ANNUAL REPORT
July 1, 2002 – June 30, 2003
SACKLER INSTITUTE FOR DEVELOPMENTAL PSYCHOBIOLOGY
AT COLUMBIA UNIVERSITY
Table of Contents
Pages
Part IIntroduction 1
Narrative of Events1 - 4
Part IIResearch Programs
1. Basic Science Division4 - 7
2. Behavioral Neuroscience Division7 - 12
3. Clinical Research Division12 - 17
4. Developmental Neuroimaging Laboratories17 - 20
5. Sackler Awardee20 - 25
Part IIIFinancial ReportEnclosure
This report covers the second year of operation of the Sackler Institute, established at Columbia April 27th 2001 with a gift from the Sackler Foundation made in December 2000. The Institute is an organization within the College of Physicians and Surgeons and the Department of Psychiatry that brings together federally funded scientists active in research on the developmental origins of vulnerability to psychiatric illness. The income from the endowment supports a professorship for the Director of the Institute, and has made a major contribution to the construction of the new Sackler Laboratories at the New York State Psychiatric Institute. In addition, it provides support for new directions in faculty research and funds the annual Sackler Award, a stipend for a postdoctoral fellow/junior faculty worker to facilitate their transition to becoming an independent researcher. Together with an annual contribution to the Director’s Fund by Columbia University, the Institute sponsors conferences and symposia at National and International meetings, makes ‘mini-grants’ to selected Sackler Fellows for their research costs, gives small seed money grants for novel research pilot studies that enable subsequent grant applications for federal support, and provides administrative support for the Institute.
The administrative structure and faculty of the institute over the past year were as follows:
Director, Dr. Myron A. Hofer
Assistant Director, Dr. William P. Fifer
Administrative Assistant, Jennifer Knowles
Chief, Basic Science Division - Dr. Thomas Jessell
Chiefs, Behavioral Neuroscience Division - Drs. Michael Myers and William Fifer
Chief, Clinical Division - Dr. Myrna Weissman
Head, Developmental Neuroimaging Laboratory - Dr. Bradley Peterson
Liason, Cornell - Sackler Institute - Dr. Jonathan Polan
Sackler Awardee: 2003-2004 Dr.Cheryl Corcoran
The research programs of the faculty and the Sackler Awardee are described in the second section of this report along with their publications for the year and their current Federal and other grant support.
Part INarrative of Events
A ribbon-cutting ceremony for the Sackler Institute Laboratories and dedication of the plaque commemorating the founding of the Sackler Institute took place in late January of 2003. A description of the event is given below at the end of Part I.
[In the past year] several of the Sackler Faculty received honorsand awards. Myrna Weissman was elected fellow of the New York Academy of Medicine and was invited to be on the editorial board of the American Journal of Psychiatry. Dr. Jessell received the Mayor’s Award and Dr. Peterson, an Independent Investigator Award from the National Association for Research in Schizophrenia and Depression. Dr. Fifer gave the Presidential address to the International Society for Developmental Psychobiology. Drs. Myron Hofer and Michael Myers were awarded a 5 year renewal of the NIMH Research Fellowship Training Program that provides support for Sackler Fellows (see below). Dr. Daniel Schecter, one of these Sackler Fellows, was awarded a 5 year Research Scientist Development Award from NIMH beginning in July 2003. In addition, he was appointed to the National Child Traumatic Stress Network and the New York City Department of Health Early Childhood Strategic Work Group.
“September 11th : Trauma and Human Bonds” was published by the Analytic Press in early 2003, edited by Susan Coates, director of the Columbia Parent Infant Program (founded with Sackler Award support), Daniel Schecter and Jane Rosenthal of the Columbia Psychoanalytic Institute. This book is the product of the Sackler- funded conference last year and contains chapters by Myron Hofer in addition to Coates and Schecter. The book has been very well reviewed and was described by Dr. Alicia Lieberman of San Francisco General Hospital as making “… a compelling case for the importance of human bonds in the recovery from trauma. “
The Sackler Award Dr. Cheryl Corcoran submitted a progress report for the first year of her research to the Award Committee and after review, a second year of support was awarded. Dr. Corcoran has submitted an application for a 5 year Research Scientist Development Award (K05) from the National Institute for Mental Health to begin funding in April 2004. Her research is aimed at identifying the earliest expressions of prodromal symptoms of schizophrenia.
A webpage for the Columbia Sackler Institute has been established at the internet address < In addition to a brief description and history of the Institute and a listing of the faculty, the web page provides links to the personal home pages of individual faculty members. A list of Affiliated Programs at the medical center provides links to the home pages for the Center for Neurobiology and Behavior, The Department of Pediatrics, The Parent Infant Program and others. There is a link to the most recent Annual Report for more details about the kinds of programs and activities supported. We are in the process of completing a Directory of all developmental research being carried out in departments and laboratories at the medical school with e-mail addresses and links to the researchers’ home pages. We intend this Directory to provide a central source of information on current developmental research going on at Columbia and foster cross disciplinary collaborative projects.
An International Scientific Advisory Committee has been formed with the plan that all members will receive the Annual Report each year for their comments and from time to time members of the committee will be invited to Columbia to give a Sackler Institute Lecture and to meet with individuals and groups of faculty members and fellows to give their perspective and advice on the progress of the Institute. Committee members that have accepted are:
Ronald Dahl - University of Pittsburgh
Alison Doupe – University of California at San Francisco
Barry Keverne - Cambridge University, UK
Michael Meaney – McGill University, Montreal
Charles Nelson - University of Minnesota
Herbert Pardes – Columbia University
Michael Rutter - University of London, UK
A joint meeting of the two New York City Sackler Institutes with members of the new Glasgow/Edinburgh Sackler Institute is being planned for the year 2004. Dr. BJ Casey of the Cornell Institute will host this meeting which will serve to introduce us to our Scottish sister institute and help promote international collaborative projects in the future.
Sackler Fellow small grants were awarded to Inge-Marie Eigsti, who is a cross - campus post doctoral research fellow with Bill Fifer and BJ Casey, to support her work on shared attention and autism. A second was awarded to Jeff Muller, a post doctoral fellow with Michael Myers, for his novel animal model research mapping localized changes in brain gene expression in infant rats as a result of certain interactions with their dams. Two other grants were awarded: one to Sanjay Mathews to support his imaging study of adults first identified as depressed in adolescence and another to Adrianna Feder to support her analytic study of sleep and cortisol levels in previously studied prepubertal depressed children.
Sponsored Symposia An invited Sackler Symposium was given at the annual meeting of the International Society for Developmental Psychobiology on October 31, 2002 in new Orleans on the Development of Memory. At the Winter Developmental Conference in Cancun, Mexico, a Sackler Workshop took place on the emerging technology of magnetoencephalography – the first method for studying fetal brain function in utero.
Visiting Scientist Program Three workshops were funded here at Columbia:
Magnus Magnuson – October 23, 2002 – talk on “Discovering Hidden Time Patterns in Behavior.” Jeffrey Cohen – December 2002 – talk on “Automated Recognition of Facial Expressions.” and Mathias Koelliker – January 16, 2003 – talk on “Role of Family Conflicts in the Evolution of the Parent-Infant Relationship.”
The ribbon cutting ceremony for the dedication of the new Sackler Laboratories was held in the atrium of New York State Psychiatric Institute on January 31, 2003. The Dean of the medical school, Dr. Gerald Fischbach, the C.E.O of the New York Presbyterian Hospital, Dr. Herbert Pardes, and the acting chairman of the Department of Psychiatry, Dr. Timothy Walsh spoke briefly, describing the critically important role that the Institute plays in fostering research and teaching at the medical school campus on of developmental processes at all levels, from molecular genetics to epidemiology. Many thanks were given to the Sackler family for their generosity and vision that together have made the Institute possible.
Members of the Sackler family present were Ilene Sackler Lefcourt, Dr. Kathe Sackler and, Dr. Mortimer D.A. Sackler .A letter of greeting and appreciation from Dr. Mortimer Sackler was read by Ilene Lefcourt, and Dr. Hofer recognized the special contributions to the construction of the laboratories made by Steven Papp and Frank Mucha, administrators of the Psychiatric Institute; Donald Tapert, architect for the planning of the laboratories; Ronald Hellman, the builder; Peter Reynolds, the Psychiatric Institute engineer; and Jennifer Knowles, Susan Rotgard and Christine Fontaneda who planned the reception for the ceremony.
A blue ribbon across the entrance to the laboratory corridor was cut by Ilene Lefcourt with some assistance from the dean in wielding an enormous pair of ceremonial scissors. Upon cutting the ribbon, a plaque was unveiled, commemorating the establishment of the laboratories and listing the members of the Sackler Foundation who made this possible. Finally a tour of the laboratories was conducted by Dr. Michael Myers, Director of the Department of Developmental Psychobiology at New York State Psychiatric Institute as well as Faculty Member in the Sackler Institute.
Part II - RESEARCH PROGRAMS
1. Basic Science Division
Dr. Thomas Jessell – Early Development of the Vertebrate Nervous System
Our work has addressed the mechanisms that control the assembly of neural circuits in the vertebrate central nervous system. These studies have explored the link between neuronal identity and circuitry: how does the early specification of neuronal identity define the position of neurons, the projection pattern of their axons, and the selectivity of their synaptic contacts? We have focused on neurons that form the monosynaptic stretch reflex circuit in the spinal cord, for two reasons. First, this circuit forms early in development, in an activity-independent manner, suggesting that its assembly is genetically encoded. Second, a century of anatomy and physiology, from the pioneering studies of Sherrington and Ramón y Cajal onward, has provided a rigorous cellular and functional framework for interpreting molecular steps in the assembly of sensory-motor connections.
Over the past year we have continued our studies of the roles of signaling factors and transcriptional regulators in the specification of motor neuron identity in the developing spinal cord. We have found that retinoid signaling, mediated by the transcriptional activator function of retinoid receptors, acts in concert with the gene Shh, to pattern the expression of homeodomain and bHLH proteins in ventral progenitor cells, and to specify motor neuron identity. We also revealed that Fibroblast Growth Factors (FGFs) are potent repressors of progenitor homeodomain protein expression, implying that the evasion of FGF signaling and subsequent exposure to retinoid and Shh signals are obligate steps in the emergence of ventral neural pattern. Indeed, joint exposure of neural progenitor cells to retinoids and FGFs is sufficient to induce motor neuron differentiation in an entirely Shh-independent manner.After their initial generation, motor neurons acquire distinct subtype identities that determine their projection patterns and connectivity. In the spinal cord, as in many regions of the CNS, the grouping of neurons into columns links cell body position to axonal trajectory, thus contributing to the establishment of topographic neural maps. In the developing spinal cord columnar sets of motor neurons innervate distinct targets in the periphery. We have found that sequential phases of Hox-c protein expression and activity control the columnar differentiation of spinal motor neurons. Hox expression in neural progenitors is established by graded FGF signaling and translated into a distinct motor neuron Hox pattern. Motor neuron columnar fate then emerges through cell autonomous repressor and activator functions of Hox proteins. Hox proteins also direct the expression of genes that establish motor topographic projections, thus implicating Hox proteins as critical determinants of spinal motor neuron identity and organization.
We have also found that retinoid receptor activation in newly-generated spinal motor neurons has a crucial role in specifying motor neuron columnar subtypes. Blockade of retinoid receptor signaling in brachial motor neurons inhibits lateral motor column differentiation, and converts many of these neurons to thoracic columnar subtypes. Conversely, expression of a constitutively active retinoid receptor derivative impairs the differentiation of thoracic motor neuron columnar subtypes. Thus retinoids also have a regionally restricted role in the post-mitotic specification of motor neuron columnar identity.
Publications
Hippenmeyer, S., Shneider, N.A., Birchmeier, C., Burden, S.J., Jessell, T.M., and Arber, S. (2002). A role for Neuregulin 1 signaling in muscle spindle differentiation. Neuron 36, 1035-1049.
William, C.M., Tanabe, Y. and Jessell, T.M. (2003). Regulation of motor neuron subtype identity by repressor activity of Mnx homeodomain proteins. Development, 130, 1523-1536.
Gunhaga, L., Marklund, M., Campbell, K., Jessell, T.M., and Edlund, T. (2003). Dorsoventral patterning of the prospective telencephalon by hierarchical Wnt and BMP signaling. Nat. Neurosci. 6, 701-707.
Kania, A. and Jessell, T.M. (2003). Topographic motor projections in the limb imposed by LIM homeodomain protein regulation of Ephrin-A: EphA interactions. Neuron, 38, 581-596.
Patel, T.D., Kramer, I., Kucera, J., Niederkofler, V., Jessell, T.M., Arber, S., and Snider, W.D. (2003).Peripheral NT3 signaling is required for ETS protein expression and central patterning of proprioceptive sensory afferents. Neuron, 38 403-416.
Brivanlou, A.H., Gage, F.H., Jaenisch, R., Jessell, T., Melton, D., and Rossant, J. (2003). Setting standards for human embryonic stem cells. Science 300, 913-916.
Novitch, B.G., Wichterle, H., Jessell, T.M., and Sockanathan, S. (2003). A requirement for retinoic acid mediated transcriptional activation in ventral neural patterning and motor neuron specification. Neuron, In Press.
Grant Support
Howard Hughes Medical Institute9/01/2002 - 8/31/200335%
(Jessell))$496,751 (operating expenses)
Molecular Analysis of Vertebrate Neural Development
Research support from HHMI is focused on the inductive interactions that control neural identity in the spinal cord.
RO1 NS33245 (Jessell)9/24/2001-8/31/200510%
NIH$211,398
Control of Motor Neuron Differentiation
To study the mechanisms by which the diversity of different motor neuron subpopulation are generated.
1P50 MH50733
NIH/NIMH (Kandel,)9/20/1994 - 8/31/200410% $130,727 (Proj 1 Jessell)
Center for Neuroscience Research (Kandel): Genetic Approaches to Neural Plasticity and Learning
Project 1(Jessell): The Development of Neural Circuits for a Simple Reflex Behavior: Genetic Analysis of Motor Neuron Identity. This project aims to define the mechanisms whereby distinct classes of motor neurons and interneurons are generated and assembled into functional motor circuits in the spinal cord.
The G. Harold and Leila Y.
Mathers Charitable Foundation (Kandel) 9/1/2001-8/31/20045%
$175,000 (Proj Jessell)
Molecular Approaches to cognition: The Development and Modification of Internal Representations within the Brain.
The aim of this project is to determine how individual genes contribute to the cellular properties essential for the development and maintenance of cognitive maps.
WELLT066790-C-02-Z
The Wellcome Trust5/01/2002-4/30/200710%
$123.115
Functional Genomics of Neuronal Identity
The aim of this project is to define the molecular cascades and gene networks involved in the determination of two defined neuronal cell types – the motor neuron and the olfactory neuron.
RGP0161/2001
Human Frontier Science Program 4/01/2002-3/1/200510%
$45,455
Functional Analysis of Genetically Defined Interneurons in the Ventral Spinal Cord
The aim of this project is to develop a genetic basis for neuronal classification in the spinal cord.
Project ALS 1/22/2003 (each year)5%
$270,025
Regulated Gene Expression in Motor Neurons and Neuron Progenitor Cells.
The aim of this proposal is to apply contemporary methods of gene manipulation in the mouse to the study of the origins of ALS and to the design of novel strategies to prevent the death of motor neurons that occurs in ALS and other neurodegenerative disorders.
2.Behavioral Neuroscience Division
Dr. William Fifer - Human Fetal Behavior and Intrauterine Influences on Vulnerability to Psychiatric Illness
Our general research program focuses on the effects of the early environment on fetal and infant brain/behavior development. We continue to investigate the effects of prenatal risk factors including maternal nicotine and alcohol use during pregnancy, as well as maternal stress and anxiety, on autonomic nervous system development. With Dr. Monk, from the Department of Behavioral Medicine, we continue our studies on the influence of maternal depression and anxiety on fetal and infant development. With Dr. Myers we continue to study early markers of risk for Developmental Disorders and Sudden Infant Death (SIDS) in high-risk populations in Washington Heights and on the Pine Ridge Reservation in South Dakota. We are anticipating funding for an expansion of these studies to other Aberdeen area reservations to study the influences of alcohol and other factors on unexplained fetal demise and early neurobehavioral disorders. A further extension of this work, with the Department of Pediatrics, focuses on the developing nervous system in prematurely born infants and, together with colleagues from the Division of Environmental Health Science at Columbia, assessments of sleep dependent physiology in infants exposed to environmental toxins during pregnancy.
During this past year we have applied for funding to continue our collaborative studies with colleagues from the Sackler Institute at Cornell, B.J.Casey, Inge-Marie, and Bruce McCandliss. These studies involve the use of high density EEG technology to investigate the ontogeny of sensory evoked potentials as well as the emergence of early conditioning capacities in very young infants. We are also evaluating the new magnetoencephalography technology for the study of fetal brain development and exploring funding possibilities for this expensive, but potentially revolutionary approach to the study of early brain development.