ANNUAL REPORT
July 1, 2007 – June 30, 2008
SACKLER INSTITUTE FOR DEVELOPMENTAL PSYCHOBIOLOGY
AT COLUMBIA UNIVERSITY
Table of Contents
Pages
Introduction 2
Part I Highlights 3 - 5
Part II Research Programs 5
1. Basic Science Division 5 - 9
2. Behavioral Neuroscience Division 9 - 13
3. Clinical Research Division 13 - 17
4. Developmental Neuroimaging Laboratories 17 - 23
5. Department of Pediatrics-Neonatology 23 - 24
6. Sackler Awardees 24 - 29
Part III Financial Report enclosure
This report covers the seventh 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. Our faculty has more that 7 million dollars in outside support this year. The income from the endowment supports a professorship for the Director of the Institute, and made a major contribution to the construction of the new Sackler Laboratories at the New York State Psychiatric Institute in 2002-2003. In addition, it provides support for new directions in faculty research and funds the annual Sackler Awards, stipends for postdoctoral fellow/junior faculty workers to facilitate their transition to becoming independent researchers. The Institute sponsors conferences and symposia at national and international meetings, awards ‘mini-grants’ to selected Sackler Fellows for their research costs, gives ‘seed money’ grants to faculty for novel research pilot studies that enable subsequent grant applications for federal support, and provides administrative support for the Institute. An additional gift from the Sackler Foundation in June of 2007 is supporting a special project on the early developmental role of serotonin transporter function.
The administrative structure and faculty on June 30, 2008 were as follows:
Director, Dr. Myron A. Hofer
Assistant Director, Dr. William P. Fifer
Administrator, Jennifer Knowles
Chief, Basic Science Division – Dr. Jay Gingrich
Sackler Scientist – Dr. Mark Ansorge
Chiefs, Behavioral Neuroscience Division - Drs. Michael Myers and William Fifer
Sackler Scientists – Drs. Susan Brunelli and Catherine Monk
Chief, Clinical Division - Dr. Myrna Weissman
Head, Developmental Neuroimaging Laboratory - Dr. Bradley Peterson
Department of Pediatrics (Neonatology) – Drs. Raymond Stark and Marianne Garland
New Sackler Institute Scientists appointed: Dr. Alan Brown - Clinical Division, Dr. Frances Champagne - Department of Psychology at Columbia University Morningside Campus, Dr. Christoph Kellendonk - Basic Science Division
Sackler Awardees: (2nd Year) – Dr. Amir Levine and an award shared by Drs. Rachel Marsh and Dr. Phil Grieve
The research programs of the faculty and the three Sackler Awardees of ’07-‘08 are described in the second section of this report along with their publications for the year and their current Federal and other grant support. A financial report is available separately.
Part I – Highlights
The first Mortimer D. Sackler, M.D. Prize was announced in December of 2007 and presented on April 25th to Avshalom Caspi, PhD for his studies on the interactions of defined early experiences and specific gene variants in determining later vulnerability to a range of psychiatric disorders. The first prize was given in honor of Mortimer D. Sackler’s 90th birthday by his 7 children. The prize of $60,000 is “For distinguished achievement in developmental psychobiology” and plans are in progress for the prize to be endowed in perpetuity. The presentation of the prize will be shared on alternate years with the Cornell Sackler Institute. The recipient will give Grand Rounds at Cornell and Columbia as well as participate in formal workshops at both institutes. The prize committee will include representation from all 5 Sackler Institutes who will be invited to the prize presentation, Grand Rounds and workshops.
On May 28th of 2008 Dr. Thomas Jessell, who was chief of our Basic Science Division from 2001-2008, was named by the President of the Norwegian Academy of Science as co-recipient of the first Kavli Prize in Neuroscience. This is a million dollar prize that will be awarded biannually in Nanoscience and Astophysics as well as in Neuroscience. Dr. Jessell was honored for his research that “has revealed the chemical signals behind the differentiation of early progenitor cells into the complex assembly of different types of neurons that make up neuronal circuits”.
During the spring of 2008 a new chief of the Basic Science Division was appointed and we expanded our faculty to include three additional Sackler Scientists, bringing new expertise, areas of research and interdepartmental collaborations. Dr. Thomas Jessell stepped down from his position as chief of the Basic Science Division in June, after nearly 10 years in that position, to pursue new responsibilities in the Department of Neuroscience. Dr. Jay Gingrich, head of the Sackler Mouse Genetics and Behavior Laboratory, became the new Chief of the Basic Science Division on June 30, 2008.
A new Sackler Scientist, Dr. Christoph Kellendonk will join the Basic Science Division with a joint appointment in Pharmacology and Psychiatry. Dr. Kellendonk has been working in the Eric Kandel lab where he has been studying the genetic/molecular mechanisms that may underlie the development of certain cognitive deficits that are characteristic of schizophrenic patients, using a mouse genetic model. He has found that the deficit in working memory in adult mice caused by (experimentally induced) over-expression of the Dopamine 2 receptor gene is not due to abnormal gene activity in adulthood, as it had been expected, but rather to genetic over-expression during early development, in the pre-or early postnatal periods. This finding opens up a new area in research on the developmental origins of schizophrenia.
Dr. Alan Brown, associate professor of clinical psychiatry and epidemiology, has joined the Clinical Research Division. Dr. Brown works closely with Dr. Weissman and brings special expertise in identifying early developmental contributors to the onset of mental illness. He is currently working with a large Finnish population database providing records of extensive prenatal and postnatal developmental risk factors compiled many years ago. Dr. Brown was the first to demonstrate that serologically documental prenatal exposure to viral illnesses such as influenza and inflammatory markers are risk factors of schizophrenia.
Dr. Frances Champagne, assistant professor of Psychology at Columbia’s downtown campus has joined the Behavioral Neuroscience Division. During her doctoral work in Michael Meaney’s lab at McGill University using mouse models, Dr Champagne discovered a number of early developmental mechanisms involving gestational stress and estrogen-oxytocin receptor interactions regulating the later development of maternal behavior. Last year, at the University of Cambridge, she investigated epigenetic mechanisms for these efforts and for the transmission of maternal behavior patterns across generations.
We had a record number of Sackler Award applications this year (13) and were able to fund 2 stipends for 2 years. Tiziano Colibazzi was funded for a project titled “Longitudinal Imaging in Adolescents Prodromal for Schizophrenia”. His proposed research aims to identify the neuroanatomical changes in MRI scans of cortical surface and mantle during adolescence and into early adult development in subjects, 30 of whom are identified as showing prodromal signs of developing schizophrenia and in 30 controls. His mentors will be Drs. Peterson, Lieberman and Cheryl Corcoran (a former Sackler Awardee – ’02-’04). The second awardee, Dr. Amar Sahay proposes to study the role of a particular genetic transcription factor (Klf-9) regulating activity-dependant processes, such as synapse maturation and dendrictic branching, that are hypothesized to mediate the effects of early life stress on anxiety-like behavior in adult mice. His mentor will be Rene Hen, director of the Division of Integrative Neuroscience.
The Final Reports of the previous 3 Sackler Awardees are presented in Part II No. 6 of this report.
The five divisions of the Sackler Institute are united in a common project – “The Developmental Role of the Serotonin Transporter in Affective Illness and Its Treatment”, that was funded last year by a gift from the Sackler Foundation. Progress reports on this aspect of Sackler faculty activities can be found in each of the Division reports. This project is an interlocking set of human and laboratory animal studies using novel approaches to understanding how and why genetic reduction of serotonin transporter function (acting from conception on) or infant and juvenile pharmacologic inhibition of transporter function in mice with selective serotonin reuptake inhibitors (SSRI) drugs, can increase vulnerability to depression in adulthood, whereas these drugs effectively relieve depression or depression-like behaviors when given to adult humans or mice. The question of the immediate and long term risks to offspring of SSRI’s taken by mothers during pregnancy or taken later by adolescents, and the mechanisms of such effects, are urgent clinical questions and a focus of both animal and human studies in our project. A small grant was awarded to Mark Alter who applied for bridging funds to enable him to complete and prepare for publication, a series of remarkable studies revealing novel epigenetically-mediated developmental processes in genetically identical strains of mice.
At the 2007 annual meeting of the International Society for Developmental Psychobiology, the Sackler Institute funded a symposium entitled "Maternal Effects on Offspring Behavioral and Neuroendocrine Development ". The leaders in the field , Drs. Frances Champagne, Columbia University, Karen Parker, Stanford University; Dario Maestripieri, University ofChicago; Kai McCormack and Mar Sanchez,; Emory University and J. Dee Higley, at National Institute onAlcohol Abuse and Alcoholism, presented their latest research. Society members and their students were uniformly impressed, interested and interactive during the symposium and in the collaborative discussions that followed. Several of these interactions were made possible by Sackler Institute travel grants for students from Europe, Israel, Mexico, and New Zealand who also presented papers at the meeting.
Sponsored Symposia : At the 23rd annual meeting of the Winter Conference in Developmental Psychobiology, we co-sponsored, with the Cornell Sackler, two symposia. This meeting brings together a multi-disciplinary group of outstanding scientists in a warm, friendly and highly interactive forum. The growing reputation of this invited only conference, with the help of a small amount of Sackler Institute funding, enables world experts from disparate fields to share data, ideas and techniques and form long lasting and often unique collaborations. This year's Sackler sponsored symposia were focused on "The Psychobiology of Social Engagement" and on "Understanding the Development of Neural Circuitry".
Part II - RESEARCH PROGRAMS
1. Basic Science Division
Jay Gingrich, Chief – Laboratory of Translational Neurogenetics
Our laboratory is currently pursuing different lines of research related to the genetics of neuropsychiatric disorders. Mice offer an excellent model to understand the developmental contribution of genes to normal brain maturation and thus are employed extensively in our studies. Mice with transiently-reduced transporter function during early life matured into adult mice with numerous abnormalities in depression and anxiety-related behaviors. We are taking a multilevel approach to understand the underlying biology—using techniques of anatomy, electrophysiology, gene expression, and behavioral analyses. We are in the second year of an RO1 grant from NIMH to examine the biological underpinnings of environmental influences on mice with genetically-reduced serotonin transporter (SERT) function. We also received a second RO1 from NIMH on this project, which focuses on investigating the role of developmental serotonin signaling in circuit maturation. Specifically, the second project aims at identifying biological mechanisms that underpin the effects of post-natal SSRI exposure. Lastly, Mark Ansorge, a former Sackler Fellowship Awardee, has received a K99 career development award from NIMH. In 2008, Mark Ansorge has also been promoted to faculty, both at the Sackler Institute as well as at the NYSPI. Prior and ongoing Sackler support through the Serotonin Transporter project has been crucial for achieving these research milestones and obtaining federal funding.
We have two projects directly related to schizophrenia and autism, that have received either NIMH funding or funding from the Simons Foundation. In the first, Neuregulin1 (NRG1) has been identified as a susceptibility gene in schizophrenia. Mice with reduced expression of different NRG1 isoforms exhibit several behavioral abnormalities that are consistent with both positive and negative symptoms of schizophrenia. We have identified that these mice exhibit social deficits, olfactory deficits (as do some schizophrenics). We have found that these mice have underlying deficiencies in the targeting of newly generated neurons to the olfactory bulb. Thus, we are working to discover to what degree NRG1 is involved in brain development and to what degree it serves a maintenance function.
The second project (funded by the Simons Foundation) examines the role of aberrant DNA methylation as a possible epigenetic contribution to autism susceptibility. We have developed an animal model of advanced paternal age effects on complex behaviors in the offspring. We are exploring the hypothesis that methylation accuracy of years of replication of spermatagonia DNA decreases with increased number of divisions (as would occur over time in older fathers).
The fourth project examines the role of a major post synaptic receptor for the neurotransmitter serotonin 5HT2A in behavioral control of anxiety-like behaviors and in psychosis-related endophenotypes. We have recently developed the technology to specifically manipulate receptor signaling in specific brain areas. This will allow us to define the minimal circuits that are sufficient to mediate serotonin effects on anxiety and schizophrenia-related behaviors. This work was recently published in the journal, Science.
In 2008, Dr. Gingrich was promoted to Associate Professor of Psychiatry at Columbia and was elected to the NARSAD Scientific Advisory Board.
Publications
Salomon L, Lanteri C, Godeheu G, Blanc G, Gingrich JA, Tassin JP (2007): Paradoxical constitutive behavioral sensitization to amphetamine in mice lacking 5-HT(2A) receptors. Psychopharmacology (Berl) 194:11-20.
Ansorge, M., Hen, R, Gingrich, JA (2007): Developmental Origins of Depressive and Anxiety Disorders. 7:8-17 Current Opinions in Pharmacology 7 (1): 8-17.
Kayser V, Elfassi IE, Aubel B, Melfort M, Julius D, Gingrich JA, Hamon M, Bourgoin S. (2007): Mechanical, thermal and formalin-induced nociception is differentially altered in 5-HT1A-/-, 5-HT1B-/-, 5-HT2A-/-, 5-HT3A-/- and 5-HTT-/- knock-out male mice. Pain (3):235-48