January 1, 1999

Name: Barry E. Kosofsky

Office Address:Laboratory of Molecular and Developmental Neuroscience

Place of Birth: Queens, New York (US Citizen)

Education:

1978 B.A. Biophysics Johns Hopkins University, Baltimore, MD

1978 M.A. Biophysics Johns Hopkins University, Baltimore, MD

1985 M.D. Medicine Johns Hopkins U. School of Medicine, MD

1985 Ph.D. Neurosci. Johns Hopkins U. School of Medicine, MD

Postdoctoral Training:

1985-87 Intern/Assistant Resident, Department of Pediatrics,

The Children's Hospital, Boston, MA

1987-90 Assistant Resident/ Chief Resident (Child), Department of Neurology,

The Massachusetts General Hospital, Boston, MA

1990-92 Post-Doctoral Fellow, Molecular Neurobiology Laboratory,

Steven E. Hyman M.D., Laboratory Director, MGH-East, Boston, MA

Licensure and Certification:

1985- Medical License- New York (#164142)

1987- Medical License- Massachusetts (#73489)

1993- Board Certification: Neurology with Special Competence in Child Neurology (#877)

Academic Appointments:

1992-94 Instructor of Neurology, Harvard Medical School, Boston, MA

1994- Assistant Professor of Neurology, Harvard Medical School, Boston, MA

Hospital Appointments:

1990-92 Research Fellow, Department of Neurology, MGH

1992-96 Assistant in Neurology, Department of Neurology, MGH

1997- Assistant Neurologist, Department of Neurology, MGH

Hospital Clinical Responsibilities (MGH):

1993- Attending Neurologist- Child Neurology Service

1993- Director- Prenatal Substances of Abuse Exposure Follow-Up Clinic

1994- Coordinator- Congenital Toxoplasmosis Neurology Follow-Up Clinic

1996- Attending Pediatrician- Pediatric Service

Major Administrative Responsibilities/ Committee Assignments:

1992- Residency Training and Education, MGH Neurology

1993- Computer Resources and Applications, MGH Neurology

1993- Faculty Advisor: Division on Addictions, HMS

1995- Faculty Affiliate: Program in Neuroscience, HMS

1996- Training/ Education, Partners Neurology

1996- Steering Committee: HNSB Course, HMS

1997- Faculty Affiliate: Mind, Brain, and Behavior Initiative, HMS

1998- Information Technology Initiative, HMS

1998- Steering Committee: Division on Addictions, HMS

1998- Member- Substance Abuse Working Group, MBB Initiative, HMS

1998- Chair- Development Working Group, MBB Initiative, HMS

Professional Societies:

1980- Society for Neuroscience

1984- American Academy of Pediatrics

1988- Child Neurology Society/ American Neurological Association

1989- American Academy of Neurology

1991- Second Decade Society (Johns Hopkins University)

1995- Neurobehavioral Teratology Society

1997- Organization for Human Brain Mapping

Awards and Honors:

1978 Medical Scientist Training Program Award

1985 Paul Erlich Award in Clinical Investigation

1990 William Randolph Hearst Award

1990 Nancy Lurie Marks Foundation Fellowship

1992 NIDA Scientist Development Award for Clinicians

1996 NIDA: The Next Generation Award

1998 NIDA Independent Scientist Development Award

Major Research Interests:

Brain Development (neuroanatomy, molecular biology)

Drugs of Abuse (transplacental cocaine exposure)

Monoaminergic Systems (anatomic and functional organization)

Image Analysis/ Three Dimensional Neuroanatomic Reconstruction

Functional Brain Imaging

Narrative Description of Research:

The focus of the Kosofsky laboratory is to apply molecular, anatomic, behavioral, and electrophysiologic methods to characterize the effects of cocaine on developing brain. Clinical data suggests that infants exposed to cocaine in utero demonstrate a spectrum of structural and behavioral deficits, implying altered CNS maturation consequent to gestational drug exposure. We have created an animal model, in mice and rats, to identify growth, behavioral and neuroanatomic consequences of transplacental cocaine exposure, and to characterize molecular mechanisms whereby brain development is modified. Observations to date include:

By administering cocaine during critical developmental periods we have reproduced both the growth retardation (including brain and body), and an inattention syndrome. By performing restricted gestational administration and dose fractionation experiments we have been able to dissociate the growth effects from the behavioral effects; lower doses of cocaine and less severe malnutrition impair brain and body growth, but do not have effects on the ontogeny of learning a conditioned aversion, or on the ability of adult animals to demonstrate blocking (i.e., selective attention).

We have found that the brains of mice exposed to cocaine in utero are thinner, with an imprecision in the horizontal organization of cortical lamination, with an admixture of cell types across individual layers. In addition there is a thinning of the axo-dendritic bundles. In thymidine "birth dating" studies we have shown that cells born synchronously are widely dispersed through multiple neocortical layers.

We have made progress understanding some of the molecular correlates of the inattention syndrome induced in mice exposed to cocaine in utero. We have demonstrated that the G-coupled protein that positively couples aminergic receptors (norepinephrine-B; serotonin-4,6,7; dopamine-1,5) to cAMP (Gs) is 40-60% blunted in response.

In other experiments, we have demonstrated altered expression of a class of transcription factors termed immediate early genes, which occurs at short time points after acute postnatal cocaine exposure. Moreover, the specific immediate early genes altered, and the particular cells in specific brain regions affected varies with the developmental age of the animal studies. Recent experiments are directed at establishing the relationship of these early molecular changes in IEG expression with the lasting structural and behavioral alterations we have defined, and to identify determinants underlying and consequences resulting from the spatial and temporal specificity of drug-induced gene dysregulation.

Molecular methods employed include northern gel analysis and gel shift experiments; anatomic studies include immunohistochemistry and histochemical methods (for evaluation of transgenic mice); behavioral experiments are conducted in juvenile and adult animals (including "knockouts"). We have combined molecular approaches with anatomic studies by developing in situ hybridization histochemistry (ISHH) methods, including non-radioactive ISHH. Current efforts are directed at correlating behavioral findings with drug-induced molecular and neuroanatomic perturbations, to better understand how cocaine-induced changes in gene expression result in permanent alterations in brain structure and function.

Research Funding Information:

1990-92 Hearst Fund P.I. "The Effect of Cocaine on Developing Brain"

1992-97 NIH (NIDA) P.I. "Ontogeny of IEG Response to Drugs of Abuse"

K20DA00175

1994-99 NIH (NIDA) Co-P.I."Functional Brain Mapping of Cocaine Action"

P01DA09467

1995-00 NIH (NIDA) P.I."Cocaine-Induced Disturbances of Mouse

R29DA08648 Brain Development"

1998-03 NIH (NIDA) P.I. "Cocaine-Altered Brain Growth: Dopamine

KO2DA00354 Knockout Analysis"

Self Report of Teaching:

1. Local Contributions

a) Medical School Courses

1990-91 Laboratory Instructor- Human Nervous System and Behavior

1992- Lab Section Leader- Introduction to Neurobiology

1992- Lecturer- Neurobiological Aspects of Mental Retardation

1992- Lecturer- Introduction to Neurobiology (HST 130/ NB 200)

1993- Lecturer- Neurobiology of Substance Abuse (PS521.M.O.)

1993- Lecturer- Human Nervous System and Behavior (HMS- Year 2)

1993- Child Psychiatry Basic Science Course (Children's Hospital)

1995- Co-Director of Neuroanatomy Laboratory- HNSB/HMS

1997- Lecturer- Multidisciplinary Approaches to Drug Policy

b) Hospital Courses and Local Invited Teaching Presentations

1990 Ob/ Gyn Grand Rounds (Beth Israel Hospital, Boston)

1990- Neurology Grand Rounds (MGH-1990/94/97; Longwood-1991/94) West Roxbury V.A.- 1992; Bedford V.A.- 1993; BU-1995)

1992- Pediatrics Grand Rounds (MGH- 1992/96; Beverly Hospital-1996)

1993- MGH Core Curriculum Lectures for Pediatric House Officers

1994- MGH Core Curriculum Lectures for Neurology House Officers

1995- Shriver Center "Tutor" for Rotating Neurology House Officers

1997- Harvard Mahoney Neuroscience Institute "Dialogues"

1997- MGH Addiction Services Fellows Conference

1998- HUSC/MBB Conference

1998- MGH Neonatology Service Conference

c) Continuing Medical Education Course Presentations

1990- MGH Child Neurology Division, Continuing Education

1998- MGH Neurology Department, Continuing Education

1992- MGH Neurosurgery Department, Continuing Education

1999- MGH Teratology Division, Continuing Education

2000- MGH Speech Pathology Division, Continuing Education

2001- HMS Psychiatry Department, Continuing Education

1995- MGH Child Psychiatry Service, Continuing Education

Attention Deficit Disorders

2. National Contributions

a) Invited Presentations

1990 NIDA Technical Review: "The Effect of Cocaine on Developing Human Brain"

1992 NIDA Technical Review: "The Ontogeny of IEG Response to Drugs of Abuse"

1991 Child Neurology Society Symposium: "Transplacental Cocaine Exposure: A Mouse Model"

1992 NIDA Technical Review: "Anatomic and Molecular Correlates of the Effect of Cocaine on Developing Brain"

1993 NINDS Clinical Neurogenetics Unit: "Neurobiologic Consequences of Fetal Exposure To Cocaine"

1994 Child Neurology Society Symposium: "Prenatal Cocaine Exposure: Cerebral Dysgenesis and Behavioral Deficits"

1995 NIDA Intramural (ARC): "Clinical, Molecular, Behavioral, and Neuropathologic Correlates of Gestational Cocaine Exposure"

1995 MCP Substance Abuse PPG: "Behavioral and Neuropathologic Correlates of Gestational Cocaine Exposure"

1995 Family Builders Network: "A Clinical Perspective on Gestational Cocaine and Alcohol Exposure"

1996 WCBR: "Anatomic Specificity of Anatomic Organization of Ascending Serotonergic Projections"

1996 Brown University Neurobiology: "Molecular, Neuropathologic and Behavioral Correlates of Gestational Cocaine Exposure"

1996 NEMC Pharmacology Department: "Molecular, Neuropathologic and Behavioral Correlates of Gestational Cocaine Exposure"

1997 Massachusetts Association of Biology Teachers: "The Effects of

Drugs of Abuse on Brain Development"

1998 LICH Lamm Institute: "Transplacental Cocaine Exposure:Behavioral Consequences"

1998 MEC Early Childhood Intervention Strategies: "Neuroscience Perspective on Brain Development and Special Education"

1998 National Association Biology Teachers: "The New Biology of the Brain: Learning About Learning"

b) National Advisory Councils

1997- National Center for Responsible Gaming

c) National Conferences Organized

1997- Cocaine: Effects on the Developing Brain (NYAS)

Self Report of Clinical Activities:

In addition to Attending at MGH in (Child) Neurology one month each year, and in Pediatrics two weeks each year, Dr. Kosofsky established and directs SAEF Clinic (Substances of Abuse Exposure Follow-up) in the Department of Neurology at MGH. This weekly clinic session coordinates the evaluation of infants and children who have sustained prenatal exposure to substances of abuse (alcohol, cocaine, and other drugs). This multidisciplinary clinic coordinates referrals for substance-abusing mothers through MGH Addiction Services, and provides care for substance-exposed children, specializing in diagnosis and management of the unique problems evident in this population.

Bibliography (Original Articles):

1. Ide CF, Kosofsky BE, Hunt RK. Control of pattern duplication in the retinotectal system of xenopus. Dev Bio 1979;69:337-360.

2. Kosofsky BE, Molliver ME, Morrison JH, Foote JL. The serotonin and norepinephrine innervation of primary visual cortex in the Cynomolgus monkey (Macaca fascicularis). J Comp Neurol 1984;230:168-78.

3. Kosofsky BE. The neuroanatomic organization of ascending serotonergic projections to cerebral cortex (dissertation). Baltimore (MD): The Johns Hopkins University School of Medicine (1985).

4. Kosofsky BE, Molliver ME. The serotonergic innervation of cerebral cortex: Different classes of axon terminals arise from dorsal and median raphe nuclei. Synapse 1987;1:153-68.

5. Fritschy JM, Lyons WE, Mullen CA, Kosofsky BE, Molliver ME, Grzanna R. Distribution of locus coeruleus axons in the rat spinal cord: a combined anterograde transport and immunohistochemical study. Br Res 1987;437:176-80.

6. Gressens P, Kosofsky BE, Evrard P. Cocaine-induced disturbances of corticogenesis in the developing murine brain. Neurosci Lett 1992;140:113-6.

7. Nguyen TV, Kosofsky BE, Birnbaum R, Cohen BM, Hyman SE. Differential expression of c-fos and zif/268 in rat striatum after haloperidol, clozapine, and amphetamine. Proc Natl Acad Sci, USA 1992;89:4270-4.

8. Hope B, Kosofsky BE, Hyman SE, Nestler EJ. Regulation of IEG expression and AP-1 binding by chronic cocaine in the rat nucleus accumbens. Proc Natl Acad Sci, USA 1992;89:5764-8.

9. Leifer D, Krainc D, Yu YT, McDermott J, Breitbart RE, Heng J, Neve RL, Kosofsky BE, Nadal-Ginard B, Lipton SA. A novel MADS/MEF2-family transcription factor expressed in a laminar distribution in cerebral cortex. Proc Natl Acad Sci, USA 1993;90:1546-50.

10. Kosofsky BE, Wilkins AS, Gressens P, Evrard P. Transplacental cocaine exposure: A mouse model demonstrating neuroanatomic and behavioral abnormalities. J Child Neurol 1994;9:234-41.

11. Kosofsky BE, Genova LM, Hyman SE. Postnatal age defines specificity of immediate early gene induction by cocaine in developing rat brain. J Comp Neurol 1995;351:27-40.

12. Kosofsky BE, Genova LM, Hyman SE. Substance P phenotype defines specificity of c-fos induction by cocaine in developing rat striatum. J Comp Neurol 1995;351:41-50.

13. Peterfreund RA, Kosofsky BE, Fink JS. Cellular localization of dopamine D2 receptor messenger RNA in the rat trigeminal ganglion. Anesth Analg 1995;81:1181-5.

14. Speliotes EK, Kowall NW, Shanti BF, Kosofsky B, Finklestein SP, Leifer D. Myocyte-specific enhancer binding factor 2C expression in gerbil brain following global cerebral ischemia. Neuroscience 1996;70:67-77.

15. Mandeville JB, Marota JJA, Kosofsky BE, Keltner JR, Weissleder R, Rosen BR, Weisskoff RM. Dynamic functional imaging of relative cerebral blood volume during rat forepaw stimulation. Magn Reson Med 1998;37:615-24.

16. Wilkins AS, Genova LM, Posten W, Kosofsky BE. Transplacental cocaine exposure 1: a rodent model of drug-induced inattention. Neurotox Teratol 1998;20:215-26.

17. Wilkins AS, Jones K, Kosofsky BE. Transplacental cocaine exposure 2: the effects of cocaine dose and gestational timing. Neurotox Teratol 1998;20:227-38.

18. Wilkins AS, Marota JA, Tabit E, Kosofsky BE. Transplacental cocaine exposure 3: mechanisms underlying altered brain development. Neurotox Teratol 1998;20:239-49.

Bibliography (Invited Reviews/Book Chapters):

1. Kosofsky BE, Duitch DD, Dooling EC. Neurological Disorders. In: The Mass. General Hospital Handbook of Psychiatric Aspects of General Hospital Pediatrics, (Jellinek MS, Herzog DB, eds.) Year Book Medical Pub., 1990. 156-166.

2. Kosofsky BE. The effect of cocaine on developing human brain. In: NIDA Research Monograph #114. Methodologic Issues in Controlled Studies on Effects of Prenatal Exposure to Drugs of Abuse (Kilbey MM, Asghar K, eds.). DHHS Pub. No. (ADM)91-1837. Washington D.C.: U.S. Govt. Print. Off., 1991. 128-143.

3. Kosofsky BE, Hyman SE. The ontogeny of immediate early gene response to cocaine: A molecular analysis of the effects of cocaine on developing brain. In: NIDA Research Monograph #125. Activation of Immediate Early Genes by Drugs of Abuse (Grzanna RG, Brown RM, eds.). NIH Pub. No. 93-3504. Washington D.C.: U.S. Govt. Print. Off., 1993. 25-38.

4. Hyman SE, Kosofsky BE, Nguyen TV, Cohen BM, Comb MJ. "Everything activates c-fos; how can it matter?". The complexity and biological significance of immediate early gene expression in substance abuse research. In: NIDA Research Monograph #125. Activation of Immediate Early Genes by Drugs of Abuse (Grzanna RG, Brown RM, eds.). NIH Pub. No. 93-3504. Washington D.C.: U.S. Govt. Print. Off., 1993. 161-171.

5. Hyman SE, Cole RL, Konradi C, Kosofsky BE, Kobierski L, Cole D. Dopamine regulation of transcription factor - target interactions in rat striatum: regulation of proenkephalin, prodynorphin, and c-fos gene expression by transcription factor CREB. In: Molecular and Cellular Mechanisms of Neostriatal Function (Ariano MA, Surmeier DJ, eds.) Austin, TX: RG Landes, 1995. 129-141.

6. Hyman SE, Cole RL, Konradi C, Kosofsky BE. (1995) Dopamine regulation of transcription factor - target interactions in rat striatum. Chem Senses. 20: 257-260.

7. Wilkins AS, Kosofsky BE, Romano AG, Harvey JA.. Transplacental cocaine exposure: behavioral consequences. In: Prenatal Cocaine Exposure (Konkol RJ, Olsen GD, eds.) Boca Raton: CRC Press, 1996. 151-167.

8. Raut CP, Stephen A, with Kosofsky B. Intrauterine effects of substance abuse. In: Source Book of Substance Abuse and Addiction (Friedman LS, Fleming NF, Roberts DH, Hyman SE, eds.) Baltimore: Williams & Wilkins, 1996. 269-287.

9. Kosofsky BE. Cocaine-induced alterations in neuro-development. In: Seminars in Speech and Language (Mentis M, ed.) New York: Thieme Medical Publishers, (1998), 109-121.

10. Kosofsky BE, Wilkins AS. A mouse model of transplacental cocaine exposure. In: Cocaine: Effects on the Developing Brain (Harvey JA, Kosofsky BE, eds.) New York: NYAS Press, (1998), 248-261.

12. Kosofsky, BE. Effects of Alcohol and Cocaine on Brain Development. In: Neurobiologic Foundation of Mental Illness (Charney DS, Nestler EJ, Bunney BS, eds.) New York: Oxford University Press, 1998 (In press).

Bibliography (Clinical Articles and Case Reports):

1. Kuhn MJ, Mikulis DJ, Ayoub DH, Kosofsky BE, Davis KR, Taveras JM. Wallerian degeneration after cerebral infarction. Evaluation with sequential MR imaging. Radiology 172 (1989) 179-182.

2. Marchuk DA, Gallione C, Prenger V, Kosofsky BE, Louis DN, Gusella JF, Davis LE, Morrison LA. A locus for cavernous angiomas maps to proximal 7q in two families. Genomics 28 (1995) 311-314.

3. Johnson EW, Green ED, Rich SS, Orr HT, Gil-Nagel A, Kurth JH, Zabramski JM, Marchuk DA, Weissenbach J, Clericuzio JCL, Davis1 LE, Hart BL, Gusella JF, Kosofsky BE, Louis DS, Morrison LA, Smith LM, Weber JL. Refined Localization of the Cerebral Cavernous Malformation Gene (CCM1) to a 4 cM Interval of Chromosome 7q Contained in a Well Defined YAC Contig. Genome Research 5 (1995) 368-380.

4. So GM, Kosofsky BE, Southern JF. Acute hydrocephalus following carbon monoxide poisoning. Pediatric Neurology 17 (1997) 270-273.

Bibliography (Books Edited):

1. Cocaine: Effects on the Developing Brain (Harvey JA, Kosofsky BE, eds.) New York: NYAS Press, (1998).