Graduate Studies in NEUROSCIENCE US D 1. 2: N 39 ISO LOCKWOOD U88ARY ' .INIVERSITY AT BUFFALt~ St.P l u 1996 UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES F. EDWARD H EBERT SCHOOL OF MEDICI E BETHESDA, MARYLAND Graduate Studies in NEUROSCIENCE UNIFORMED SEIN ICES UNIVERSITY OF THE HEALTH Sc iENCES F. EDWARD H EBEHT Sc H ooL OF M EDICINE BETHESDA, MAHYLAN D 1996 Edition The cover photomicrograph, kindly donated by Dr. Donald Newman, Department of Anatomy, USUHS, is a Golgi-labeled pyramidal neuron from the rat cerebral cortex. The Ph.D. Graduate Program In Ne uroscie nce At Uni formed Se rv ices Unive rs ity Of The Health Scie nces WHAT AHE TilE 1\E:-JEFITS OF OIITAI:'\11:'\IG A PH.D. DEGHEE ? There are many benefits! In addition to the intellectual satisfaction of completing a rigo rous course of instruction in a fascinating field, there is the personal reward of developing and working on a research project that will contribute to knowledge and be published in a scientific journal. You will meet many very interesting and talented colleagues and faculty , and form friendships that will last a lifetime . A Ph.D . degree opens up many career possibilities , including stimulating and reward ing research and administrative careers in academia, government. and the pharmaceutical , che mica l and biotechnology industries, that would not be open to you if you did not have a Ph.D . degree . If you have a strong undergraduate academic record and are interested in the biomedical scie nces , you owe it to yourself to consider seriously the possibility of entering a Ph.D . program. A graduate degree can be the introduction to an exciting and challenging career in biomedical research. Explore the possibilities. If the cost of graduate programs is a concern to you , do not forget that stipends are available and there are no tuition charges at the Unifo rmed Services University of the Health Sciences (USUHS) . WHAT IS NEUitOSCIENCE ? Neuroscience is the study of the structure , development and function of the nervous system . This is the most complex organ in the body and it plays a regulatory role controlling or influencing the functions of all physiologic systems. Understanding the ways in which the brain and peripheral nervous system function requires a multidisciplinary approach. Techniques from those of the molecular biologist to those of the experimen tal psychologist are all required to generate an understanding of the interrelated connections and functions of nerve cells and their supporting glial cells . Knowledge from these and many other fields is required to understand the operation of even a small functional component of the brain. Over the last two decades it became apparent to scientists working to understand the nervous system that an interdisciplinary approach to research and education in neuroscience was the only way a comprehensive understanding of the functions of the nervous system can be achieved. Interdisciplinary programs in neuroscience such as that offered at USUHS draw from the skills of many basic science disciplines in an integrated effort to expand our knowledge of how the brain works , of how it becomes disturbed in various psychiatric and neurologic diseases , and of how we can use drugs or behavioral approaches to modify and correct malfunctions when they occur . This is a time of great opportunity in neuroscience. In recognition of the opportunities provided by these discoveries , the 1990s were proclaimed by President Bush to be The Decade of the Brain . Fundamental discoveries at the molecular and cellular levels of organization of the brain are rapidly clarifying the role of the brain in translat ing neurophysiologic events into behavior, thought and emotion . Advances in molecular biology and genetics have yielded strategies effective in preventing several forms of severe mental retardation and are promising breakthroughs in the study of inheritable neurologic disorders such as Huntington's disease and mental disorders such as affective disease . Technological advances have made it possible to image structures in the brain to more directly observe changes in their function during thought and activity. CAREERS IN NEUROSCIENCE Neuroscientists are in demand for faculty positions in medical, dental , pharmacy , nursing and veterinary schools . Other neuroscientists are employed in research and administrative positions in government laboratories such as the National Insti tutes of Health , in private research foundations , and in the pharmaceutical , biotechnology , and chemical industries. There are also employment opportunities in government regulatory agencies such as the Food and Drug Administration , the Environmental Protection Agency, and in industrial organizations interacting with these agencies . NEI!ROSCIENCE PH.D. GRAOllATE PROGRAM AT USUHS The Graduate Program in Neuroscience is an interdiscip linary program with courses and research training provided by Neuroscience Faculty holdi ng primary appointments in the Departments of Anatomy and Cell Biology, Biochemistry , Medical Psychology , Med icine , Microbiology, Neurology, Pathology , Pediatrics , Pharmacology, Physiology, and Psychiatry in the Medical School at the Uniformed Services University of the Health Sciences . The interdisciplinary nature of the program permits considerable flexibility in the choice of courses and research areas ; training programs are tailored to meet the individual requirements of each student. The Program is designed for students with a strong undergraduate background in biology, physical sciences , or psychology who wish to pursue a professional career in neuroscience research . The Neuroscience Program at USUHS is a young , growing and dynamic graduate program . The first students were accepted into the program in 1991 . The Neuroscience Graduate Program currently enrolls more than 12 students . USUHS also has Ph.D . programs in departmentally-based basic biomedical sciences and an interdisciplinary graduate program in Cell and Molecular Biology. ln addition to the Graduate and Medical Programs in the Medical School, the Nursing School has graduate programs for Nurse Practitioners and Nurse Anesthetists . Graduates with USUHS neuroscience-related degrees now hold faculty , research associate , postdoctoral and other appointments in universities , medical schools , and government and industrial research laboratories and programs . PHOGH.Al\1 OF STIJIW T he Program of study is divided into course work in fundamental and advanced areas of neuroscience, and laboratory thesis research leading to the doctor of philosophy degree (Ph .D.). During the first year, students take courses and participate in research rotations in 31aboratories (of the ir choice). At the end of the first year, a mentor will be chosen and research continued in the mentor's lab du ring subsequent years . Additional advanced courses are taken in the second year afte r wh ich the successful completion of the qualifying exam will advance the student to candidacy for the Ph.D. degree. After presentation of a written doctoral dissertation proposal, completion of original neuroscience research , preparation of the doctoral dissertation , and the successful oral defense of the dissertation , the Ph.D. will be awarded. A dissertation advisory committee , comprised of the major advisor and at least 4 other USUHS faculty, will guide the direction and progress of the students dissertation research . The basic structure of the course work section of the Program is divided into required Core Courses and approved Electives. Students must maintain an average grade of 3.0 (B) or better throughout graduate training to remain in good academic standing in the Program. Opportunities for students to obtain teaching experience in neuroscience courses are available. TYPICAL SCIIEOl TLE OF CotJHSES Year 1 Fall Quarter Introduction to Neuroscience Biostatistics I, or Experimental Statistics Medical Biochemistry Neuroscience Sem inar Winter Quarter Neuroanatomy Introduction to Neurophysiology Biostatistics II or Experimental Statistics (continued) Neuroscience Seminar Electives Spring Quarter Advanced Topics and Techniques in Neuroscience (taken yr 1 or 2, as offered) Introduction to Neurophysiology (continued) Neuroscience Seminar Neuroscience Tutorial Electives Year 2 Fall Quarter Ethics & Responsible Conduct of Research Fundamentals of Immunology Neuroscience Seminar Electives Winter Quarter Neuropharmacology Neuroscience Tutorial Neuroscience Seminar Electives Spring Quarter Biological Basis of Disease of the Nervous System (taken yr 1 or 2, as offered) Electives Neuroscience Seminar Neuroscience Qualifying Examination (written and oral components) Anatomy & Cell Biology Department: Gross Anatomy Microscopic Anatomy Practical Histological Techniques Techniques & Experimental Design in Anatomical Sciences Molecular and Cell Biology Program , and Biochemistry Department: Cell Biology I and II Genetics Introduction to Computers Macromolecule-Ligand Interactions Membrane Biochemistry Microbiology Department: Cellular and Molecular Immunology Eukaryotic"Gene Expression Fundamentals of Immunology Fundamentals of Virology Techniques in Molecular Biology Medical Psychology Department: Appetitive Behaviors Behavioral Pharmacology Cogn itive Psychology Psychopharmacology Psychoneuroimmunology Stress Pathology Department: General Pathology Recombinant DNA Technology and Applications Pharmacology Department: Concepts in Drug Metabolism and Toxicology Introduction to Instrumental Methods Medical Pharmacology Novel Concepts in Neurotransmission Recent Progress in Cellular and Molecular Endocrinology Physiology Department: Experimental Neurophysiology Medical Physiology Sensory Neurophysiology Neuroscience students participate in the biweekly Neuroscience seminar series that brings renowned neuroscientists to the University, and present a seminar each academic year. In addition , participation in a journal club and attendance at both local and national neuroscience meetings are strongly encouraged and supported . ENVmONMENT A;-.;n REsEARCH FACILITIES USUHS has modern well-equipped laboratories for the support of a wide variety of neuroscience research projects . Laboratories suitable for research in most areas of neuroscience are available to students , including behavioral studies , electrophysiology, molecular and cellular neurobiology, neuroanatomy, neurochemistry, neuropathology, neuropharmacology, and neurophysiology. High resolution transmission and scanning electron microscopes, video-based computer graphics , laser cytometers, and confocal microscope are available . The biomedical instrumentation center contains oligonucleotide and peptide synthesizers, a BiaCore system , Scanlytics CELLScan system , automated DNA and protein sequenators, fluorescentactivated cell sorter, and an ACAS workstation. A centralized animal facility , a medical library and learning resource center, audiovisual and computer support are all available within the University. All laboratories, offices and the Learning Resource Center are interconnected through an ethernet system that allows for direct access to medical and research databases , the University VAX complex, individual local area networks within the University , and remote computers. USUHS is located in Bethesda , MD , an immediately adjacent northern suburb of Washington , D.C. The University is located in a park-like setting on the National Naval Medical Center. Wooded areas , jogging and biking trails surround the University. A nearby Metro subway station provides convenient access to Downtown Washington and surrounding areas. The D.C. metropolitan area has about 3 million people, contains 7 major Universities (including 3 othe r medical schools), numerous colleges, and internationally renowned research facilities . The National Institutes of Health (NIH), the National Library of Medicine , and the National Naval Medical Center are within walking distance of USUHS. Also located nearby are the National Institutes of Standards and Technology , the Food and Drug Adm inistration, and the Walter Reed Army Medical Center. Cultural and recreational activities are plentiful , with a major park system , recreation facilities, museums, theaters , symphonies , opera, major league sports teams . The Chesapeake Bay , the Atlantic Coast and Shenandoah Mountains are easily access ible . The cost of living is comparable to that in other major metropolitan areas . AnMISsi()N REQllmEMENTS Applicants are accepted as full-time students to a Ph.D . program and must devote full-time effort to the Graduate Program in Neuroscience. All applicants must satisfy the University requirements for admission . Each applicant must complete a baccalaureate degree from an accredited academic institution before matriculation at USUHS. We recognize that neuroscience students come from a wide variety of backgrounds. A strong undergraduate training in science with completion of courses in biochemistry, biology, chemistry, mathematics , physics, physiology and psychology is desirable . The University requires that applicants must arrange for official transcripts of all prior college level courses they have taken and their resul ts in the Graduate Record Examination (taken within the last two years) to be sent to the Office of Graduate Education, USUHS . Students may elect to submit in support of their application scores obtained in one or more Graduate Record Examination Subject tests from the subject areas listed above. Applicants must also arrange for letters of recommendation from three persons who are familiar with their academic work to be sent to USUHS. In addition, applicants whose native language is not English must submit their results in the test of English as a Foreign Language (TOEFL), unless their undergraduate education has been at an accredited academic institution in the USA or at an equivalent academic institution in an English speaking country , or unless the Program Director decides that this test is unnecessary. Students transferring into the Neuroscience Program from other institutions may transfer academic credit to meet the Neuroscience and Graduate Program requirements, with the approval of the USUHS Graduate Education Committee and the Neuroscience Executive Committee . APPLICATION A:--JI1 FINA:- THEm REsEARCH INTEREsTs The research areas that are strongly represented at USUHS and the faculty working in th ose areas are listed below . More detailed information about the research programs of Neuroscience Faculty are listed in alphabetical order on the following pages. NEURONAL DEVELOPMENT AND PLASTICITY Juanita Anders, Ph.D., Anatomy & Cell Biology. Astrocyte-neuronal interaction in eNSdevelopment and remodeling . Regina Armstrong, Ph.D., Anatomy & Cell Biology . Cellular and molecular mechanisms of glial cell development and regeneration. Rosemary C. Barke, Ph.D., Anatomy & Cell Biology. Neuronal plasticity in development and regeneration . Su Yun Chung, Ph.D. , Bioc hemistry. Homeobox gene expression in the developing cent-ral nervous system. James Coulombe, Ph.D. , Anatomy & Cell Biology. Control of neurotransmitter expression in developing neurons. Cinda Helke, Ph.D., Pharmacology. Epigenetic influences regulating neurochemicals in visceral sensory neurons. Sharon Juliano, Ph.D. , Anatomy & Cell Biology. Development and plasticity of the mammalian neocortex. Donald Newman, Ph . D., Anatomy & Cell Biology. Comparative organization of brainstem reticular formation. John Sarvey, Ph .D. , Pharmacology. Synaptic transmission & activity-dependent plasticity (long-term potentiation) in the CNS . MoLEcUlAR NEUROBIOWGY I~ECEPTOH FL·r-.;cnoN AND S IGNAL TRANSDUCTION Thomas Cote, Ph.D., Pharmacology. Receptor regulation of GTP binding proteins that control second messenger systems. Brian Cox, Ph.D., Pharmacology . Molecular and cellular mechanisms of drug tolerance and dependence; neurochemical effects of opiate drugs and cocaine. John Sarvey, Ph .D., Pharmacology . Synaptic transmission , second messengers, & protein synthesis in activity-dependent plasticity Felix Strumwasser. Ph .D., Psychiatry. Novel calcium mobilizing enzyme, ADP ribosyl cyclase, in the CNS . Ajay Verma , M.D. , Ph.D., Capt, MC, USA, Anesthesiology . Free radical mediation of protein damage and disregulation of neuronal calcium homeostasis in the nervous system. GENE E XPHESSION AND NEUHOLOGIC DISEASES Su Yun Chung, Ph.D. , Biochemistry. Homeobox gene expression in the developing central nervous system . Franziska Grieder, D.V.M. , Ph.D., Microbiology & Immunology. Molecular basis of Venezuelan equine encephalitis virus pathogenesis. A viva Symes, Ph.D., Pharmacology. Cytokine regulation of neuronal gene expression. N EU RO I'EPTI DE PROCESS ING AND f UNCTION Ann Marini, Ph.D., M.D. , Neurology. Excitatory amino acid neurotransmitters and neurotoxicity. Joseph McCabe, Ph.D. , Anatomy & Cell Biology. Histochemistry and molecular biology of hypothalamic-neurohypophysial hormone synthesis. Gregory Mueller, Ph.D., Physiology. Neuroendocrine regulation , neuropeptide gene expression and gene transfer into neurons. STRucTURE AND F UNcTioN oF MAMMAliAN CoRTEx Sharon Juliano, Ph.D., Anatomy & Cell Biology. Development and plasticity of the mammalian neocortex. Linda Porter, Ph.D. , An atomy & Cell Biology. Integration of peripheral input in cat sensorimotor cortex . John Sarvey, Ph.D., Pharmacology. Pharmacology of synaptic transmission and activitydependent plasticity (long-term potentiation) in the CNS. ENVIRONMENTAL ADAPTATION, STREss, AND INJURY Juanita Anders, Ph.D., Anatomy & Cell Biology. The effects of light on nerve regeneration . Rosemary C. Barke, Ph.D., Anatomy & Cell Biology. Plasticity in development and regeneration . Brian Cox, Ph.D., Pharmacology. Molecular and cellular mechanisms of drug tolerance and dependence; cellu lar adaptations to opiates and cocaine. Patricia A. Deuster, Ph.D., Military and Emergency Medicine. Regulation of neuroendocrine responses to exercise and environmental stress. Andrew Dutka, M.D., CDR, MC, USN, Neurology. Cerebral ischemia; neurologic consequences of high pressure and decompression . Neil Grunberg, Ph.D., Medical & Clin . Psychology. Psychological and biochemical mechanisms of appetitive and addictive behaviors . Harry Hollo way, M.D., Psychiatry. Clinical psychiatry; alcohol & drug misuse, post-traumatic stress. Ann Marini, Ph.D. , M.D., Neurology . Excitatory amino acid neurotransmitters and neurotoxicity. Ann Norwood, M.D., MAJ, MC, USA, Psychiatry . Clinical psychiatry, effects of HIV, and post-traumat ic stress . Mark Rollag, Ph.D. , Anatomy. Role of the pineal in photoendocrine control of circadian and circannual biological rhythms . Andres Salazar, M.D., COL, MC, USA, Neurology. Clinical studies of head injuries resulting from trauma and viral infections. Anna-Leena Siren, M.D. , Ph.D., Neurology. Cardiovascular regulation; hypertension and stroke . Thomas A. Tatham, Ph.D., Psychiatry. Behavioral pharmacology, discriminative and reinforcing effects of abused and therapeutic drugs. Lydia Temoshok, Ph.D., Psychiatry. Biopsychosocial aspects of acquired immunodeficiency disease and cancer. Robert J. Ursano, M.D., Psychiatry. Post-traumatic stress disorders. Ajay Verma , M.D. , Ph.D., Capt, MC, USA, Anesthesiology. Free radical mediation of protein damage and disregulation of neuronal calcium homeostasis in neuronal injury. NEURAL REGULATION OF PHYSIOLOGIC FUNCTION Howard Bryant, Ph.D., Physiology . Electrophysiology of vascular smooth muscle ; optical detection of electrical activity. Patricia A. Deuster, Ph.D., Mil. & Emergency Medicine. Regulation of neuroendocrine responses to exercise and environmental stress. Cinda Helke, Ph.D., Pharmacology. Co-existence and regulation of neurotransmitters in autonomic control systems. Joseph McCabe, Ph.D., Anatomy & Cell Biology. Neuroendocrinology: gene transcription regulation and neuron function . Gregory Mueller, Ph.D., Physiology. Neuroendocrine regulation, neuropeptide gene expression and gene transfer into neurons . John O 'Neill, Ph.D. , Physiology & Pediatrics. Neurotransmitter and ionic influences on cerebral blood flow . Merrily Path, M.D., Pediatrics. Neuroendocrinology and neuroimmunology: interactions of cytokines and hormone systems. Mark Rollag, Ph.D. , Anatomy & Cell Biology. Role of the pineal in photoendocrine control of circadian and circannual biological rhythms. Terez Shea-Donahue, Ph.D., Medicine. Gastrointestinal physiology; role of mucosal eicosanoids in the neural regulation of gastrointestinal motility. Anna-Leena Siren, M.D ., Ph .D. , Neurology. Cardiovascular regulation ; hypertension and stroke . CUNICAL NEUROSCIENCE SidneyM. Blair, M.D. , Ph.D., CAPT, MC USN, Psychiatry. lnformation processing and the effects of drugs and other treatments in psychiatric patients. Andrew Dutka, M.D., CDR, MC, USN, Neurology. Cerebral ischemia; neurologic conse quences of high pressure and decompression. Carl Gunderson, M.D ., COL, MC, USA, Neurology. Neurological health care delivery. Harry Holloway, M.D., Psychiatry. Clinical psychiatry; alcohol and drug misuse, post-traumatic stress. Merrily Path, M.D. , Pediatrics. Neuroendocrinology and neuroimmunology. Michael Rosenberg, M.D. , Neurology. Neuro-ophthalmology. Andres Salazar, M.D., COL , MC, USA., Neurology. Clinical studies of head injuries resulting from trauma and viral infections. Lydia Temoshok, Ph.D., Psychiatry . Biopsychosocial aspects of acquired immunodeficiency disease and cancer. Robert J. Ursano, M.D., Psychiatry. Post-traumatic stress disorders. CINDA HELKE Director, Graduate Program in Neuroscience Professor, Department of Pharmacology Ph.D., Georgetown University, 1978 NEUROTRANSMITIER PLASTICITY AND COEXISTENCE IN AuToNOMIC CoNTROL SYSTEMs Dr. Helke's lab is interested in understanding the coexistence of multiple putative neurotransmitters in individual neurons, and the epigenetic factors that influence the presence and amounts of putative neurotransmitters in mature neurons. The phenomena of coexist ence of transmitters and their changing expression alte r the chemical communication between neurons. Visceral sensory neurons of the vagus nerves are used as a model system for some of these studies. These sensory neurons innervate organ systems of the thorax and abdomen, and transmit information concerning such diverse stimuli as blood pressure, gastric distention, bronchiolar irritation and blood oxygenation to the CNS . The cell bodies of these epibranchial placode-derived sensory neurons are located in the nodose ganglion. We found that they contain multiple putative neurotransmitters (and associated mANAs) and combinations of coexistent transmitters, the content of which is not static. The removal of afferent input from the periphery, with axotomy or inhibition of retrograde transport in the peripheral axon, resulted in a marked upregulation of vasoactive intestinal peptide (VIP) mANA and VIPimmunoreactivity (ir), and a downregulation of tyros ine hydroxylase (TH) mANA and TH-ir in nodose ganglion neurons. These data suggest that influences from peripheral targets, perhaps a retrogradely transported factor, play a role in the regulation of the expression of VIP and TH . Studies of the presence and role of target-derived neurotrophic factors on the expression of putative neurotransmitters in these mature neurons are underway. We have recently found a pattern of transport of labeled neurotrophins (NGF, BDNF, NT-3, NT-4) and the presence of neurotrophin receptor mANA (Trk A, TrkB , TrkC) expression which is unique to these sensory neurons. These studies are important to understand the epigenetic target derived factors which affect neurotransmitter expression in visceral sensory neurons. This neurotransmitter plasticity may be particularly important in visceral afferent reflexes and their role to maintain homeostasis. Chemical communication in CNS bulbospinal pathways influencing brain regulation of sympathetic nervous system outflow to the cardiovascular system is another area of emphasis. This work involves multidisciplinary studies of neuronal projections from the ventral part of the medulla to the intermediolateral cell column (IML) of the thoracic spinal cord, their chemical neuroanatomy, receptor types and localization, neurotransmitter coexistence, and function in regulation of sympathetic neurons. We have found numerous putative neurotransmitters (e.g. serotonin , substance P, neurokinin A, TAH) coexisting in these CNS neurons. Current studies focus on the significance of the coexistence of multiple putative transmitters with a particular interest in the concepts of corelease of colocalized agents, frequencydependent modulation of their release, and interactions of the colocalized agents in the regulation of sympathetic outflow. We have recently found that serotonin and substance Pare each released from this autonomic region of the thoracic spinal cord and their release is at least in part from neurons which colocalize the two agents, however, the regulatory influences on the release of each agent are different. Moreover, we have found interactions of one coexisting neurochemical on the release of the other. These studies are important to provide information on the neurochemical and functional significance of the presence of multiple putative transmitters in IML-projecting neurons, provide insights into a possible neurochemical basis for discrete modulation of sympathetic input to the cardiovascular system, and provide more general insights into the neurobiology of colocalized neurochemicals. RECENT PUBLICATIONS Zhuo. H . S1nclatr , C . and Helke , C J.~ Plashctty of tyrostne hydroxylase and vasoactive tntest inal peptide mRNAs tn visceral afferent neurons of the nodose ganglton upon axotomy -tnduced deatferentat ton. Neurosc1ence 63: 617-626. 1994. Zhu o. H .. Lewtn. A C . Ph 1lhps, E.T.. Stncla tr. C .M . and Helke. C .J .. lnh tbitton of ax oplasm tc transport in the rat vagus nerve alters the numbers of neuropepttde and tyrostne hydroxylase mANA-contatning and tmmunoreactive vtsceral afferent neurons of the nodose ganglion Neu roscrence 66: 175 -187, 1995. Yang , L. , and Helke , C .J .: Effects of coexist1ng neurochemtcals on the regulat1on of serotonin release tn the 1ntermed1ate area of ra t 1horac>C sp1nal co rd . Synapse (in press ). Yang , L .. Thomas. N .D., and Helke. C .J . Charac1enzat>on of substance P release from the intermed iate area of rat thoracic sp ina l cord . Synapse (1n press) . Thor , K.B .. N>ckolaus. S., and He lke. C .J .. Aul orad>ograph ic localization of 5-HT,.. 5-HT,. . and 5-HT,cn bind>ng S>les in the rat spinal cord. Neuroscrence 55 : 235-252, 1993. lch rka wa , H ., Aabchevsky , A . and Helke. C .J P resence and coe xrslen ce of puta tive neurolransm tllers tn carotid srnus baro-and chemoreceptor neurons Brarn Res. 611 : 67-7 4. 1993. Helk e, C.J .. McDonald, C.H. and PhillipS, E.T Hypotens>ve effects of 5-HT,. receptor act ivat ion: Ventral medullary S>les and mechamsms of aclion >n the rat J Auton Nerv. Sys . 42 : 177 -188. 1993. 1---------------JuANITA}. ANDERS Associate Professor, Department of Anatomy and Cell Biology Ph.D., University of Mary land Medical School, 1977 I RoLE oF AsTHOCYTEs l:'\j CNS DEVELOI'ME:'\jT AND REMODELING AFlTH h.Jl ' KY: TilE EFFECTS OF LK~IIT ON NEHVE REC~ENEHATION Dr. Anders has been interested in the role of astrocytes in scar formation in the CNS and has defined the astrocytic membrane changes in development and in in vivo and in vitro injury models using freeze-fracture techniques. This work has lead her to the development of an in vitro model for the study of astrocytic gap junctional communication during changes in astrocytic-neuronal interaction in response to neuronal injury. This model uses a laser microbeam for both in vitro nerve injury and for real time analysis of cellular dye coupling using fluorescent markers on living cells. Dr. Anders is also currently examining the effects of low energy laser irradiation on facial nerve regeneration in vivo. In this study , the effects of laser irradiation on the number of surviving motoneurons and reinnervation of the target tissue following nerve transection is being quantitatively determined. Also the effects of laser irradiation on transection-induced neuronal and perineuronal changes are being examined using immunocytochemical and molecular biological techniques. Techniques used in these studies include: tissue culture, animal surgery, laser microsurgery, low power laser irradiation , histochemical procedures, immunocytochemistry, and quantitative PCR. Light microscopic techniques include: fluorescence and DIC optics and video microscopy. REcENT P uBLICATIONS Anders J .J . and J ohnson J.: Tran section of the rat olfactory nerve increases glial fibrill ary ac idic protein (GFAP) immunoreactivity from the olfactory bulb to the piriform cortex . Glia 3:17-25, 1990. Anders J .J . and Woolery S.: Microbeam laser-injured neurons increase in vitro astrocyt ic gap junctional commun ication as measured by fluores ce nce recovery after la ser ph otoblea chi ng . Lasers Surg. and Med. 12:51-62, 1992. Anders J.J., Borke A. C., Woolery S.K. , Van De Merwe W .P.: Low po wer laser irradiation alters the rate of reg enera tion of the rat fac ial nerve . Lasers Surg. and Med. 13:72-82 , 1993. 14 REGINA ARMsTRONG Assistant Professor, Departme nt of Ana to my a nd Cell Bio lo gy Ph .D., University of No rth Ca rolina, 1987 CELLULAR AND MoLECULAR MECHANISMS OF GLIAL CELL DEVELOPMENT AND REGENERATION Dr. Armstrong's current research activities focus on the cellular and molecular mechanisms of glial cell development and regeneration . During development, one glial cell type, the ol igodendrocyte, forms myelin wh ich ensheaths axons to enable efficient neurotransmission in the CNS . Dr. Armstrong has studied the growth factors regulating the proliferation and migration of oligodendrocytes prior to myelin formation . Current experiments examine the differentiation of precursors of oligodendrocytes into mature oligodendrocytes, which express myelin-specific genes . This work is identifying proteins which bind to DNA and control transcription of genes expressed only in myelin-forming cells . The proliferation , migration, and differentiation of oligodendrocytes are also be ing studied in adult animals after experimental myelin damage, or demyelination . Demyelination causes neurological dysfunction in several human diseases, the most common being multiple sclerosis. In multiple sclerosis , myelin repair , or remyelination , is insufficient and recovery of function is incomplete. In the experimental model studied, demyelinated areas , with oligodendrocyte and myelin loss, are efficiently remyelinated. Dr. Armstrong is attempting to identify factors from lesioned areas which can induce cells around a lesion to proliferate , then migrate into the lesion , and express myelin-specific genes, as requ ired for myel ination. It will be interesting to determine whether factors which control these processes during development will have the same roles in adult tissue during remyelination , and whether factors which are active in rodent experimental models of demyelination can also promote remyelination in human diseased tissues . Techniques to be used in these studies include: Northern blots (DNA over RNA) , Southwestern blots (DNA over protein) , electromobility gel shift assays , RNAse protection assays, in situ hybridization , immunocytochemistry, cell cultures , and chemotaxis assays. REc ENT P uBLI CATIONS Arm strong , R.C ., Kim, J.G ., and Hudson. L. D.. Expression of myelin Tra.1scription factor I (MyTI). a zinc· finge r DNA bind ing protein, in developing oli godendrocytes . G/ia 14(4) : 303 ·32t . 1995 . Ga llo, V. and Armstrong , R.C.: Developmental and growth factor·inducec regulation of nes tin in oligodendrocyte lineage cell s. J. Neurosci. 15:395 · 406, 1995. Armstrong R.C .. Darn H.H., Kutta C. V., Friedman E .. Dubois·Dalcq , M.E.: Pre·oligodendrocytes from adult human CNS . J. Neurosci. 12:1538 ·15 47, 1992. Dubois· Dat cq M. and Armstrong R. The cellular and molec ular events of central nervous sys tem remyelination . BioEssays 12:569· 576, 1990. RosEMARY C. BoRKE Associate Professor, De partment of Anato my & Cell Biology Ph .D ., George Washington University, 1979 PLASTIC RESPONSES OF NEURONS DURIN() DEVELOPME!'.! MoToK AND AKOlTSAL MECHANISMS The brainstem reticular formation (RF) plays a crucial role in several vital life processes, including sleep and arousal , spinal motor activity, and pain supression . Yet, little is known concerning the structure and connections of this brain region . Dr. Newman is currently studying the organization of the RF in terms of its nuclear parcellation , inputs and outputs, and neurotransmitters employed by its output systems. He is especially interested in descending reticular pathways and their possible role in spinal motor activity. He is also interested in comparative aspects of the RF ; i.e ., its organization in non-mammalian vertebrates. Dr. Newman's laboratory employs a variety of neurohistological procedures including classic neuronal stains such as the Nissl and Golgi methods , modern tract-tracing techniques such as WGA-HRP labeling and fluorescent tracers , and immunohistochemical procedures to demonstrate RF neurotransmitters by their synthesizing enzymes. In the near future , Dr. Newman intends to utilize a computer microscope system to further study the morphological aspects of brainstem reticular neurons. RECENT P UB LICATI ONS Newman, D.B., Hillea ry , S.K., and Ginberg , C.Y.: Nuclear terminations of corticoreticular fiber systems in rats . Brain Behav. E vol. 34: 223·264, 1989. Newman, D. B. an d Ginsberg, C.Y.: Brainstem reticu lar nuclei that project to the cerebellum in rats; Anterograde tracer study. Brain Behav. Evol. 39: 24-68, 1992 . J. TIMOTHY O'NEILL Assistant Professo r, Departments of Pediatrics and Physiology Ph.D., j o hns Ho pkins University, 1980 MECIIA:\ISMS OF CO:\TROL OF TilE BMI:\1S BLOOD FLOW A:\D NtTRIE;\JT St :I'I'LY As an important organ system of the body, the brain has evolved processes that ensure it receives an adequate supply of oxygen and nutrients. Under stressful conditions (shock, anoxia, asphyxia) , as well as changes in blood pressure, the brain blood supply remains stable, and blood flow is altered to accommodate changing needs for oxygen and glucose. We are investigating these adaptive processes by determining how some molecules (nitric oxide , adenosine , hemoglobin and neurotransmitters) act to control blood flow in the brain and the eye . Several approaches to measure blood flow are employed including, radioactive and colored microspheres , electromagnetic flow probes, and laser-Doppler techniques . We are particularly interested in developmental aspects of blood flow control. Newborns can sustain severe brain damage when the blood, oxygen or nutrient supply to the brain is inappropriate. It appears that some of the control mechanisms operative in the adult are not present or are not fully developed in the newborn . Alternatively, some distinct mechanisms are ope rative during the newborn period , but are not present in adults . The brain's response to low blood sugar (hypoglycemia) is also of interest. Hypoglycemia, for example, can cause brain damage in newborn and adult animals. It is thought hypoglycemia (in adult tissue) causes the release of excitatory neurotransmitters (amino acids) in adult animals, which in turn can initiate a cascade of events that can result in neuronal cell death . We are presently using microdialysis techniques to study the possible role of excitatory amino acids as endogenous toxins during hypoglycemia in newborn animals. RECENT PUBLICATIONS O'Neill, J.T ., Golden , S .M., Franklin, G.A. , Alden , E.A.: Cerebral vascular response to hemorrhagic hypotension in newborn lam bs : the influence of developing anemia . Soc. Exptl. Bioi. Med. 205 : 132-139, 1994. Darling , B.K., Pellett, G ., Payne , A.M., Gallagher, K.L. , 0 Neill, J.T. Developmental differences in the release of excitatory am ino acids during severe hypoglycemia. Am . J. Perinatol. 1993. O'Neill, J .T .. Sogn , A., Hunt , T ., Palacino, J . Inhibition of n itric oxide synthase alters the cerebral blood flow response to hemorrhagic hypotens ion in piglets . Pediatr. Res. 37:227 A, 1995. LINDA L. PoRTER Associate Professor, Department of Anatomy and Cell Biology Ph.D. Bosto n Univers ity, 1985 CORTICAL 1:--lFORMATIO:--l PROCESSI:--:G AND THE , CORTICAL DOPAMINE SYSTEM Dr. Porter's research interests focus on sensorimotor integration and information processing at the cortical level. Anatomical and physiological techniques have been used to study various aspects of the connectivity and interactions between different subdivisions in the somatosensory and motor cortices. The detailed connectivity of many of these regions and the effects of input on neuronal activity in these regions have been determined to better understand how information is processed in the sensorimotor cortex. In addition , various aspects of the intrinsic connectivity of the motor cortex have been addressed. Techniques that are used in the laboratory to study these aspects of cortical function include extracellular electrophysiological recording, cortical stimulation and inactivation, analysis of neuronal tracers and immunostaining at the light, including confocal, and electron microscope levels. Recently, she has begun to assess the physiological and morphological characteristics of the dopamine system in the mammalian motorcortex. This will serve as the basis for future studies of normal dopamine function and the effects of dopamine depletion upon motor cortex neuronal activity. The dopaminergic innervation of the cortex plays an important role in normal cortical function and its depletion has been impl icated in the pathophysiology of neurological disease processes. For example , some aspects of the motor deficits of Parkinson 's disease may be linked to the cortical dopamine system. Current studies in the laboratory include an analysis of the connectivity of dopamine containing axons with identified cortical neurons . lmmunostaining for analysis at the light and electron microscope levels is used to determine the patterns of innervation and synaptic connections of dopamine with intrinsic cort ical neurons and with identified output neurons. lmmunostaining for dopamine receptor subtypes is also being performed to determine the relationship of receptor distribution to dopamine input and dopamine function. The physiological correlates of dopamine connectivity and dopamine receptor distribution is being studied using extracellular recording of identified cortical neurons coupled with iontophoresis of dopamine and specific antagonists to dopamine receptor subtypes. Extracellular recording of neuronal activity in response to dopamine or dopamine agonists are used as a determinant of dopamine's effects on identified cortical neurons. In addition , studies on the development of the cortical dopamine system have been initiated . REcENT PuBLICATIONs lzraeli, A. and Porter. l.L. : Effects of localized inactivation of somatosensory cortex . area 2. on the cat motor cortex . Somatosens. Mot. Res. 10:189-202 . 1993. Porter, LL. and lzraeli, A.: The effects of localized inactivat ion of somatosensory cortex. area 3a , on area 2 in cat. So matosens . Mot. Re s. 10:399·414 ,1993. l zraeli , R. and Porter, L.L.: The vibrissa I motor cortex in the rat: connections with the barrel field . Exp . Bra in Res. 1 04:41 ·54 . 1995. Porter, L. L. : Distribution and synaptic relationsh ips of dopaminergic fibers in the motor cortex . Soc. Neurosci. Abstr. 21 ( 1 ):365 . 1995. MErum..Y Porn Professor, Department of Pediatri cs M.D , Tul ane University , 1975 INTERACTIONS OF IMMUNE AND ENDOCRINE SYSTEM: EFFECT OF NALOXONE ON HYPOTHALAMIC Pin;rrARY ADRENAL AxiS A CoLLABORATION WITH DH. jANE SASAKI, DEPT OF PsYCIIIATHY Research activities include the study of the interactions of immune and endocrine systems, the effect of DH EA on immune function, the mechanisms for diabetic complications, and the importance of nitric oxide as mediator in endocrine systems. This research group was the first to describe activity of DH EA as an antiglucocorticoid compound and the first to report the inhibiting effects of TNF on endocrine tissue activation {human thyroid and rat adrenal cortex). They have implicated adrenal nitric oxide synthase as a mediator of TNF effects on adrenal steroid secretion . Studying the interactions of endocrine systems and immune function is important to the understanding and prevention of the medical complications of stress under conditions of war. Another active project involves the study of the effects on mood of injected long acting progestational steroids used for contraception in adolescent patients. Research funding has been provided by grants from the Office of Naval Research , Department of Clinical Investigation at WRAMC and USUHS. Dr . Poth serves on the Medical and Sc ientific Advisory Board, Diabetic Action, Research and Education Foundation and served on the ad hoc Study Section, Health Behavior and Prevention , NIMH . RECENT P UBLICATIONS Sch wab . N., and Path . M.: Effects of somatostatin and captopnl on glomerular prostaglandin E, production 1n norma l and diabetic rats . Prostaglandins 46:61 -73 , 1993 . Nickels, D.A. , Sabnis , S.G., Antonovych, T.T. and Path , M .: Effect of chronic growth hormone administration on diabetic nephropathy 1n the rat. Ann. Clin. Lab. Sci. 23(6) :432 -468 , 1993. Nickels . D.A.. Welch , C ., W atson . M.E .. Path , M., Hong . T. And Francis , G.L. : Evidence to suggest n itric oxide is an interstit ial regulator of Leyd1g cell steroidogenesis. Metabolism 44 :234 -238 , 1995. Zimmerman , P .. Fran cis, G.L. , and Path . M .: Hormone-containing cosmeti cs may cause signs of early sexual development. M il. Med. 160:628 , 1995. Gartner, L.A. and Path . M.: Grave' s disease in ch ildren and adolescents. The Endocrinologist 5:422 -430 , 1995 . MARK D. ROLIAG Professor, Department of Anatomy and Ce ll Bio logy Ph.D ., Colorado State University, 1977 EFFECT OF LI(;JIT A\lf) MELATO;\IIN ON MELA\IOPHORES The long term research goals of this laboratory relate to the physiological impact of environmental light upon vertebrate systems . The major thrust is directed towards elucidating the mechanisms by which seasonal changes in photoperiod are translated into changes in locomotor and reproductive behaviors in mammals . It is known that the pineal gland , thro ugh its secretion of melatonin , is essential for the normal transduction of photoperiod into a seasonally appropriate change in phys iological activity. Dr. Rollag aims to determine the target site upon which melatonin works (probably a subset of neurons within the hypothalamus) and how melatonin secretion differs as a function of photoperiod or irradiance character. Currently, the amphib ian pigment cell is being used as a model system to gain insight into the molecular mechanisms of melatonin action and of extra-retinal photoreception . It has been found that both melatonin and light inhibits cAMP dependent pigment migration in isolated melanophores via a pertussis toxin sensitive mechanism and efforts are under way to determine other molecular components underlying the transd uction of these signals . REcENT PuBLICATIONS Rollag , M.D .: Pertussis toxin sensitive photo-aggregation of pigment in isolated Xenopus tail -fin metanophores . Photochem . Photobiol. 57:862·866, 1993. Rollag, M.D. and Lynch G.R.: Melatonin-induced desensitization in amphibian melanophores . J. Expt. Zoo/. 265:488·495 , 1993. Brainard , G .C., Barker, F.M .• Hoffman , R.J., Stetson, M.H., Hanifin, J.P., Podolin, P.L. and Rollag , M.D.: Ultraviolet regulation of neuroendocrine and circadian physiology in roden ts. Vision Res. 34: 1521 · 1533, 1994. lata, M., G. D. Lange, and M.D. Rollag : What does changing the temperature do to the melatonin rhythm in cultured chick pineal cells? Am. J. Physiol. 35 :R50· R58, 1994 . jOHN SARVEY Professor, De partme nt o f Pharmacology Ph.D., State Unive rsity o f Ne w York , 1976 CELLULAR AND MOLECULAR MECHANISMS OF SYNAPTIC PLASTICITY The major goal of Dr. Sarvey's research is determining the roles of various neurotransmitters and receptors in long-term potentiation (LTP) , a form of synaptic plasticity that has become the leading candidate for the cellular mechanism of learning and memory. Highfrequency electrical stimulation of synaptic inputs in the hippocampal formation results in an increased response to those inputs that lasts for several hours in an in vitro brain slice or several days in a freely moving rat. Contributions of this laboratory that are often cited include the demonstration that ( 1) norepinephrine, acting through a P-adrenergic receptor, is both necessary and sufficient to induce a long-lasting enhancement of responses (or norepinephrine-induced long-lasting potentiation: NELLP) in medial perforant path synapses in the dentate gyrus of the hippocampal formation, (2) p-adrenergic agonists induce a long-lasting depression at lateral perforant path synapses, concomitant with potentiation in the medial perforant path, (3) inhibitors of protein synthesis block both L TP and NELLP, (4) activation of specific muscarinic cholinergic receptor subtypes can either facilitate induction of LTP or depress synaptic transmission , and (5) in addition to serving several inhibitory transmitter functions, -y aminobutyric acid (GABA) ca n be an important modulator of synaptic plasticity and P-adrenergic function, and can even induce epileptic activity in the dentate gyrus. Dr. Sarvey's group recently began to examine the role of tyrosine kinases in induction of L TP. The serine/threonine kinases, such as cAMP-dependent protein kinase (PKA), calcium calmodulin kinase type II (CaMKII), and protein kinase C (PKC) , are the best characterized kinases in LTP . However, tyrosine kinases may be involved in induction of L TP. Dr. Sarvey's group has shown that inhibitors of tyrosine kinases block the induction of both L TP and NELLP in the dentate gyrus. Furthermore , they have found, using antiphosphotyrosine antibodies, that specific bands in Western blots from hippocampal slices become transiently phosphorylated shortly after induction of either L YP or NELLP. They are currently using antibodies to the phosphorylated forms of mitogen activated protein kinase (MAPK; also known as ERK1 and ERK2) to determine their roles in L TP and NELLP . In addition, they are using Western blot analysis to demonstrate phosphorylation of the nuclear transcription factor cyclic AMP response element binding protein (CREB) following induction of LTP and NELLP. Using in situ hybridization, Dr. Sarvey's group (with Drs . Miles Herkenham and Linda Brady at NIH) have found that expression of mANA of neurotrophins (NGF, BDNF, and NT3) and their receptors are seen following the induction of LTP in the dentate gyrus of freely moving rats. Thus, neurotrophins and their receptors may be involved in maintenance of L TP. Finally, Dr. Sarvey has begun to use hippocampal slices from transgenic mice that lack a-CaMKII to elucidate its role in L TP , NELLP , and other forms of long-lasting potentiation. Extracellular, intracellular, and patch clamp recording techniques are used in rodent hippocampal slices and freely moving and acute in vivo rodent hippocampus. Western blot, cyclic AMP assays, in situ hybridization , membrane purification by differential centrifugation, and other biochemical and pharmacological methods are often combined with electrophysiology. REc ENT PuBLICATIONS Sarvey, J.M., Burgard, E.C ., Decker, G .: Long -term potentiation : studies in the hippocampal slice . J. Neurosci. Meths. 28:109-124, 1989. Bu rgard, E. C. , Sarvey, J.M.: Long -lasting potentiation and epileptiform activity produced by GABA8 receptor activation in the dentate gyrus of rat hippocampal slice. J. Neurosci. 11 :1198-1209, 1991 . Nowa k, T.S. Jr., Zhou , Q . , Voulalas , P.J. , Sarvey, J.M. Gene expression as an index of pathophysiology associated wi th slice preparation . In : Bra in Slices in Bas ic and Clinical Research. A Schurr and BM Rigor, Editors . CRC Press , Boca Raton, Florida , pp. 257-271, 1995 Bramham , C .R. , Southard , T ., Sarvey, J.M., Herkenham , M., Brady, L.S. Unilateral L TP triggers Bilateral increases in hippocampal neurotrophin and trk receptor mANA expression in behaving rats. J. Comp. Neural. In press . TEREZ SHEA-DONOHUE Associate Professor, Departments of Medicine and Physiology Ph .O., Georgetown University, 1979 GASTROINTESTINAL PHYSIOLOGY: ROLE OF MUCOSAL IMMUNE ANO INFLAMMATORY CELL PRODUCTS IN THE NEURAL REGULATION OF GASTROINTESTINAL MOTILITY The major characteristic of inflammatory bowel disease (I BD ) is uncontrolled inflammation , which is thought to be secondary to activation of the immune system. Active IBD is associated with a wide spectrum of events including increases in neutrophilic infiltration, oxygen radicals, immunoglobulins, cytokines, and eicosanoids. Although the initiating factor in IBD is unknown, each of these elements has been proposed to play a role in the secondary amplification of the response which underlies many of the functional changes associated with IBD. Dr. Shea-Don ohue's research is focused on identifying the mechanisms responsible for the abnormal motility associated with mucosal damage and inflammation in the gastrointestinal tract. She has found that production of the ch anges in smooth muscle function require that the inflammation be induced in vivo. The alterations in smooth muscle activity induced by inflammation , however, are conserved in vitro. Changes in mucosal function are assessed by histology, immunohistochemistry, and assays for excitatory and inhibitory neuropeptides, cytokines, and inflammatory mediators such as eicosanoids. Alterations in in vivo motility are evaluated by recording gastrointestinal myoelectric activity or by measuring the transit of a ma rker through the gut. Changes in in vitro smooth muscle function are determined by monitoring contractility of smooth strips in response to nerve stimulation, neurotransmitters, and inflammatory and immune cell products. Electrophysiological studies on individual smooth muscle cells are performed to evaluate changes in membrane potential in response to nerve stimulation. This laboratory demonstrated a stereotypic intestinal response to acute inflammation induced by two dissimilar agents, characterized by increases in eicosanoid generation, mucosal damage, granulocyte infiltration, and smooth muscle contractility. The inflammationinduced alterations in intestinal motility were attenuated or prevented by prior administration of a leukotriene Dreceptor antagonist, capsaicin which produces sensory denervation, or 4 brefeldin, a funga l antibiotic. None of these agents modified the inflammatory response of the mucosa. Inflammation also increased non-cholinergic excitation indicating a change in tachykinin (excitatory) and/or nitric oxide (inhibitory) dependent neurotransmission. Dr. Shea-Donohue continues to investigate how products released from activated immune and inflammatory cells directly or indirectly alter nerve and/or smooth cell activity to further elucidate the mechanisms by which mucosal events modulate smooth muscle function. REcENT PuBLICATIONS Shea -Donahue. T ., Kandasam y, A., and Dubois. A.: Effects of a prostacyclin analog , U68 ,215 , on gastric acid secretion. gastric empty1ng and system ic blood pressure in pnmates . J. Pharmacal Exp. Ther. 260: 1023-1 027 , 1992. Montcalm -Mauilli, E. and Shea -Donahue, T.: Effect of leukotreine D, on gastric emptying and secretion in rhesus monkeys. J. Pharmacal. Exp. Ther. 262 :850-854 , 1992. Sjogren. A. , Colleton. C .. and Shea -Donahue. T.: Stereotyped intestinal myoelectric response to acute enteric inflammation in rabbits . Am. J. Phys iol. 267:G329·G337, 1994. Sjogren R, Colleton C. Pineiro V, Goldhill J , Shea -Donahue T.: Capsaicin effect on the myoelectric and inflammatory responses to acute ric in-indu ced ententis . Gastroenterol. 104:562 , 1993. Goldhill, J.M .. Sanders , K.M .. SJogren, A. , and Shea-Donahue. T.: Changes in enteric neural regulation of smooth mu scle in a rabbit model of small intestinal1nflammat1on. Am . J. Physiol. 268:G823-G830, 1995. ANNA-LEENA SIREN Research Associate Professor, Department of Neurology M.D., University of Oulu (Finland), 1979, Ph.D. University of Oulu, 1982 IMMUNE CELL-E:'\:DOTIIELIAL l:\rTEKACTIO;\;S A:\D s ·moKE We have proposed that hypertension and age, two major risk factors for stroke, may increase stroke likelihood via an intensified cytokine mediated interaction between the endothelial cells and monocyte/macrophages . Accumulation of monocyte/ macrophages into a perivascular location in brain blood vessels could transform the overlying endothelial surface from an actively nonthrombogenic to a procoagulant surface increasing the risk for an occlusion of brain blood vessels due to thrombus formation in these localized vessel segments. Dr. Siren demonstrated activation of endothelium and monocytes , increased endothelial expression of adhesion molecules and upregulation of endothelial adhesion and accumulation of monocytes into perivascular locations in brai n blood vessels of hypertensive or aged animals . She hypothesizes that the perivascular cells transform the overlying endothelium to a procoagulant state via release of proinflammatory, chemotactic and prothrombotic cytokines such as tumor necrosis factor alpha and interleukin-1 . Her recent studies demonstrated increased cytokine release and gene expression in vascular tissues of animals with stroke-risk factors . Ongoing studies will characterize which cell types in the brain can express cytokine message and proteins . Dr. Siren also aims to prevent or reduce the incidence of strokes in genetically stroke-prone animals by therapies blocking the cytokines and/ or monocyte adhesion. She will extend the animal studies to examine its significance to clinical stroke by investigation of cytokine and adhesion molecule expression in carotid atherosclerotic plaques. In vivo studies in rats , immunohistochemistry, in situ hybridization , Northern blots , immunoassays, FACS , and tissue and cell cultures are used to perform these studies. REcENT P uBLICATIONS Siren A.· L. . He ldman . E. , Doran, D.A ., Lysko , P., Vue, T .-L. , Feuerstein , G., and Hallenbeck , J .M.: Release of pro inflammatory and p rothrombotic mediators in the brain and peripheral circulation in spontaneously hypertensive and normotensive W istar-Kyoto rats. Stroke 23 :1643-165 1, 1992. Siren A.· l., Liu , Y., Feuerste in , G., and Hallenbeck , J .M .: Increased release of tumor necrosis factor alpha into the cerebrospinal fluid and pe ripheral circ ula tion o f aged rats. Stroke 24:660-666, 1993. Liu , Y ., Jacobowitz , D.M., Barone, F., McCarron , A .M., Spatz, M., Feuerstein , G ., Hallenbeck, J .M., and Siren , A.-L. : Ouantit ation of perivascular monocyte/ macrophages around cerebral blood vessels of hypertensive and aged rats . J. Cereb. Blood Flo w Meta b. 14(2) :346-352 . 1994. Liu, T ., McDonnell, P.C., You ng , P.R. , Wh ite, R .F., Siren, A.-L., Ha llenbeck, J .M., Barone, F.C ., Feuerstein, G.: lnterleukin-1 mA N A expre ss ion in ischemic rat cortex . Stroke24:1746-175 1, 1993. FELIX STRUMWASSER Professor, De p artme nt o f Psyc hiat ry Ph .D ., Uni ve rsity o f Ca lifo rni a, Los Angel es, 1957 CAI.Cil'M RE<.;t 'LATIO:'>:: RotE OF A NEw CA2+-MoBILIZI:\:<.; E:-.iZYl\IE A:\:D HYDHOLASE Calcium is an extraordinary ion. It is involved in mediating a large number of important cellular processes including, fertili zat ion , contraction, secretion , synaptic facilitation, and cell death. There are two routes by which Ca2• can enter the cytoplasm: through channels in either the external plasma membrane or the smooth endoplasmic reticulum, where internal Ca2• is sequestered. While the phosphol ipid IP3 is well known to release Ca2• from internal stores, there is now good evidence that cyclic adenosine diphosphate ribose (cADPR) is another important Ca2·-mobilizing agent in a variety of mammalian cell types and microsomes (anterior pituitary cells, ~-cells of the pancreas , brain microsomes) . Dr. Strumwasser and colleagues recently purified and cloned ADP ribosyl cyclase (an NADase) , the enzyme that synthesizes cADPR from the subst rate NAD. The cyclase is aqueous soluble and relatively abundant in the eggs of the mollusc Aplysia. To date, in mammals the cyclase has been purified from spleen cell membranes by another group and is the antigen CD38 on the plasma membrane of lymphocytes. Dr. Steven Sczekan , in Dr. Strumwasser's group has partially purified the cyclase from rat bra in and finds that these are multiple isoforms of the enzyme. cADPR hydrolase breaks down cADPR into ADPR , which does not mobilize Ca2 • from internal stores. The hydrolase must be of importance in adjusting the temporal and spatial characteristics of any rise in cADPR after an appropriate stimulus. In Aplysia the cyclase is also a hydrolase-a bifunctional enzyme . In rat brain it has been possible to partially purify cyclase isoforms. The lab is interested in the regulation of the isoforms and obtaining app ropriate probes for the mammal ian brain cyclase and hydrolase so that they can determine their distribution in brain. Dr. Coetzee 's lab is studying intracellular Ca2 ·-dysregulation in relationship to depression by examing Ca2· -homeostas is in platelets and lymphocytes. REcENT P uBLICATIONS Hellm ich . M.R. and Strum wasser , F.: Purification and characterization ol a mollusca n eg g·speci fic NAD ase. a secon d messeng er enzyme . Cell Reg. 2: t93· 202 .. t99t . G lick , D. L. . Hellm ich . M. R .. Beushausen S .. Tempst . P. J .. Bayley, H. and Str umwa sse r, F.: Pri mary structu re of a moll uscan egg · specific NADase. a sec ond messenger enzyme. Cell Reg . 2:2t 1·218, 1991 . Strumwasse r, F .• Mcintyre. J. and Rainville, C. A.: Long·tenm monitoring of Ca'· in cultured Aplysia neuron s with fluorescent probes . Bioi. Bull. 18t :331·332 . 1991 . Strum wasser . F. and Vogel. J.M.: Cellular oscillators and biolog ical tim ing: The role of proteins and ca•· . Prog. Brain Res. 92:309·320, 1992. Strum wasser , F.: The relations between neurosc ience and hu man behavio ral science. J. Exptl. Anal. Beha vior6 1:30 7· 3 17. 1994. AVIVA SYMES Assistant Professor, Departme nt of Pharmacology Ph.D., University College of London, 1990 CYTOKI\:E Rrt~l"I.ATIO\: OF NITHO\:i\1. GE\:E EXI'HFSSI0:'\1 Cytokines, traditionally thought to be messengers within the immune system , are now known to have a much broader range of functions throughout the body. In the nervous system cytokines can influence survival and differentiation: protecting neurons when injured or stressed and altering neuronal phenotype in response to environmental signals. Neurons constantly receive environmental information, yet they respond uniquely to each signal, carrying out a distinct program dependent upon the signal received and the responding cell. Understanding how neurons recognize these signals and respond appropriately is a vital component of understanding how the nervous system functions. Dr. Symes' laboratory is investigating the molecular mechanisms through which cytokines exert their effect on the nervous system, in particular how cytokines mediate long term changes in neuronal function through altering neuronal gene expression. Dr. Symes research concentrates on the regulation of neuropeptide gene expression by the neuropoietic cytokines; a cytokine family which includes interleukin-6, ciliary neurotrophic factor, leukemia inhibitory factor and cardiotrophin 1. This cytokine family performs a variety of significant developmental and maintenance functions in the nervous system. Dr. Symes has mapped the cytokine response element of the neuropeptide VIP gene and is characterizing the signaling pathways and transcription factors which interact with this element, and mediate these cytokine signals. Research in this laboratory involves basic molecular biology procedures, northern and western blotting, immunoprecipitation, enzyme assays, mammalian tissue culture, transfections and a variety of other assays to examine DNA-protein interactio••s. RECENT PUBLICATIONS Baummann, H., Symes, A.J ., Comeau, M., Morella , K.K., Wang , Y., Friend, D., Fink , J .S. and Gearing , D.P.: Specific regions within the cytoplasmic domains of the leukemia inhibitory factor receptor and gp 130 cooperate in signal transduction in hepatic and neuronal cells . Mol. Cell. Bioi. 14:138-146, 1994. Symes, A.J ., Lewis, S.E. , Corpus, L. , Rajan , P., Hyman, S.E. and Fink, J.S.: STAT proteins participate in the regulation of the VIP gene by the CNTF family of cytokines . Mol. Endocrinol. 8: 1750-1763, 1994. Symes , A.J ., Rajan , P., Corpus, L. and Fink, J .S.: CIEBP-related sites in addition to a Stat site are necessary for CNTF? LIFdependent transcriptional activation by the VIP cytokine response element. J. Bioi .Chem. 270:8068-8075 , 1995. Symes, A.J ., Corpus, L. and Fink, J.S.: Differences in nuclear signaling by LIF and INF-y. the role of STAT proteins in regulating VIP gene expression. J. Neurochem . 65 :1926-1933, 1995. 1---------------THOMAS A. TATHAM Assistant Professor, Department of Psyc hiatry Ph.D., Temple Unive rsity , 1987 BEHAVIORAL PHARMACOLOGY OF DRUG AIWSE A\:D A\:XIETY Dr. Tatham's laboratory studies the effects of behavioral and pharmacological history on the behavioral effects of centrally-acting drugs. These studies are designed to improve understanding of the determinants of drug abuse . In addition , the laboratory investigates anxiety-related issues. The behavioral effects of abused drugs are determined by a variety of causes, including environmental and historical factors . For example, cocaine can function as either a stimulant or as a depressant, depending upon the environmental circumstances under which it is administered. Furthermore, the behavioral effects of abused drugs can also depend upon behavioral history. The importance of behavioral history is exemplified by the effects of cocaine on punished responding . Punished responding is established by first training subjects to press a lever for food pellets . However, lever presses also occasionally produce momentary, mild electric shocks . The delivery of these response-dependent shocks decrease the rate of lever pressing. The rate of responding is normally further decreased by administration of anxiety-inducing drugs and dopamine agonists, such as cocaine and amphetamine. In contrast , anxiolytic drugs, including benzodiazepines and barb iturates, increase punished responding . Interestingly, a history of responding under a shock postponement schedule , in which lever pressing prevents the occurrence of shock, profoundly alters the effects of cocaine on punished responding . Monkeys with a shock-postponement history display increases in punished responding following cocaine administration . This effect occurs even months after the shock postponement schedule has been discontinued. This effect is fascinating, because the direction of cocaine's effects depend upon behavioral history. The laboratory is concluding a series of studies designed to determine the necessary and sufficient conditions under which behavioral history alters the effects of abused drugs , using the punishment paradigm described above . One of the most fundamental questions in drug abuse research is the relation between the subjective (perceptual) effects of drugs and their abuse potential. For example, do people abuse cocaine because of the sensations it produces? This is being examined by training mon keys to report whether they have received an i.v. infusion of cocaine or saline, using drug discrimination techniques . By varying the discrimination training dose of cocaine, the threshold for identifying coca ine can be controlled . The laboratory is currently assessing whether monkeys trained to discriminate very low doses of cocaine will also voluntarily press a lever to receive cocaine infusions at lower doses than monkeys trained to identify only higher doses. If the subjective and reinforcing effects of abused drugs overlap, then drug discrimination manipulations should alter self-administration dose-response functions. Pharmacological history as a determinant of drug abuse is also being investigated . Clinical drug abuse reports refer to gateway effects in which the use of one drug is associated with subsequent use of other drugs. For example, intravenous drug abuse is associated with an increased incidence of prior inhalant abuse. This raises the possibility that certain pharmacological histories increase or decrease the likelihood of abusing some drugs. The laboratory is planning to undertake a research program to use non-human primate models of drug self-administration to understand the circumstances and mechanisms responsible for pharmacological history effects. The second major research theme of the laboratory is the behavioral pharmacology and molecular biology of anxiety . An ongoing series of studies has been relating the effects of anxiety-inducing behavioral experiences to regional changes in brain mRNA levels associated with anxiety-relevant receptors and receptor subunits. This project could lead to new strategies for the treatment of anxiety. REcENT PuBLICATI ONS Tatham. T.A. and Barrett , J.E.: Punishment alters the discrim inative stimulus effects of midazotam . Exper. Clin. Psychopharmacol., in press. Sasaki , J .E. , Tatham , T .A. and Barrett , J .E. : Discriminative stimulus effects of methamphetam ine in pigeons . Psychopharmacology 120,303-310, 1995. Tatham , T.A., Gyorda , A.M . and Barrett , J.E.: Treadle-press avoidance history reverses the effects of cocaine on the punished pecking of pigeons . Pharmacal .. Biochem. Behav. 48:491 -495, 1994. Tatham . T.A. , Gyo rda , A.M. and Barrett. J.E.: Gene ralization of behaviora l history across responses in the reversal of the effects of coc aine and d-amphetamine on the pun ished behavior of squ irr el monkeys. Behav. Ph armacal. 4: 6 1-68, 1993. LYDIA R. TEMOSHOK Research Associate Professor, De partment o f Psychiatry Ph .D., Unive rsity o f Michi ga n , Ann Arho r, 1976 BEIIAVIORAL PREVENTION oF HIV; PsYCIIOIMMUNOLOGY oF CANCER AND HIV As the past Director of Behavioral Prevention Research within the Military HIV Research Program (1989-1994), Dr. Temeshok was Principal Investigator of the largest probability survey of H IV risk-relevant factors in the US, conducted with over 18,000 soldiers. Results of the survey were used to inform the development of behavioral strategies and formats for preventing HIV and other sexually transmitted diseases, which are currently being evaluated in clinical trials at Ft. Bragg , NC . Dr. Temeshok has strongly advocated including in the US HIV prevention agenda the forgotten focus of HIV transmission among those who are already HIV-infected (HIV+). Toward this objective, she directed a survey of HIV transmission risk-relevant behaviors in over 1000 HIV+ military personnel, which documented a significant level of such behaviors. Findings from this study suggest the target ing of comprehensive biopsychosocial prevention programs to HIV+ persons , and have been used to develop innovative behavioral interventions , including a computerized individual risk appraisal and feedback system, an interactive videodisc, and an audiotape intervention. Currently, Dr. Temeshok is located in Geneva , Switzerland, where she has been the Department of Defense liaison for behavioral and social aspects of international HIV vaccine trials to the Vaccine Development Unit, Global Programme on AIDS , World Health Organization . She is particularly concerned with developing, implementing, and evaluating new methodologies, such as audio computer-assisted self interviewing systems, to address the multiple challenges involved in ensuring truly informed consent and obtaining valid data about HIV exposure risk among participants in international HIV vaccine trails. It will also be important to develop behavioral prevention approaches that are complementary to present and projected vaccine and other biomedical prevention strategies. Dr. Temoshok continues to be actively involved in writing and international consultation related to the psychoneuroimmunology of cancer and other immune-related diseases, such as HIV/AIDS. REcENT P uBLICATIONs Temoshol< , L.: Behav1ora l res earch contributions lo planning and conduc ting HIV vaccine effic acy sludies. AIDS Res . Human Retroviruses. 10(Suppi2):S227-S2 80, 1994. Temos hol< , L . Jenk1ns. RA. and Virochsiri, K. : Incentives and disincentives to participate in prophylactic HtV vaccine res ea rch . J. AIDS, 9:36-42 , 1995 . Horberman , A.B .. Temoshol< , LR.. and Besedovsky, H.O.: Psychoneuroim munology and cancer : 15th Sapporo Cancer Sem inar. Cancer Res. 56, 1995 (in press). Tem oshol<, LR. : On biobehavioral models of cancer stress and disease cou rse . Amer. Psycho/. 50( 12) :1 104-1105 , 1995 . ROBERT J. URSANO Professor and Chairma n , De p artme nt o f Psychiatry M.D., Yale Unive rsity, 1973 PosT-TKAt 'MATIC STKESS DtsoKDEK: PsYCI IIATKIC REsJ>o:\sEs TO TKAL:MA A:\D DtsASTEK The research activities of our clinical neurosciences research group focuses on the psychiatric resportses of individuals and groups to traumatic events. Psychiatric responses include neuroendocrine, physiologic, and psychosocial alte rations. Research from th is laboratory has documented both the development of disease and the extreme res iliency of individuals exposed to traumatic events. The critical role of social supports in disease onset and recovery is a major focus of the laboratory. In addition, studies on cognitive responses to trauma and intervention studies of debriefing following traumatic events are underway. The laboratory maintains a psychosocial approach to the study of responses with major collaborators in biological areas for the development of collabo rative studies to better elucidate biological mechanisms. Studies are usually field-based and longitudinal in nature. Several laboratory studies have also been undertaken. The development of clinical skills in consultation to disaster communities is a critical part of the research scientist's ability to work in this area. The interdisciplinary team includes psychiatrists, psychologists , sociologists, and social workers skilled in working with difficult populations during times of extreme stress . Dr. Ursano's group is presently study ing psychiatric and stress responses to motor vehicle accidents, Hurricane Andrew and the U.S . Air crash in Pittsburgh. Studies of Hurricane Andrew population include adults and adolescents . A recent grant has funded specific studies of gender as a predictor of risk or resiliency in response to military deployment, combat and contingency missions. Survey methodology, interview methodology, endocrine correlates , and other neurobiological correlates are examined . Skills in data management and data analysis using sophisticated statistical procedures is central to the development of models for understanding this complex area of behavior and stress adaptation. REcENT PuBLICATIONs Ursano. R. J., McCaughey, 8 ., and Ful lerton , C. S. (Eds.): Individual and Com mun ity Responses to Trau ma and Disaster: Th e Struct ure of H uman Ch aos . Cam bridge University Press, London (199 4). Ursano, R. J., Fullerton, c. s .. and Norwood , A. E.: Psychiatr ic dimen sions of disaster: pat ient care, commun ity consultat ion , and preventive med icine. Harvard Re v. Psychiat. (in press). Ursano, R. J . and Norwood, A. (Eds.): Em otional Altermath o f the Pers ian Gulf War: Veteran s, Families , C ommunities, and Nations. American Psych iatric Press , Washington, DC (i n press). Fullerton , C. S . and Urs ano, R. J . (Eds.): Post-tra umatic Stress Disord er: Acute and Long-Term Responses to T rauma and Disaster. American Psychiatry Press, Wash ington, DC (in press). McC arroll, J. E., Ursano, R. J., Fullerton, C . S., and Lundy, A.: Antici patory stress of handling human rema ins from the Persian Gulf War: predictors of intrusion and avoidance. J. Nerv. Ment. Dis. 183(11 ):698-703, 1995 . llllliiT~IIliim~r~iliillllll r 3 9072 02246274 5