the gene-environment interface that sets the stage for neuronal vulnerability. The research program of the lab seeks to explore the basis of selective neuropathology by focusing on a neurodegenerative disease, Huntington disease (HD), caused by a single gene defect and leveraging environmental influences sharing common modes of neurotoxicity or neuropathology. We have discovered that metals and metal exposure significantly modulate HD neuropathology. By exploring the basis of this gene-environment interaction we seek to elucidate pathophysiological processes capable of influencing disease progression. This research will provide mechanistic detail for how genetic and environmental factors intersect to modulate neuronal activity and survival.
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Nervous System Development
Kendal S. Broadie
Department of Biological Sciences
6270A MRB III, 465 21st Av S 37232
936-3937
kendal.s.broadie@vanderbilt.edu
What are the molecular mechanisms underlying coordinated movement, coordinated behavior, cognition, learning and memory? How does the nervous system circuitry underlying these behaviors develop, and how are these circuits modified by experience? How do these mechanisms go awry in inherited neurological diseases and age-related neurological decline? These questions center around the common themes of information transfer and information storage in cells of the nervous system. My long-term interest has been to understand the fundamental principles of nervous system development, function and plasticity by applying systematic genetic analyses to address these questions. My experimental organism, Drosophila melanogaster, has a long and distinguished history as a foremost forward genetic model of neurobiological mechanisms. The primary focus of my laboratory is on the synapse, the specialized intercellular junction which functions as the communication link between neurons. Chemical synapses mediate the vast majority of communication in the nervous system and exhibit plastic properties underlying the behavioral and cognitive malleability of the brain. Our experimental approach is to use a combination of forward genetics, reverse genetics and functional genomics to identify synaptic genes, generate mutants and then assay mutant laboratory uses this strategy to investigate three closely related questions: 1) How do synapses develop?, 2) How do synapses function?, and 3) How do synapses maintain adaptive plasticity?
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Neuroinflammatory Mechanisms of Axonal Degeneration in Optic Neuropathies
David J. Calkins
Dept. Ophthalmology and Visual Sciences
1115 Light Hall-MRBIV
2215B Garland Avenue
(615) 936-6412, Fax: (615) 936-6410
david.j.calkins@vanderbilt.edu
Optic neuropathies blind through the progressive degeneration of the retina and optic nerve. As with other diseases of the central nervous system, optic neuropathies involve complex interactions between glial cells and retinal neurons and their axons. These interactions comprise a broad inflammatory response that includes both protective mechanisms and cascades that contribute to programmed degeneration. Our laboratory focuses on neuronal-glial interactions in glaucoma, an optic neuropathy that is blinding some 80 million people worldwide. In glaucoma, sensitivity to pressure in the eye causes the slow retraction of the axons in the optic nerve, which arise from the roughly 1.5 million retinal ganglion cells that collect the light signals used for vision. We utilize both in vivo and in vitro models to isolate the inflammatory signals from microglia and astrocyte glia in the retina and optic nerve that contribute to ganglion cell death. We also focus on the molecular mechanisms intrinsic to ganglion cells and their axons that mediate their sensitivity to ocular pressure and could represent novel therapeutic targets. Students working in our laboratory will receive training in many modern techniques in neuroscience, including primary neuronal cell culture, digital microscopy, quantitative real-time PCR, immunocytochemistry and ELISA. Students are also expected to participate in journal club and laboratory meetings on a regular basis.
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Mechanisms of Neurotrophin Signal Transduction
Bruce D. Carter
Department of Biochemistry
Center for Molecular Neuroscience
418 Medical Research Building-II
936-3041
bruce.carter@mcmail.vanderbilt.edu
The neurotrophins are a family of dimeric proteins, with nerve growth factor (NGF) as the prototypical member. These factors promote the survival, differentiation and, in some instances, proliferation of developing neuroblasts. As neurons mature and send axonal projections to their specific targets, where the neurotrophins are produced, they rely on these proteins for continued survival and further phenotypic specification. The neurotrophins exert their effects through binding to two types of receptors, the Trks, which have a tyrosine kinase domain, and a receptor referred to as p75, which is a member of the Fas/ TNF receptor family. Neurotrophin binding to Trk has been shown to activate canonical growth factor signaling pathways, although much remains to be determined regarding the regulation of these paths in neurons. In contrast to the Trks, neurotrophin binding to the p75 receptor has only recently been shown to activate a signaling pathway, which includes stimulation of a transcription factor (NFkB) and, surprisingly, apoptosis in specific cell types. However, the components of these signaling pathways remain to be determined.
The goal of our lab is to delineate the molecular mechanisms of neurotrophin signaling, particularly via the p75 receptor in neurons and their progenitors using a number of molecular and cellular approaches. To understand how receptor activation by these growth factors can lead to cellular responses such as NfkB activation and cell death, we are looking for intracellular signaling proteins. Recently, we identified a novel protein associated with the cytoplasmic domain of p75. Current studies are aimed at investigating its role in neurotrophin signal transduction. In addition, a transgenic approach is being used to determine the effects of gene deletion of this protein. Through structure-function analysis we are also assessing the domains and residues of the receptor involved in activating the signaling pathways. Further, since most neurons express both Trk and p75 and these have seemingly opposing actions (i.e. survival vs. apoptosis) we are also investigating the cross-talk between the signaling pathways. These studies are important not only for understanding the basic mechanisms of neural function, but are also relevant to ongoing clinical trials of neurotrophins in the treatment of neurodegenerative diseases.
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Organization and Development of the Mammalian Visual System
Vivien Casagrande
Department of Cell Biology
T-2302 Medical Center North
343-4538
vivien.casagrande@mcmail.vanderbilt.edu
The overall aim of Casagrande's research program is to understand how visual information is processed in the brain and how nerve cells in the visual system become appropriately organized and connected during development.
The research is divided into two programs with separate aims. The first program is designed to understand the functional significance and structural correlates of proposed parallel information channels. Approaches include single unit recording including, pharmacological manipulation, light and electron microscopic examination of circuitry using tract tracing, immunocytochemisty and morphometry, optical imaging and neural modeling. In current experiments Casagrande's students are using pharmacological tools to block or manipulate electrical signals in each pathway to determine how the visual system combines information within individual visual cortical cells. Experiments are also underway to examine differences in the circuitry and neurochemistry of layers and functional compartments in visual cortex using a combination of electron microscopy and immunocytochemical labeling for transmitters and transmitter receptors. Finally, collaborative experiments are underway that use optical imaging to examine functional organization in visual cortex.
The second program is designed to investigate how cellular patterns and connections of the adult nervous system are generated during embryo logical and early postnatal development. This program uses anatomical, immunocytochemical, surgical, and molecular biological tools to examine how axons find their targets and become topographically organized within the visual thalamus and cortex. Currently Casagrande's lab has been investigating the earliest stages of axon ingrowth and connections between the lateral geniculate nucleus and primary visual cortex. Projects are underway that examine the function of glycoproteins and other extracellular matrix proteins in axon guidance in mice in which specific genes (i.e. either N-CAM or L1) have been deleted (knocked out). In vitro and in vivo studies are currently underway to examine axon guidance and cell migration in these models.
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Mammalian Sensory Systems with a Focus on Cortical Organization, Function, and Development
Ken Catania
Assistant Professor of Biological Sciences
8270 BSB/MRB III
343-1079
ken.catania@vanderbilt.edu
In my laboratory, we study the organization and function of mammalian sensory systems. Our investigations take a wide range of approaches including studies of animal behavior, investigation of peripheral sensory receptor structure and function, and studies of the organization of the central nervous system with an emphasis on neocortex. Information from these different approaches is integrated to obtain a broad view of how animal behavior, sensory receptors, and central nervous systems have evolved to meet the challenges mammals face in diverse sensory worlds.
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Regulation of Excitatory Synapses
Roger Colbran
Professor of Molecular Physiology and Biophysics
724 Robinson Research Building (MRB1)
936-1630
roger.colbran@vanderbilt.edu
Modulation of the synaptic glutamate receptors and synaptic morphology by postsynaptic phosphorylation/dephosphorylation plays a central role in normal earning and memory and is ofter disrupted in diseased states. In particular, calcium/calmodulin-dependent protein kinase II (CaMKII) and protein phosphatase 1 (PP1) are known to play critical roles in long-term potentiation (LTP), long-term depression (LTD) and other forms of synaptic plasticity that underlie learning and memory. This laboratory employs a broad array of approaches to investigate the molecular basis for synaptic regulation of CaMKII and PP1 and the physiological roles of these molecular mechanisms. Disruptions of these mechanisms in diseased states such as Parkinson's Disease and Angelman Syndrome are being uncovered, suggesting potential novel strategies to treat these devastating neurological disorders.
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Neuropharmacology/Drug Therapies for Brain Disorders
P. Jeffrey Conn
Department of Pharmacology
417-D Preston Research Building
936-2478 (office)
jeffrey.conn@vanderbilt.edu The primary focus of research in our laboratory is to develop a detailed understanding of the cellular and molecular mechanisms involved in regulating chemical and electrical signaling in the central nervous system (CNS). Such changes in neuronal function are likely to play important roles in all normal physiological processes in the brain and are critical for development of a variety of brain diseases, including Alzheimer's disease, Parkinson's disease, schizophrenia, epilepsy, drug dependence and other neurological and psychiatric disorders. We are especially interested in understanding how signaling is regulated in identified neuronal circuits that are important for these human neurological and psychiatric disorders. This is a highly multidisciplinary endeavor and we employ a broad range of techniques including electrophysiology, biochemistry, imaging, anatomy, and molecular biology techniques. Since our ultimate goal is to understand the impact of cellular and molecular changes to changes in intact neuronal networks and animal behavior that impact CNS disorders, we also employ a range of techniques in behavioral and systems neuroscience. By developing this range of understanding, we hope to develop new strategies for treating neurological and psychiatric disorders. Our current research is especially focused on development of novel treatment strategies for schizophrenia and Parkinson's disease. Also, we have increasing interests in drug addiction, Alzheimer's disease, and severe anxiety disorders. In each of these areas, recent basic and clinical studies are shedding light on new approaches to develop novel treatment strategies. Our basic science studies are revealing a number of key regulatory proteins that have exciting potential as novel drug targets for treatment of serious psychiatric and neurological disorders. In addition to pursuing the basic research needed to identify these novel drug targets, we are directly involved in taking these findings to the next step by pursuing early stage drug discovery efforts. This is an innovative and exciting endeavor that is rare in academic institutions. We have now purchased or gained access through collaborations with chemical companies to libraries of over 1 million novel small molecules with drug-like properties. In addition, working in the Vanderbilt Institute for Chemical Biology, we have established the infrastructure needed for high throughput screening these molecules for unique compounds that have potential for development into novel drugs. The combination of high throughput screening and synthetic chemistry provides an unprecedented opportunity for discovery and development of small molecules that may pave the way to eventual discovery of new drugs. By moving aggressively to move our basic science efforts into early stage drug discovery programs, we are making exciting advances that could lead to novel treatments for schizophrenia, Parkinson's disease, and other CNS disorders.
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Depression and Drug Abuse
Ronald L. Cowan
Medical Psychiatry/General Adult Psychiatry
3009, Village at Vanderbilt
322-2303 (office)
ronald.l.cowan@vanderbilt.edu
www.cowanlab.com
He studies the role of brain monoamines in mood and reward system function with the goal of understanding substance use disorders. The lab is currently utilizing neuroimaging, genetic analysis, and cognitive neuroscience to study the effects of the putative selective serotonin neurotoxin, MDMA (Ecstasy), on the brain's structure, function, and chemical composition. The lab studies the neural substrates of reward function, including the neural basis of dysphoria and euphoria using functional neuroimaging during substance-induced mood changes. Dr. Cowan's explorations of monoamines in the context of reward function and drug abuse are rooted in his belief that the interaction between modern societal structure and the ancient, largely automatic brain processes influenced by monoamine systems are the basis for many contemporary social problems such as depression and drug abuse.
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Neurotransmitter Transporters for Serotonine, Norepinephrine, and Dopamine: Biophysical and Molecular Studies
Louis DeFelice
Department of Pharmacology
410 RRB
343-6278
lou.defelice@vanderbilt.edu
The DeFelice laboratory studies neurotransmitter uptake mechanisms, that is, how transporters clear transmitters from the synaptic terminal after release. They apply biophysical techniques to study uptake mechanisms. These techniques are similar to those used to study ion channels. The laboratory focuses primarily on serotonin (5HT) and norepinephrine (NE) transporters, which are related to the transporters for dopamine, GABA, and other neurotransmitters. Serotonin transporters (SERTs) and NE transporters (NETs) are integral membrane proteins composed of approximately 600 amino acids. Drugs that block or otherwise interfere with the transport of 5HT and NE dramatically affect human behavior. Cocaine inhibits 5HT and NE re-uptake, and one consequence of this inhibition is an abnormal increase in extracellular transmitter concentration. Amphetamines actually enter the neurons via transporters, whereas commonly prescribed antidepressants, as fluoxetine (Prozac), bind strongly to SERTs and virtually dislodge 5HT uptake. The interactions of amphetamines and antidepressants with transporters, like the interactions of cocaine with transporters, account for essentially all of the action of these drugs; nonetheless, the mechanisms underlying these inhibitory mechanisms against normal uptake remain essentially unknown. With the help of modern molecular biology and biophysics, the DeFelice lab can study how uptake mechanisms work and how drugs and antidepressants interfere with uptake at the molecular level. They transfect cloned monoamine transporters into host cells and study transport mechanisms in two ways. Using radio-ligand uptake and cocaine-binding assays, they measure transmitter transport and transporter number. They also measure the transmitter-induced currents that arise in these same cells. For these studies DeFelice employs the patch-clamp technique. The patch-clamp method also allows the internal perfusion of the cell and enables us to study how internal regulators, such as Ca and phosphorylation, modulate the uptake mechanism. By using cell-detached patches, they have also been able to examine the kinetics of individual transporters on the cell surface. This technique is analogous to studying single ion channels. Transporter currents are less evident and far more difficult to measure than ion channel currents. Neurotransmitters and co-transported ions (e.g., NE and Na) act similar to ligands on receptors; unlike traditional ligand-gated receptors, however, in transporters the ligands actually cross the membrane as if in an ion channel. The mechanistic picture of 5HT and NE transporters that is emerging from this laboratory will help to understand the basic mechanisms of transmitter uptake at synapses. They will also help to understand drugs of abuse and prescription drugs. To further study these mechanisms, the laboratory is designing mutants and chimeras of NETs and SERTs that have different potencies to ligands and drugs. This helps us to identify important domains in the molecule that interact with these molecules. Ultimately this research will help design new compounds for the treatment of depression and mental illness.
Selected Publications
Galli A, Jayanthi LD, Ramsey IS, Miller J, Fremeau R, DeFelice LJ: L-proline and L-pipecolic acid induce enkephalin-sensitive currents in HEK-293 cells transfected with the high affinity mammalian brain L-proline transporter. J Neurosci 1999;19:6290-6297.
Petersen I, DeFelice LJ: Ionic interactions in dSERT indicate that serotonin transporters are serotonin channels. Nature Neurosci 1999;2:605-610.
Galli A, Blakely RD, DeFelice LJ: Patch-clamp and amperometric recordings from norepinephrine transporters: channel activity and voltage-dependent uptake. PNAS 1998;95:13260-13265. See commentary PNAS 95: 12737-12738.
DeFelice LJ, Galli A: Fluctuation Analysis of Norepinephrine and Serotonin Transporter Currents. Methods in Enzymology 1998;296: 578-593.
DeFelice LJ: Electrical Properties of Cells: Patch Clamp for Biologists, Plenum Press NY, 1997, 244 pages.
DeFelice LJ, Blakely RD: Pore models for Transporters? Biophysical Journal 1996;70:579-580.
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Behavioral Phenotypes of Persons with Genetics Syndromes Associated with Developmental Disabilities
Elisabeth M. Dykens
Professor, Department of Psychology and Human Development
Associate Director, Kennedy Center
406 MRL Building
322-8945
elisabeth.dykens@vanderbilt.edu
Elisabeth M. Dykens, Ph.D. is Professor of Psychology and Human Development and Associate Director of the Vanderbilt Kennedy Center for Research on Human Development. Her research examines the behavioral phenotypes of persons with genetics syndromes associated with developmental disabilities, primarily Williams, Prader-Willi, and Down syndromes. Although much of her work focuses on psychopathology, Dykens also examines profiles of neurocognitive, personality, and adaptive strengths and weaknesses in these disorders, and how these unusual profiles refine treatment and shed light on typical development.
Current studies examine: (1) physiological and neurological mechanisms of compulsive and hyperphagic behavior in persons with Prader-Willi syndrome, including specific neuropeptides involved in aberrant satiety and behavior, and EEG/ERP studies; (2) visual-spatial strengths in persons with Prader-Willi syndrome; (3) physiological and neurological factors involved in both high rates of anxiety and unusual musical talents in persons with Williams syndrome, including clinical, EEG/ERP and fMRI studies; (4) the development and trajectory of maladaptive behaviors and unusual strengths in syndromes, and how these relate to genetic status, aging, and intervention; (5) families of persons with mental retardation, including stress, coping, and positive outcomes for family members; and (6) interface between positive psychology, and research and interventions for persons with developmental disabilities.
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Normal and Impaired CNS Plasticity
Ford Ebner
Professor of Psychology and Cell Biology
Room 501 Wilson Hall
343-0239
ford.ebner@vanderbilt.edu
NOTE: Sponsors maximum of 4 students per semester
Our research focus is on specific brain mechanisms that are important for synaptic plasticity, learning and memory. We relate these processes to causes of perceptual deficits and intellectual disabilities. Around the time of birth spontaneous and experience-generated cortical activity participates in the maturation of brain mechanisms that will be required for learning from sensory experience throughout life. If the cortical mechanisms for plasticity fail to develop properly, it is still a central issue to understand why they remain deficient throughout life. We study the responses of excitatory glutamate receptors, inhibitory GABA mechanisms and global modulators of cortical function to determine how they regulate the response of cortical neurons to sensory stimulation. We relate these results to how the excitation/inhibition balance facilitates synaptic strength modifications needed for learning and memory. We study the effects of prenatal toxins and postnatal sensory deprivation on normal plasticity and learning from sensory experience. These conditions share the capacity to reduce spontaneous activity in cortex, to reduce the levels of response (spikes/stimulus) to sensory stimulation in cortex, and to delay or prevent cortical plasticity as measured by physiological recordings from single cortical neurons. One idea that we are testing at the moment is whether the toxic effect of substances such as prenatal alcohol may arise through its negative impact on activity-dependent gene expression. It is possible that the excitability of cortex at the time of birth can be inadequate for activity-dependent maturation of cortical synapse modulation mechanisms. This idea is supported by our observation that sensory deprivation after birth produces cortical deficits that are strikingly similar to those produced by toxin exposure before birth. We are currently studying interventions that can reverse the intellectual deficits produced by developmental insults.
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Regulation of Neuronal Function by RNA editing; physiological role(s) of CGRP
Ronald B. Emeson
Associate Professor of Pharmacology and Molecular Physiology & Biophysics
460 Preston Research Building
phone: 936-1688 fax: 936-1689
ron.emeson@mcmail.vanderbilt.edu
Our laboratory is examining the molecular mechanisms involved in the editing of numerous RNA transcripts in the mammalian central nervous system. RNA editing is a post-transcriptional modification in which specific adenosine residues in pre-messenger RNAs are converted to inosine moieties (A-to-I editing) via the actions of double-stranded RNA-specific adenosine deaminases (ADARs). As a result of these deamination events, the coding potential of RNAs can be subtly altered to change as little as a single amino acid residue in resultant proteins. In the case of glutamate-gated ion channels, RNA editing can dramatically alter both the ion permeation and electrophysiologic properties of these ionotropic receptors. Since glutamate-gated channels are critically involved in processes of excitatory neurotransmission, slight alterations in RNA editing patterns have profound effects upon the normal neurophysiology of the brain.
RNA editing events within the 2C-subtype of serotonin receptor (5HT2CR) can modulate the efficacy by which this seven transmembrane-spanning receptor can couple to its specific intracellular signaling pathways. Since this serotonin receptor has been implicated in a number of neuropsychiatric disease states, including anxiety, depression and schizophrenia, aberrant RNA editing patterns may play an important role in the etiology of these disorders. Mutant mice solely expressing the non-edited form of the 5HT2CR demonstrate deficits in maternal behavior, while animals solely expressing the fully-edited isoform have a number of phenotypic alterations characteristic of human Prader-Willi syndrome. Current research efforts in the laboratory focus upon the regulation of ADAR expression, the role of RNA editing in central feeding behavior and further analyses of the phenotypic consequences resulting from changes in the editing of 5HT2CR transcripts.
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Molecular Mechanisms Required for Normal Brain Development
Kevin C. Ess
Assistant Professor, Neurology and Pediatrics
MRBIII, Suite 6160
322-0486
kevin.ess@.vanderbilt.edu
Research in my laboratory is focused on deciphering the molecular mechanisms required for normal brain development and how disruptions of these processes lead to malformations of the cerebral cortex. Children with such aberrations typically suffer from severe seizure disorders (epilepsy) as well as severe cognitive and behavioral problems such as autism. To approach these complex neurologic disorders, we have been studying tuberous sclerosis complex (TSC), a disease that prominently features cortical malformations and is caused by loss of either the TSC1 or TSC2 genes. TSC is fairly prevalent and is the most common genetic cause of both seizures and autism in children. Our previous investigations led us to hypothesize that the TSC1/2 genes are essential for neural progenitor cell function and control the differentiation and migration of neurons and glia. Abnormalities of these developmental processes may cause the cortical malformations in TSC that underlie epilepsy as well as autism in these patients. To study these complicated abnormalities of the human brain, we have generated experimental models of TSC using genetically engineered mice as well as in vitro progenitor cell systems. The ability to manipulate Tsc1 or Tsc2 gene expression in mouse progenitor cells allows us to determine the role of these genes during neuronal and glial cell specification, differentiation, and migration. Our long term goal is to use these models to precisely define the molecular pathways used by the TSC1/2 genes during human brain development. This knowledge will facilitate the development of rational and hopefully more efficacious therapies for children who suffer from epilepsy or autism.
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Visual Perception
Robert Fox
Department of Psychology
512 Wilson Hall
322-0869 or 269-7234
robert.fox@.vanderbilt.edu
My long-term interest has focused on binocular vision, which refers to how the two eyes work together, and on the specific phenomena related to binocularity: fusion, stereoscopic depth, and binocular rivalry. A special emphasis has been the induction of these phenomena by random arrays of elements. Although most of the work has involved normal adult human observers, some issues related to development have been examined in which the observers are infants, young children, and elderly adults. In addition, the discovery that persons with mild mental retardation encounter difficulty perceiving second order stimuli has motivated an inquiry into the relationships among perception, retardation, and intelligence.
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Visual Object Recognition
Isabel Gauthier
Department of Psychology
308A Wilson Hall
322-1778 (office)
isabel.gauthier@vanderbilt.edu
Gauthier studies visual object recognition, with particular emphasis on the plasticity of recognition mechanisms and their neural substrate. One issue that is of particular interest to her is how the visual system organizes itself into what appears to be category-specific modules. For instance, face recognition is often given as an example of a highly specialized module that may function independently from general object recognition mechanisms. However, faces are among the most visually similar objects that we need to recognize individually and most of us acquire a large amount of expertise in doing so throughout our lives. A diversity of techniques (e.g., expertise training with computer-generated objects, brain-lesion studies, functional magnetic resonance imaging experiments) can be used in order to explore factors that may contribute to the tuning of general mechanisms for the particular problem of face recognition. Current research continues to explore the role of expertise in object recognition, including new lines of research into perceptual expertise with letters and also haptic expertise. Other projects include looking at the role of spatial frequencies in various visual areas involved in object recognition and investigating interactions between the visual and semantic systems.
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Neural Basis of Cognitive Control and Regulation of Emotion in Depression, Neurobiology of Stress
Merida Grant
Department of Psychology
305 Wilson Hall
322-1781(office); 343-2094 (lab)
merida.grant@vanderbilt.edu
Early adverse events have been linked to the onset and maintenance of depression but the mechanisms underlying this relationship are less clear. The focus of Dr. Grant’s research is on developing and investigating neurobiological models of the transduction of stress into changes in brain structure and function in depression that underlie disturbances in cognitive control and self-regulation of emotion using novel behavioral paradigms, fMRI and MR spectroscopy. The general focus of the lab is on spatial localization/mapping of brain regions central to efficient cognitive control in relation to affective disorders, including functional subdivisions of the anterior cingulate [dorsal and rostral-ventral], lateral PFC and amygdala. Our work to date suggests considerable disturbances in both behavioral and neural response to tasks that require high attention load and varied affective valence in patients with unipolar depression. Further research will continue to investigate the link between efficiency of stimulus processing and mood congruence. In addition, more recent work in our lab is now focusing on the link with stress including HPA activity, with a particular focus on cortical GABA and glutamate levels, in addition to cortisol.
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Gene Discovery in Complex Human Diseases
Jonathan Haines
Molecular Physiology and Biophysics
Program in Human Genetics
519 Light Hall
343-8555
jonathan@phg.mc.vanderbilt.edu
Dr. Haines' primary research interest is in the localization and identification of genes involved in common and genetically complex human diseases. Our lab concentrates on identifying, collecting samples, and examining the DNA from patients and their families for a number of different diseases. The gene discovery approach uses a combination of methods adopted from the fields of genetics and epidemiology. These include family (genetic linkage) studies and association (primarily linkage disequilibrium) studies. Molecular methods being used include microsatellite marker genotyping, single nucleotide polymorphism genotyping, SSCP, dHPLC, OLA, and sequencing. Statistical methods include model-dependent and model- independent linkage analysis, case-control and family-based allelic association studies, segregation analysis, and logistic regression. The molecular and statistical methods are combined to discover genes that affect risk and/or expression of human diseases. The primary diseases of interest are Alzheimer disease, multiple sclerosis, macular degeneration, epilepsy, and autism with additional efforts in other neurological, neuromuscular, ophthalmologic, and psychiatric disorders.
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Molecular Basis of Signaling Mechanisms Mediated by G Proteins
Heidi Hamm
Professor and Chair, Department of Pharmacology
432 MRB-I
343-3533
heidi.hamm@mcmail.vanderbilt.edu
My work is focused on understanding the molecular basis of signaling mechanisms mediated by G proteins, which are switch proteins. G proteins are normally active, but a receptor that has received a specific signal can activate G proteins, leading to changes in the activity of enzymes that produce second messengers such as cyclic AMP and calcium. The research in my laboratory is aimed at understanding how G proteins become activated by receptors, how they in turn activate effector enzymes, and how they turn off. We determined the sites of interaction between proteins using a method of decomposing the proteins into small synthetic peptides and determining which peptides blocked interaction sites. To understand the process more fully, we determined the atomic structure of the proteins in collaboration withthe group of Paul Sigler. We used X-ray crystallography to solve the three-dimensional structures of G proteins in their inactive and activated forms. These high-resolution structural studies allowed us to postulate specific hypotheses regarding mechanisms of receptor: G protein interaction and activation, G protein subunit association-dissociation and effector activation.
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Cellular/Molecular Biology of Biological Clocks
Carl Johnson
Department of Biology
U8211 BSB/MRB III
322-2384 or 322-2008
carl.h.johnson@vanderbilt.edu
My lab studies daily biological clocks in a variety of organisms, and we use luminescence as a tool to monitor these clocks. In mammals, our lab uses transgenic mice and mammalian fibroblasts expressing different kinds of light-emitting enzymes ("luciferases") to monitor rhythms of gene expression and calcium levels by the rhythmic glow of the reporter luciferase. Therefore, our lab uses luminescence as a tool to monitor circadian rhythms in the brain and in cell cultures. These studies are directed towards understanding the calcium signal transduction pathway to the core clock and the role of clock genes in the fundamental mammalian clockwork. We have recently extended our studies to the genetics of the human biological clock. We are examining clock gene polymorphisms in human populations to determine how the neurogenetics of the biological clock affects our ability to adapt to shiftwork cycles and how it can influence mental health (esp. depression).
My laboratory also studies rhythmic behavior in bacteria (specifically, blue-green algae). To study the clock mechanism in cyanobacteria, we used a bacterial luciferase reporter as a genetic marker in order to find other genes that control clock function. My lab, in collaboration with labs in Japan and Texas A&M, has identified three bacterial genes that are essential for biological clock function. In collaboration with Drs. Martin Egli and Phoebe Stewart at Vanderbilt, we study the structural biology of these bacterial clock proteins. The three purified proteins exhibit circadian oscillations in a test tube! Therefore, the Johnson/Egli/Stewart labs are taking advantage of our past structural work to analyze and explain how these proteins can oscillate in vitro. Furthermore, my lab is using clock mutants of the bacteria to provide the first rigorous evidence for the adaptive significance of circadian clocks in fitness.
Finally, we developed a new method for measuring protein-protein interactions based upon the resonance energy between a luciferase and a fluorescent protein. This method is called Bioluminescence Resonance Energy Transfer, or BRET. This technique has allowed the development of novel reporters for intracellular calcium and hydrogen ions. A bright future is envisioned for BRET.
See our laboratory website at: http://www.cas.vanderbilt.edu/johnsonlab/
Mori, T., D.R. Williams, M.O. Byrne, X. Qin, H.S. Mchaourab, M. Egli, P.L. Stewart, and C.H. Johnson. 2007. Elucidating the Ticking of an in vitro Circadian Clockwork. PLoS Biology 5: e93.
Fan, Y., A. Hida, D.A. Anderson, M. Izumo, and C.H. Johnson. 2007. Cycling of CRYPTOCHROME Proteins Is Not Necessary for Circadian-Clock Function in Mammalian Fibroblasts. Current Biology 17: 1091–1100.
Xu, X., M. Soutto, Q. Xie, S. Servick, C. Subramanian, A. von Arnim, and C.H. Johnson. 2007. Imaging Protein Interactions with BRET in Plant and Mammalian Cells and Tissues. Proc. Natl. Acad. Sci. USA 104: 10264-10269.
Woelfle, M.A., Y. Xu, X. Qin, and C.H. Johnson. 2007. Circadian rhythms of superhelical status of DNA in cyanobacteria. Proc. Natl. Acad. Sci. USA 104: 18819–18824.
Bonneau, R., M.T. Facciotti, D.J. Reiss, A.K. Schmid, M.Pan, A. Kaur, V. Thorsson, P. Shannon, M.H.
Johnson, C.J. Bare, W. Longabaugh, M. Vuthoori, K. Whitehead, A. Madar, L. Suzuki, T. Mori, D.-E. Chang, J. DiRuggiero, C.H. Johnson, L. Hood and N.S. Baliga. 2007. A predictive model for transcriptional control of physiology in a free living cell. CELL 131: 1354-65.
Johnson, C.H. 2004. As time glows by in bacteria. Nature 430: 23-24.
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Brain Organization, Development, Evolution, and Plasticity
Jon Kaas
Department of Psychology
061 Wilson Hall
322-7491
jon.h.kaas@vanderbilt.edu
Our interests are in how sensory and motor systems are organized, process information, and relate to behavior. Because we are especially interested in how the human brain is organized, much of our research is on primates, including human brain tissue. Our approaches are anatomical, histochemical, and electrophysiological. We are also quite interested in how these systems recover from injury and adjust to sensory change. We work on visual, somatosensory, auditory and motor systems. Some of our research is on the development of these systems. Other research is comparative, in an effort to understand how mammalian brains vary, and how complex brain systems might have evolved.
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Behavioral Neurogenetics of Aggression
Craig H. Kennedy, Ph.D.
Professor of Special Education and Pediatrics
John F. Kennedy Center
304 MRL Building
322-8185
craig.kennedy@vanderbilt.edu
We study gene-brain-behavior relations that contribute to aggression. Our research is primarily focused on understanding the nature of aggression in the developmental disabilities (e.g., autism or mental retardation) with the goal of improving early identification and effective intervention. We use both preclinical and clinical approaches. Preclincally, we use mouse model systems to understand the neurotransmitter circuitry involved in aggression. This work focuses on operant conditioning, biogenic amine pharmacology, and neuroanatomy. Clinically, we are using a candidate gene approach to understanding why some people are more likely to become aggressive than others. Our work is currently focusing on polymorphisms in genes regulating serotonergic circuits that interact with environmental events to predispose people toward impulsive aggression.
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Visual Perception: Psychophysical Research on the Perception of Shape, Space, Motion, and Binocular Vision
Joseph Lappin
Professor of Psychology
510 Wilson Hall
322-2398
joe.lappin@vanderbilt.edu
The purpose of my research is to describe and understand how thevisual system functions to obtain information about the spatial structureof the environment. How are the perceived 3D shapes and locations ofenvironmental objects obtained from 2D optical images in the eyes? How isthe perceived spatial structure of the environment obtained from thecontinually moving and changing patterns of optical stimulation? How isperception of solid object shapes derived from the spatial patterns of intensities, textures, and motions, and from the slight spatial differencesbetween the simultaneous images on the two eyes?
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Molecular and Developmental Basis of Neuropsychiatric Disorders:
Pat Levitt
Professor of Pharmacology
Director of the John F. Kennedy Center
Kennedy Center Senior Fellow and Investigator
405 MRL
322-8242
pat.levitt@vanderbilt.edu
Dr. Levitt studies the molecular and cellular mechanisms that control the development of the forebrain, and the causes for developmental and neuropsychiatric disorders such as autism, anxiety and schizophrenia. The brain begins to establish functional circuits before birth, but has its greatest growth period from birth until around three years of age. The brain then undergoes a substantial period of remodeling during childhood and adolescence. The laboratory is comprised of a group of highly collaborative researchers who investigate the genetic basis for the establishment of forebrain circuits that regulate mood, emotion, stress and complex higher functions. The laboratory also studies the impact of experience and environmental factors, such as social interactions or exposure to drugs of abuse, which may alter the formation and functioning of these systems. Mammalian model systems are used to probe experimentally these issues. Genes implicated in neurodevelopment are studied in human neuropsychiatric and developmental disorders. The goal of combining animal model and human genetic research is to identify mutations and polymorphisms that may alter function of genes sufficiently to increase the risk for expressing a particular disorder.
The laboratory applies a variety of tools in the research projects. For example, microarrays, which contain information on the entire genome, are used to develop gene expression profiles that may be unique to specific neuropsychiatric disorders, genetically altered mice, or animals exposed prenatally to drugs such as cocaine. Genetically engineered mice are created by the laboratory to express mutations of specific genes that may be involved in emotion and mood disorders. By using sophisticated in utero surgical methods, genes are introduced into specific developing brain regions to disrupt normal patterns of gene expression. Analyses of animal models are carried out using sophisticated microscope imaging methods, virus-based neural circuitry tracing, and biochemical, molecular and murine behavioral assays. Finally, informed by fundamental discoveries in developmental neurobiology projects, a candidate gene approach is used in schizophrenia, autism and attentional deficit hyperactivity disorder (ADHD) to define genetic vulnerability for specific disorders, to perform functional analysis in cells and animals of specific variants, and to study associations with particular quantitative traits related to each disorder.
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Cognitive Human Visual Neuroscience
Rene Marois
Assistant Professor of Psychology
530 Wilson Hall
322-1779
rene.marois@vanderbilt.edu
Research in the lab centers on the neural basis of attention and information processing in the human brain using fMRI and psychophysical tools. We are particularly interested in understanding the neural basis of attentional capacity limits (e.g. Why can we only attend to very few objects at a time? Why can't we select or execute more than one task at a time?). We are also interested in understanding the relationships between attention, working memory, and awareness.
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Epilepsy
Gregory C. Mathews
6128 C MRB III
343-0575 (office)
gregory.c.mathews@vanderbilt.edu Current research in the laboratory focuses on synaptic transmission in the hippocampus. In particular, I am interested in how inhibitory synapses adapt in order to maintain the precise balance that exists between excitation and inhibition. Inability of the brain to counterbalance excitatory drive with sufficient inhibition is a potential mechanism for the generation of epileptic seizures. My recent research has focused on how changes in metabolism of the brain's major inhibitory neurotransmitter, GABA, affect inhibitory synaptic strength. I have shown that the amount of GABA packaged in synaptic vesicles, a determinant of synaptic strength, is up (or down) regulated in response to corresponding changes in the uptake of GABA's precursor, glutamate, via specific glutamate transporter proteins. Since glutamate is the brain's major excitatory transmitter, it is possible that glutamate released from excitatory synapses modulates the strength of neighboring inhibitory synapses using this mechanism. It is also likely that glutamate transporters on inhibitory neurons are themselves regulated by cellular signals to modulate inhibitory synaptic transmission. Using electrophysiological methods in acute hippocampal slices and organotypic cultures, I plan to further investigate the role of GABA metabolism in regulation of inhibitory transmission and in the generation or prevention of hyperexcitability and seizures. Publications: Mathews, Gergory C, Diamond, Jeffrey S. Neuronal glutamate uptake Contributes to GABA synthesis and inhibitory synaptic strength. J Neurosci, 23(6), 2040-8, 2003. Silverman, Isaac E, Restrepo, Lucas, Mathews, Gregory C. Poststroke seizures. Arch Neurol, 59(2), 195-201, 2002. Mathews, G C, Bolos-Sy, A M, Covey, D F, Forthman, S M, Ferrendelli, J A. Physiological comparison of alpha-ethyl-alpha-methyl-gamma-thiobutyrolactone with benzodiazepine and bartiburate modulators of GABAA receptors. Neuropharmacology, 35(2), 123-36, 1996. Mathews, G C, Bolos-Sy, A M, Holland K D, Isenberg, K E, Covey, D F, Ferrendelli, J A, Rothman, S M. Developmental alteration in GABBA receptor structure and physiological properties in cultured cerebellar granule neurons. Neuron, 12(1), 149-58, 1994. Blazynski, C, Woods, C, Mathes, G C. Evidence for the action of endogenous adenosine in the rabbit retina: modulation of the light-evoked release of acetylcholine. J Neurochem, 58(2), 761-7, 1992.
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Alzeimer's Disease and Neurodegenerative Disorders
James M. May, M.D.
Professor of Medicine and Molecular Physiology
Section Chief, Endocrinology, VA Hospital
Endocrine Training Program Director
736 PRB
936-1653 or 936-1661
james.may@vanderbilt.edu
Project 1:
Vitamin C, or ascorbic acid, has been shown in animal and clinical studies to help delay or prevent complications attributed to increased oxidant stress in stroke and in several neurodegenerative disorders. Normally, ascorbate is maintained at relatively high concentrations in brain and especially in neurons, where it serves as an antioxidant and supports several important neuronal functions. Ascorbate concentrations in the low millimolar range are generated in neurons by a specific ascorbate transporter, termed the SVCT2. Mice engineered to lack this transporter have very low brain ascorbate contents and die at birth with cerebral hemorrhage, indicating that the vitamin is crucial for survival. The overall goal of this proposal is to determine how the SVCT2 transporter is regulated in neurons, and whether changes in transporter number can affect neuronal function and antioxidant defenses, both in vitro and in vivo.
Project 2:
Alzheimer's disease is the most common dementia in aging humans, but its etiology is poorly understood. There is consensus that it relates in part to the toxicity and deposition of beta-amyloid fragments of the amyloid precursor protein. A key finding of beta-amyloid toxicity, even early in the clinical course of disease, is oxidant stress. This manifests as lipid peroxidation and DNA damage in select cortical areas, followed by neuronal cell death. It follows that antioxidants, and particularly antioxidant vitamins such as ascorbic acid and alpha-tocopherol, should delay or prevent oxidant damage associated with beta-amyloid toxicity. However, this hypothesis has received little study. We propose to test it at the level of cultured neuronal cells and in animal models of Alzheimer's disease. Since neurons have the highest ascorbate content of any cell in the body, and since ascorbate is important as both a neuromodulator and antioxidant, we will focus on its role in preventing oxidant injury to cortical neurons.
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Neurodegenerative and neuroprotective cell signaling pathways
BethAnn McLaughlin
Department of Neurology and Pharmacology
8110A, MRB III
936-3847 (office)
bethann.mclaughlin@vanderbilt.edu
My laboratory is interested in studying cell signaling pathways related to neurodegeneration and protection. We have two major research programs ongoing in the lab. The first is the study of how a short, sublethal ischemic event in the brain can lead to subsequent neuronal resistance to a severe stroke, a phenomenon commonly referred to as ischemic preconditioning. In order to investigate the cellular and molecular events that contribute to this process, we have developed several in vivo and in vitro systems in which cortical neuronal cells can be rendered less sensitive to excitotoxic cell death following a nontoxic exposure to mild chemical ischemia or hypoxia. We are using a variety of biochemical, molecular and proteomic approaches to both enhance our understanding of signaling pathways that we have already determined to be critical for the expression of preconditioning as well as to identify new protein targets which may contribute to this phenomenon. Our findings suggest that intervention against neurological events which result in subtoxic activation of traditional cell death pathways may actually increase vulnerability to subsequent stressors.
Other ongoing lab projects include understanding how classical biochemical changes in ion homeostasis (specifically zinc, calcium and potassium homeostasis) induce the molecular pathways associated with apoptotic cell death. In this work we established a novel link between ROS and zinc induced activation of MAPKs and opening of potassium channels that are associated with apoptotic cell death.
The goal of my research program is to understand the endogenous pathways associated with neurodegeneration and protection to develop novel therapeutics for stroke, cerebral palsy and other degenerative conditions. In addition, these studies investigate signaling pathways which provide protective mechanisms against other forms of cell death.
For more details, see http://kc.vanderbilt.edu/people/pdfs/mclaughlin.pdf
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Daily Biological Clocks
Douglas G. McMahon, PhD
Professor of Biological Sciences
MRB III Room 8270A
936-3933
douglas.g.mcmahon@vanderbilt.edu
The two primary interests of my laboratory are in understanding the cellular and molecular mechanisms of the daily biological clock and the adaptation of retinal circuitry to different levels of light and darkness. To this end we are applying a variety of modern neurobiological techniques including patch clamp electrophysiological recording from neurons and brain slices, biochemical analysis of modulatory signals, real-time fluorescent imaging of gene expression dynamics in living neural tissue, cloning and heterologous expression of synaptic ion channel genes and production of transgenic mice with novel gene reporter constructs. Our goal is to combine neurophysiological and molecular genetic approaches to understand the visual and circadian systems of the brain.
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Neurobiology of Biological Clocks
Terry Page
Department of Biological Sciences
Biological Sciences/MRB III Room 8260A
343-1853
terry.l.page@vanderbilt.edu
I am interested in understanding the mechanisms by which circadian oscillators (biological clocks) in the nervous system regulate daily rhythms of behavior. My current research utilizes invertebrate preparations as model systems to investigate specific questions about the development, anatomy, and physiology of biological clocks. In the cockroach, I have developed a relatively complete description of the anatomical organization of the circadian system so that for example, we know quite precisely where the clock is located in the nervous system. I am currently using that information as a foundation to explore a variety of additional specific questions about the physiology and function of the circadian system. One area we have just begun to focus on is the regulation of insect olfactory learning and memory by the circadian system. We have recently discovered that the ability to form new memories is regulated by the biological clock – there are some times of day that cockroaches learn very well and other times where they are unable to learn at all. Current research is involved with trying to understand the mechanism and significance of circadian regulation of learning and memory.
Decker, S., S. McConnaughey, and T.L. Page (2007) Circadian regulation of insect olfactory learning. Proc. Natl. Acad. Sci. USA 104:15905-15910.
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Molecular and Cellular Characterization of Ocular Angiogenesis (Blindness)
John S. Penn
Vice-Chair and Professor of Ophthalmology
8000 MCE, North Tower
936-1485 (office); 936-1540 (fax)
john.penn@vanderbilt.edu
Dr. Penn explores methods of treating and preventing ocular angiogenesis, the leading cause of blindness in developed countries. Angiogenesis is the unregulated growth of new blood vessels from existing blood vessels. Blood vessel proliferation in the eye often leads to retinal detachment and hence blindness. Angiogenesis is a critical pathologic component of such conditions as retinopathy of prematurity, diabetic retinopathy, macular degeneration, vein occlusion retinopathy, sickle cell retinopathy and others.
Using in vitro and in vivo models developed in his laboratory, Dr. Penn is characterizing the process of angiogenesis on the cellular and molecular levels. Through this activity his lab is identifying rational therapeutic targets. The Penn lab is at the leading edge of partnering with industry to develop novel antiangiogenic drugs for application to the eye.
For more information go to http://medschool.mc.vanderbilt.edu/facultydata/php_files/part_dept/show_faculty/show_partcellbiology.php?id3=927
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Robot Vision, Human-Robot Interaction
Alan Peters
Associate Professor of Electrical and Computer Engineering
234 Jacobs Hall
322-7924
rap2@vuse.vanderbilt.edu
The Intelligent Robotics Laboratory (IRL) of the Center for Intelligent Systems in the School of Engineering is a state-of-the-art facility for research on robots that interact with human beings. A primary focus is on Human-Centered Robotics -- wherein the capabilities and needs of people shape the fundamental design constraints for the robots. The IRL performs basic research in fundamental problems of human-robot interaction, including the sensing, recognition, and interpretation of human actions, human-like and human-compatible robot behavior with respect to sensing and manipulating the environment, reactive control for human safety, human-robot cooperation, which incorporates the mutual direction of attention and human-directed local autonomy (HuDL), and robot-robot interaction using the same concepts. Problems of computer vision including object recognition, visual attention, and visual guidance of motion are of primary importance.
A primary goal of the IRL is to incorporate the results of basic research into real working systems developed with widely-available, current, low-cost, off-the-shelf technology. Therefore, our computational platforms are Pentium-class PCs running the Microsoft Windows NT operating system. Most software is developed in C++. Sensory input devices such as cameras, microphones, digitizers, and frame grabbers are all commercial products.
The combination of basic research with practical solutions has led to the development of ISAC, a stationary dual-armed humanoid with an active vision system, Helpmate, a single-armed, mobile platform fully compatible with ISAC, ROBIN, a small, climber robot, and a low-cost anthropomorphic multifingered gripper called the pneu-hand.
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Experience-dependent plasticity in the central auditory system
Daniel Polley
Hearing and Speech Sciences and Psychology
7110 MRB III
343-0577 (office)
daniel.polley@vanderbilt.edu
Research in Dr. Polley’s laboratory progresses along four broadly defined themes:
1) Systems level analysis of critical period regulation in the developing central auditory system. These studies investigate experience-dependent plasticity of auditory information processing in the auditory brainstem, midbrain, thalamus and cortex of the rodent with multi-site neurophysiological recording methods. Essentially, I create reversible imbalances in the 'statistics' of auditory stimuli (through monaural occlusion or biasing the spectral and/or temporal envelope properties of ambient sound reaching the ear) and document the expression of receptive field plasticity throughout an early period of postnatal development. Ultimately, this line of research will provide some critical insight into the subcortical origins of experience-dependent plasticity and give us some idea as to how critical periods are staggered in time and magnitude across a hierarchically organized system.
2) The perceptual consequences of auditory map plasticity. It is well documented that the functional organization of auditory maps can be modified by peripheral deafferentation, sensory deprivation, or learning. Surprisingly, little is known about how these large-scale changes impact the animal's capacity to detect, discriminate, or learn information about the stimuli corresponding to the reorganized regions of the auditory map. This line of research will utilize methods for recording neural, autonomic, and musculoskeletal activity in awake and behaving rodents as they are engaged in various auditory conditioning tasks.
3) Molecular substrates of critical periods. Preliminary work has suggested that there is a sharply defined time window in early postnatal life for exposure-based plasticity in the auditory cortex. Work in other cortical systems has identified several candidate molecules with a temporal expression pattern that correlates with these developmental ages. Future studies might investigate how artificially modifying the timing and/or expression pattern of the candidate molecules could alter the timing for critical period plasticity and possibly provide insight as to whether or not a critical period for experience-dependent plasticity could be artificially reinstated in adulthood.
4) Experience-based remediation of sensory processing deficits in rodent models for neurodevelopmental disease. My inclination is to think of plasticity as a process that can be engaged and directed, rather than simply as a set of phenomena worthy of observation. I have a real curiosity in determining whether- and how- applying specially designed sensory stimuli during the developmental critical period might be able to mitigate the progressive expression of anomalous physiological processing. To this end, I will study 'internally noisy' physiological processing in rodent models for various neurodevelopmental pathologies. The plan here is to study brains that are endowed with an auditory processing deficiency either through genetic manipulations or by perinatal exposure to neurotoxins. Once we have characterized the "physiological phenotype" in these animals and know something about when, during postnatal development, the affected brain regions are maximally influenced by sensory stimuli, than we can apply the corrective stimuli and potentially demonstrate that physiological activity and sensory discrimination abilities are re-normalized as a consequence of sensory intervention.
Bio found online at http://kc.vanderbilt.edu/people/pdfs/polleybiosketch.pdf.
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Learning and Plasticity in Space Perception, Imagery and Action
John Rieser
Professor of Psychology
219 Hobbs Building
322-8347
j.rieser@vanderbilt.edu
My research is about dynamic space perception, imagery, and action. Many of the experiments are about the perception and control of locomotion when walking without vision, some are about the perception and control of object manipulation without vision. A main phenomenon is that when people walk or manipulate objects with their eyes closed they keep up to date on their changing positions relative to the remembered surroundings and objects. Our research is focused on how people connect the afferent and efferent input from motor activity with images and memory representations of the objects and surroundings that were visually perceived at an earlier time. We use various methods. For example, to study learning we devised methods
to induce experimental changes in the coupling of action and imagery. To learn about the organization of space perception and action, we test to find out how widely those induced changes generalize to perceptually novel situations and to novel motor actions. Many of our studies involve a human comparative approach. For example, to learn about normative development we
test children who may range from one to fifteen years of age. And to learn about plasticity and the role that visual experience may play in nonvisual development, we test people who may have lost some or all of their vision at different ages in life.
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Ion Channel Biology and Personalized Medicine
Dan Roden
Professor of Medicine and Pharmacology
Assistant Vice-Chancellor for Personalized Medicine
1285B Medical Research Building-4
322-0067
dan.roden@mcmail.vanderbilt.edu
Ion channels are the fundamental units determining excitability in tissues such as heart, skeletal muscle, and brain. Research in the Roden laboratory has focused on drug block of ion channels and how this might be therapeutic (or detrimental) in heart disease. Work in the lab focuses on two broad areas: (1) studies of physiology and pharmacology of ion channels and other proteins determining excitability in heterologous systems, and in zebrafish and mice. The questions center on mechanisms of arrhythmia susceptibility and variable responses to drugs, as well as on novel roles of ion channel proteins during development. (2) The broad areas of genomics and pharmacogenomics. Dr. Roden is Principal Investigator on the Vanderbilt DNA databank, a very large DNA repository linked to electronic medical records. The resource is a tool for discovery and for studies examining how to apply genomic information to the bedside.
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Neuronal Circuitry Underlying Visual Perception
Anna Roe
Department of Psychology
066 Wilson Hall
343-0901 (office)
anna.roe@vanderbilt. Roe studies the neuronal circuitry underlying vision and touch. To map these functions in the brain, she uses a high spatial resolution (50-100 um) imaging method, termed optical imaging. Through an implanted 'window' on the brain, pictures of cortical reflectance are taken which correlate with neural activity. This method, in conjunction with electrophysiology and anatomical tracing methods, permits the study of fundamental cortical modules in the brain and their connections. Her lab is now studying how different networks of modules are activated by simple and complex visual and tactile stimuli. In particular, sensory illusions are used to tease apart different stages of sensory processing. To directly link neuronal activation patterns to specific behaviors, she is developing this technology to study cortical activity in awake animals trained on visual and tactile tasks. Relative Publications: Chen G, Lu HD, Roe AW (2008) A map of horizontal disparity in primate V2. _Neuron_, /in press/.
Roe AW, Parker AJ, Born RT, DeAngelis GC (2007) Disparity channels in early vision: a mini-review. _J Neurosci_, 27:11820-11831. /Cover figure/.
Chen LM, Turner G, Friedman RM, Gore JC, Roe AW, Avison MJ (2007) High resolution maps of real and illusory tactile activation in SI: intra-individual correlation with fMRI, optical imaging and electrophysiology. _J Neurosc__i_,/ /27(34):9181-9191.
Hung CP, Ramsden RM, Roe AW (2007) A functional circuitry for edge-induced brightness perception. _Nature Neurosci_,/ /10:1185-1190.
Lu HD, Roe AW* *(2007) Functional organization of color domains in V1 and V2 of Macaque monkey revealed by optical imaging. _Cerebral Cortex_, 18(3):516-33. /Cover figure/.
Chen LM, Friedman RM, Roe AW (2005) Optical imaging of SI topography in anesthetized and awake squirrel monkey. _J Neurosci_ 25: 7648-7659. /Cover figure/.
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Cortical Representations of Visual Information, Attention
Andrew Rossi
Department of Psychology
008 Wilson Hall
322-7466 (office)
andrew.rossi@vanderbilt.edu My research is aimed at understanding how visual information is represented in the brain and the manner in which cognitive mechanisms interact with visual representations. We use a combination of perceptual studies in humans and electrophysiological recordings in behaving monkeys to examine the relationship between brain activity and perception. Current research interests include contextual interactions in visual cortex, mechanisms of attentional selection, and the role of cortical feedback in visual processing.
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Studies of Mood Regulation
Ronald M. Salomon
Department of Psychiatry
Vanderbilt Psychiatric Hospital, Third Floor
(615) 327-7009; fax (615) 343-9640
ron.salomon@vanderbilt.edu
Mood is regulated by many factors.
Currently our work utilizes
- fMRI measurements of brain regional metabolism
- regional functional connectivity in time series
- neurochemical measurements in rapid time series
- studies of mood effects on memory
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Mechanisms of Regulation of Serotonin Receptor Expression and Function
Elaine Sanders-Bush
Professor of Pharmacology
459B Medical Research Building-II
936-1686
elaine.bush@mcmail.vanderbilt.edu
The neurotransmitter serotonin is thought to play a role in diseases such as schizophrenia and depression, as well as in normal physiological processes such as appetite, and in the abuse of drugs such as hallucinogens and cocaine. These myriad of actions are mediated by multiple serotonin receptors. Our laboratory explores the structure, function and regulation of the subfamily of serotonin 5-HT2 receptors. Questions currently being explored include the biological significance of a newly discovered mechanism of regulation of the 5-HT2C receptor: RNA editing, which generates seven previously unknown receptor isoforms, post-translational modification (e.g., receptor phosphorylation) of 5-HT2A and 5-HT2C receptors and the role of these modifications in the regulation of receptor sensitivity, trafficking and density, immunolocalization of 5-HT2A and 5-HT2C receptors in brain, role of the 5-HT2A and 5-HT2C in the mechanism of action of hallucinogenic drugs, and identification of novel molecular targets of hallucinogens and methamphetamine. Throughout, the goal is to relate studies of molecules and cells to the function of the intact brain by combining biochemical/molecular studies of serotonin receptors with behavioral studies in animals in collaboration with other scientists at Vanderbilt University.
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Visual Neuroscience, Cognitive Neuroscience
Jeffrey Schall
Professor of Psychology
Vanderbilt Vision Research Center
004 Wilson Hall
322-0868
jeffrey.d.schall@vanderbilt.edu
The goal of our research is to understand how the function of the brain gives rise to behavior and experience. The particular domain we study is vision and eye movements. We monitor the activity of neurons in the cerebral cortex of monkeys that are awake and performing specific tasks. Our aim is to decipher the signals conveyed by individual and small collections of neurons. At present, we are asking two specific questions.
1) How does the brain select the target for an eye movement? Neural activity is recorded while monkeys search for a specific visual stimulus that is embedded in an array of distracting elements. We are describing when and how neurons decide whether a given visual element is the target or a distractor.
2) How does the brain control when to shift gaze? Neural activity is recorded while monkeys perform a task that
manipulates their ability to withhold a planned movement. We are describing how different populations of neurons control or monitor the eye movement behavior.
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Regulation of G-protein Coupled Signal Transduction by Scaffolding Proteins
Bih-Hwa Shieh
Department of Pharmacology
402 Medical Research Building I
343-0441
bih-hwa.shieh@mcmail.vanderbilt.edu
My laboratory is interested in understanding function and regulation of scaffolding proteins in signal transduction. Scaffolding proteins consists of multiple protein-protein interaction motifs and acts by tethering multiple components of a signaling pathway leading to formation of a signal transduction complex. This clustering of signaling molecules may regulate specificity of signaling events. Moreover, it may facilitate protein-protein interaction for fast activation and deactivation of signaling processes. One of the prototypical scaffolding protein is INAD that is essential for visual transduction in Drosophila. Visual transduction is the process that converts the signal of light into a change of membrane potential of photoreceptors. It is a G-protein coupled phospholipase C?-mediated mechanism leading to opening of two cation channels, TRP and TRPL. In the visual cascade, light turns on rhodopsin which activates a Gq. Activated Gq?-subunit switches on a phospholipase C? (NORPA) resulting in breakdown of phospholipids to generate diacylglycerol (DAG) and inositol trisphosphate. DAG is a potent activator of protein kinase C (PKC) that exerts a negative regulation of the visual transduction.
We study how INAD regulates visual transduction. INAD contains five distinct PDZ domains. PDZ domains are protein-protein interaction domains of 90 amino acids in length and are present in many proteins involved in localization and anchoring of signaling molecules. In Drosophila visual cascade, we and others have demonstrated that INAD interacts with three key proteins including the TRP calcium channel, phospholipase C? and eye-PKC. Our current investigation focuses on function of the signaling complex in visual transduction. We employs a combined analysis of molecular biological, biochemical, electrophysiological and genetics methodologies. Insight into how INAD coordinates visual transduction will help gain understanding into regulation of signal transduction by scaffolding proteins.
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Attention to Moving Objects
Adriane E. Seiffert, PhD
Assistant Professor, Psychology
534 Wilson Hall
322-4595
a.seiffert@vanderbilt.edu Seiffert explores how people see and direct their attention to moving objects. The ability to follow the movement of objects is an important skill for many activities, such as driving through a busy intersection. Seiffert investigates research questions such as: How does attention tract object movement? What is the nueral implementation of this process? Why do errors in tracking occur? How is attention involved when people control the motion of objects? The long-term objective of this work is to understand how visual attention interacts with motion perception and visuo-motor systems to track the motion of target objects. The methods of investigation include human psychophysics, cognitive experiments and human neuroimaging (fMRI). Funding comes from the National Eye Institute of the National Institutes of Health. Representative Publications: Seiffert, A.E. & Di Lollo, V. (1997). Low-level masking in the attentional blink. Journal of Experimental Psychology | | | | |
