Sackler Institute for Developmental Psychobiology

A N N U A L R E P O R T July 1, 2004 – June 30, 2005

SACKLER INSTITUTE FOR DEVELOPMENTAL PSYCHOBIOLOGY AT COLUMBIA UNIVERSITY

Table of Contents

Part I Introduction 1

Highlights 1

Part II Research Programs 3

1. Basic Science Division 3

2. Behavioral Neuroscience Division 6

3. Clinical Research Division 14

4. Developmental Neuroimaging Laboratories 21

5. Sackler Awardee 25

Part III Financial Report enclosure This report covers the fourth 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 brought in more than 9 million dollars in outside support last 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 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 a contribution to the Director’s Fund by Columbia University, in the past year the Institute sponsored conferences and symposia at national and international meetings, made ‘mini-grants’ to selected Sackler Fellows for their research costs, gave ' small seed money ' grants for novel research pilot studies that enable subsequent grant applications for federal support, and provided 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 Head, Mouse Genetics and Behavior Laboratory – Dr. Jay Gingrich Liason, Cornell - Sackler Institute - Dr. Jonathan Polan Sackler Awardees: Dr. Mark Ansorge and Dr. Jonathan Polan

The research programs of the faculty and the two current Sackler Awardees are described in the second section of this report along with their publications for the year and their current Federal and other grant support. The proposal describing the Developmental Effects of Serotonin project, funded by a new Sackler gift this year, is appended, as is the financial report.

Part I - Highlights

The major events of the year were the first joint meeting of the two new Scottish Sackler Institutes, with the two existing New York City Institutes, and the initiation of a new project in our institute, with a gift of $528,000 from the Sackler Foundation. In addition, we added a new member to our faculty, Dr. Jay Gingrich, who will direct the new Laboratory of Mouse Genetics and Behavior. 2 In the area of the Institutes’ finances, on December 31, 2004 the initial phase of the endowment process was completed, according to the agreement of December 20th 2000. Starting in January of 2005, accumulated income was no longer returned to the endowment corpus in the Professorship and Operations accounts, and instead became available for the support of Institute operations. This change coincided with the termination of the 5 year Columbia – financed Director’s Fund on June 30th, 2005. This fund has been supporting some of the ongoing institute programs and operations. As evident in the Financial Report appended, the income from the Operations account will be more than sufficient to enable us to carry on these programs. A new research initiative on The Early Developmental Role of the Serotonin Transporter was begun in December of 2004. The new Sackler Institute Gift Fund will support 5 interlocking research projects aimed at understanding the unique roles of serotonin in the developing brain that underlie two recently reported findings: (1) the increased vulnerability to depression when serotonin transporter gene function is reduced in early development, as well as (2) the adverse clinical responses of children and adolescents to selective serotonin receptor inhibitor (SSRI) drugs, and of newborns exposed in utero by SSRI treatment of maternal depression. Scientists in our institute realized that we were especially well positioned to approach these clinical problems that were very much in the news last year. Study of the genetic mechanisms will be undertaken at the clinical level by genotyping subjects in Dr. Weissman’s three generation study of depressed women, looking especially for serotonin transporter gene variants, and by the brain imaging component of this study under Dr. Peterson. The basic science level genetics studies will focus on the novel effects observed in the serotonin receptor transporter knockout mouse studies of Dr. Gingrich and Mark Ansorge. Drs. Monk and Fifer are now beginning to study fetal behavioral and autonomic measures in utero in pregnant women on SSRIs, in the newborn and in early infancy, and Dr. Myers and Dr. Susan Brunelli are studying the mechanism of similar effects at the basic science level, in SSRI treated pregnant, infant and adolescent rats. Finally Dr. Raymond Stark and Dr. Marianne Garland have begun to study the transplacental mechanisms of transport and metabolism of SSRIs and their fetal effects in their well established and unique pregnant baboon model. For more on these projects please see the appended copy of the research proposal we submitted to the Sackler Foundation in the fall of 2004. On June 7 th and 8 th 2005, there was a joint meeting of the 4 existing Sackler Institutes at the New York Academy of Medicine: Two new Sackler Institutes, one in Glasgow and the other in Edinburgh, met for the first time with the two established New York City Institutes, one at Cornell and ours at Columbia. The meeting was followed by tours of the two New York Institutes and an informal dinner for all participants. The focus of the Edinburgh group, directed by Eve Johnstone, is on risk factors for schizophrenia, using brain imaging and genetic analysis, in the prospective study of a substantial cohort of control and at-risk populations. The Glasgow group, directed by David Wyper and Jon Cavanaugh, has a clinical and laboratory neuroscience approach with an emphasis on new technologies of brain imaging and on applying these to the study of depressed patients with different degrees of response to SSRIs. More basic animal model neuroscience research is also getting underway in Glasgow. The joint meeting was very successful. The faculties found a number of specific research interests in common. Before the meeting was over, we had worked out a collaborative study with Jon Cavanaugh in which he will apply his new high resolution 3 small bore 7 Tesla MRI to look for the effects of early serotonin transporter gene alteration and of early SSRI administration on the brains of transgenic mice created in Jay Gingrich’s laboratory here in New York. [*More information on the faculty and goals of the two new Sackler institutes can be found on our website under “FAQ” and their individual websites]. On November 4, 2004 member of our Scientific Advisory Committee, Dr. Ronald Dahl, visited our department and gave an informal laboratory talk on his long term studies of brain development in adolescence. He inspired considerable motivation within our group to extend more of our studies into that age period. Sponsored Symposia : At the 20th annual meeting of the Winter Conference in Developmental Psychobiology, we sponsored a symposium titled “Medullary Serotonergic Neurons, Autonomic Homeostasis and SIDS”, and at the 2004 annual meeting of the International Society for Developmental Psychobiology, a symposium titled “Variability and Plasticity in Perinatal Motor Development”. Sackler funding brought scientists from Saskatchewan, Canada and Marseille, France to these meetings. A ‘Mini-Grant’ of $5,000 was awarded to Daniel Schechter, a former Sackler Awardee, to add measures of maternal cortisol responses to his NIMH funded studies of the development of infants of abusive mothers. Funds to support novel pilot studies were awarded to Dr. Joseph Isler ($5,000) to adapt his multi-lead EEG power analysis method to the fetal baboon and to Drs. Brunelli and Shair ($3,000) to support gene chip analysis of gene expression levels in rats selectively bred for high or low levels of early separation anxiety–like behavior and to adapt this method for studying mice with targeted gene alterations. The two Sackler Awardees, Drs Jonathan Polan and Mark Ansorge were awarded second year extensions of their funding for 2005-2006. Announcement of competition for the 2006-2007 Sackler Award will be made in November for funding beginning July 1, 2006.

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.

4 Over the past year we have examined how spinal motor neurons acquire specific identities that direct their patterns of target connectivity -- a key step in the assembly of motor circuitry. From the perspective of locomotor control, the most critical aspect of motor neuron differentiation is the formation of precise connections with target muscles in the limb. Such precision is achieved by conferring motor neurons with discrete columnar, divisional and pool identities. Each of these facets of motor neuron identity appears to govern a distinct step in the projection of motor axons to their limb muscle targets. The acquisition of a lateral motor neuron columnar (LMC) identity directs motor axons towards the limb, and the emergence of divisional identities within the LMC directs motor axons ventrally or dorsally upon entering the limb mesenchyme. But it is with the specification of their pool identity that motor neurons within the LMC acquire the ability to form precise axonal trajectories and innervate individual muscle targets. The existence of more than fifty muscle groups in a typical amniote limb demands a corresponding diversity of motor pool identities, posing a considerable molecular challenge as motor neurons begin to innervate specific muscle targets. Our recent studies have begun to indicate how the selectivity of homeodomain transcription factor expression determines profiles of receptor expression by motor axons, thus linking motor neuron identity and connectivity. Nkx and Mnx homeodomain proteins define the generic identity of motor neurons (1), in turn directing the expression of chemokine receptors that guide motor axons out of the ventral spinal cord (2). LIM homeodomain proteins specify the two subdivisions of the LMC, in turn directing the expression of EphA receptors that guide motor axon trajectories along the dorso-ventral axis of the limb (3). Hox proteins arrayed along the rostrocaudal axis of the spinal cord direct motor neuron columnar identities, and define the initial trajectories of motor axons in the periphery (4). A Hox transcriptional regulatory network also specifies motor neuron pool identity and connectivity (5). One set of Hox regulatory interactions assigns rostrocaudal motor pool position, and a second set assigns motor pool diversity at a single segmental level. This Hox regulatory network directs both the downstream transcriptional identity of motor neuron pools and their patterns of target muscle connectivity. The self-organizing features inherent in these transcriptional regulatory networks may help to endow developing motor neurons and motor circuits with their high degree of genetic determination.

Publications: 2004-2005

Marklund, M., Sjödal, M., Beehler, B.C., Jessell, T.M., Edlund, T., and Gunhaga, L. (2004). Retinoic acid signaling specifies intermediate character in the developing telencephalon. Development, 131, 4323-4333.

Wilson, J.M., Hartley, R., Maxwell, D.J., Todd, A.J., Lieberam, I., Kaltschmidt, J.A., Yoshida, Y., Jessell, T.M., and Brownstone, R.M. (2005). Conditional rhythmicity of ventral spinal interneurons defined by expression of the Hb9 homeodomain protein. J. Neurosci. 25, 5710- 5719.

Gu, C., Yoshida, Y., Livet, J., Reimert, D.V., Mann, D., Merte, J., Henderson, C.E., Jessell, T.M., Kolodkin, A.L., and Ginty, D.D. (2005). Semaphorin 3E and its receptor

5 plexin-D1 control vascular patterning independently of neuropilins. Science 307 265- 268.

Dasen J, Tice B, Brenner-Morton S, and Jessell TM (2005) A Hox regulatory network establishes motor neuron pool identity and target muscle connectivity. Cell, In Press.

Lieberman, I., Agalliu, D., Nagasawa, T., Ericson, J., and Jessell, T.M. (2005). A Cxcl12-Cxcr4 chemokine signaling pathway defines the initial trajectory of mammalian motor axons. Neuron 47, 667-679.

Grant Support

Howard Hughes Medical Institute 09/01/2005-08/31/2006 43% Role: PI $613,992 (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 09/01/2005 – 08/31/2009 10% NIH $254,650 Role: PI Control of Motor Neuron Differentiation The aim of this project is to study the mechanisms by which the diversity of different motor neuron subpopulation are generated.

WELLT066790-C-02-Z The Wellcome Trust 05/01/2002 04/30/2007 10% Role: PI $293,732 Functional Genomics of the Motor Neuron The aim of this projects is to define the molecular cascades and gene networks involved in the determination of two defined neuronal cell types.

Project ALS 01/21/2001 – 12/20/2007 5% Role: PI $149,727 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 disorder.

SCRIB51796001 NYS Spinal Injury Research Program 01/01/2004-12/31/2007 5% Role: PI $100,000 Analysis of ES Cell Derived Motor Neurons. The aim of these studies are designed to optimize the procedures for introduction of ES cell derived spinal cord neurons into adult spinal cord in normal and injured states. Overlap: There is no overlap between this grant and the current application.

6 The G. Harold and Leila Y. Mathers Charitable Foundation (E. Kandel, M.D.) 9/1/2001-8/31/2007 5% Role: Project- Jessell $175,000 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.

CU51912001 Dana Foundation 10/01/2003 – 9/30/2006 2% Role: PI Jessell $50,000 The Functional and Signaling Pathways of the Chemokine Receptor CXCR4 in the Immune and the Central Nervous Systems. The Primary goal of this proposed project is to elucidate the physiological function of CXCR4 in the immune and nervous systems.

Project ALS 01/21/2005 – 12/20/2007 5% Role: PI $81,000 Motor Neuron Subtype Diversification: ES Cell Potentiality Deduced From Developmental Mechanism. The overall goal of this proposal is to define the normal developmental mechanisms that promote the diversification of motor neurons into specific functional subtypes.

2. Behavioral Neuroscience Division

Dr. William Fifer, Assistant Director - 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 are funded by NIH 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. 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 fiscal year we continue to receive NIH funding for two relatively new projects. One is to investigate sleep arousal mechanisms in at-risk infants from a database collected as part of the NICHD CHIME (Cooperative Home Infant Monitoring Evaluation network). The second is a phase 1 planning grant as part of an NIAAA/NICHD network to study the effects of alcohol on SIDS, unexplained fetal 7 demise and other neurobehavioral disorders. This network focuses on high risk populations in South Africa and the Dakotas.

New Appointments: Advisory Board, Stillbirth Collaborative Research Network (SCRN), NICHD

Dr. Myron Hofer - Process of Attachment and the Regulation of Development

Our research has centered on the role of the parent-infant relationship as the first major environmental influence on postnatal development. I and my colleagues have explored how early maternal separation and different patterns of mothering exert long-term effects on vulnerability to disease. Through an experimental analysis of the psychobiological events that enmesh the infant rat and its mother, we are studying the hidden regulatory processes that are the basis for the early origins of attachment, the dynamics of the separation response and the shaping of development by that first relationship. Recent work with Drs. Brunelli and Shair has focused on the infant rats' vocal response to isolation as a model of the first anxiety state. We have explored its neural basis, how it is regulated behaviorally by littermates, dams and predators, and how its developmental course can be altered by continued selection for high and/or low responders.

I am currently working on a book on developmental processes, viewed from an evolutionary perspective. This has led me to attempt to answer, in a new way, questions such as: what is development? How is it related to evolution? and when and how did development evolve? My (not so modest) goal is to find relatively simple principles that can help us organize and think about the many different developmental processes that are being discovered nearly every day at levels from cells to society.

Dr. Michael Myers - Early Nutritional Influences on Vulnerability to Disease

Work in this laboratory continues to be spurred by the renewed interest in the effects of inadequate nutrition during pregnancy, undergrowth of the fetus, and vulnerability to disease later in life. From large scale epidemiological studies, it is clear that cardiovascular disease, diabetes, schizophrenia, and depression can all be influenced by nutritional disturbances, as well as other types of environmental stress during this critical period of development. This summer a new study published in JAMA, based on investigations of the effects of a wide spread famine in China, confirmed the long-term increase in vulnerability to schizophrenia associated with malnutrition during pregnancy. While long-term effects of early experiences has been a focus of research within the field of Developmental Psychobiology since its inception, the proximal mechanisms and chain of events that account for enduring changes in disease vulnerability remain largely undiscovered. This is the ongoing focus of work in our group. In collaboration with Drs. William Fifer and Harry Shair in our department, and Dr. Morris Cohen at Newark Beth Israel Hospital, we continue to investigate these phenomena in both animal models and human infants.

8 Our studies focus on effects of variation in nutrient availability in the perinatal period on physiological, biochemical and behavioral characteristics of newborn infants. Indices derived from animal studies are incorporated into human studies, and the underpinnings of correlative findings from human studies are pursued in animal models. The studies will determine if human infants with low birth weights, or rats whose mothers were underfed during pregnancy, express differences in cardiovascular and behavioral responses to feeding and postural challenge. We are also pursuing gene expression studies from placental tissue that will allow us to determine with greater precision which infants experienced suboptimal growth conditions during gestation. Finally, we are also investigating the hypothesis that alterations in methylation of regulatory regions of certain genes are key to understanding the persistence of changes in gene expression resulting from variation in nutrition early in life.

In addition to these studies, during the past six months our laboratory has also initiated studies examining effects of SSRI treatments during gestation on infant neurobehavioral outcomes, and acute effects of SSRIs on impulse control later in life. These animal model studies are supported by the new Sackler Foundation funding awarded during the past year. This summer, important progress was made on both projects. Our results support the possibility that developmental treatment with SSRI leads to increases in separation-induced anxiety in infant rats, a finding consistent with adult outcome studies published by Ansorge and Gingrich last year. We also have solid evidence that acute treatment of juvenile rats increases impulsive behavior. This is extremely important as this may relate to the increase in vulnerability to suicide associated with acute treatment with SSRIs in both adult and adolescent humans.

Dr. Jonathan Polan –

I am currently working in the laboratory of Dr. Eric Kandel at Columbia University's Center for Neurobiology and Behavior fusing developmental psychobiologic and genetic techniques to investigate new models of psychopathology. I am fortunate that this work is funded for a second year by a Sackler Research Award.

Jay Gingrich – Mouse Genetics and Behavior

The Gingrich Laboratory is currently pursuing 4 lines of research related to the genetics of neuropsychiatric disorders. Mice offer an excellent model to understand the developmental contribution of these genes to normal brain maturation and thus are employed extensively in our studies. Over the last year, we have been focusing on the effects of reduced serotonin transporter function during early life. 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. This work has been supported by the Sackler serotonin initiative funded this year, in addition to the support received by Mark Ansorge, a current Sackler Awardee.

9 We have two projects directly related to schizophrenia, that have received NIMH funding support in the last year. 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 examines the role of aberrant DNA methylation as a possible epigenetic contribution to schizophrenia susceptibility. Researchers at Columbia, working with Dolores Malaspina, have demonstrated that paternal age in excess of 45- 50 years at the time of conception is a significant risk factor for the conceived offspring. We have developed an animal model of this phenomenon and are exploring the hypothesis that methylation accuracy 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 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.

Publications

Sahni R, Schulze KF, Kashyap S, Ohira-Kist K, Fifer WP, Myers MM. (2005) Sleeping position and electrocortical activity in low birth weight infants. Arch Dis Child Fetal Neonatal Ed. Apr 27; Jul;90(4):F311-5.

Kinney HC, Myers MM, Belliveau BA, Randall LL, Trachtenberg FL, Fifer WP. (2005) Subclinical Cardio-respiratory Dysfunction in the SIDS Associated with Arcuate Nucleus Hypoplasia and Serotonergic Brainstem Abnormalities: A Case Report. Journal of Neuropathology & Experimental Neurology, Aug;64(8):689-694..

Myers MM, Gomez-Gribben E, Smith KS, Tseng A, Fifer WP. (2005) Developmental Changes in Infant Heart Rate Responses to Head-up Tilting. Acta Paediatrica, in press.

Fifer WP, Myers M, Sahni R, Kashyap S, Stark R, Schulze K. (2005) Interactions Between Sleep Position and Feeding on Cardiorespiratory Activity in Preterm Infants. Developmental Psychobiology, in press.

Grieve PG, Myers MM, Stark RI, Housman S, Fifer WP.(2005) Topographic localization of electrocortical activation in newborn and two-four month old infants in response to head-up tilting. Acta Paediatrica, in press.

10 Fifer WP. (2005) Normal and abnormal prenatal development. In Hopkins, B, Barr R, Michel, G. and Rochat, P. (Eds). Cambridge Encyclopedia of Child Development. Cambridge, UK. Cambridge University Press, pp 173-83.

Hofer, M. A. (2005). The psychobiology of early attachment. Clinical Neuroscience Research 4, 291-300.

Shair, H. N., Brunelli, S. A., & Hofer, M. A. (2005). Lack of evidence for mu-opioid regulation of a socially mediated separation response. Physiol Behav, 83(5), 767-777.

Schechter, D. S., Zeanah, C. H., Jr., Myers, M. M., Brunelli, S. A., Liebowitz, M. R., Marshall, R. D., et al. (2004). Psychobiological dysregulation in violence-exposed mothers: salivary cortisol of mothers with very young children pre- and post-separation stress. Bull Menninger Clin, 68(4), 319-336.

Kinney HC, Myers MM, Belliveau RA, Randall LL, Trachtenberg FL, Fingers ST, Youngman M, Habbe D, Fifer WP. Subtle Autonomic and Respiratory Dysfunction in Sudden Infant Death Syndrome Associated With Serotonergic Brainstem Abnormalities: A Case Report. J Neuropathol Exp Neurol. 64:689-694, 2005.

Quigley KS, Myers MM, Shair HN. Development of the baroreflex in the young rat. Auton Neurosci, in press, 2005.

Sahni R, Schulze KF, Kashyap S, Ohira-Kist K, Fifer WP, Myers MM. Sleeping position and electrocortical activity in low birth weight infants.Arch Dis Child Fetal Neonatal Ed. 2005.

Xu, H., Kellendonk, C.B., Simpson, E., Keilp, J.G., Bruder, G.E., Polan, H.J., Kandel, E.R., Gilliam, T.C. The DRD2 C957T polymorphism and its interaction with COMT Val158Met polymorphisms in human working memory ability. American Society of Human Genetics, Salt Lake City, October 25, 2005.

Polan, H. J. In press, 2005. Probing the origins of attachment: Guidance and differentiation of the first mother-directed behaviors. Developmental Psychobiology.

Etkin, A., Pittenger, C., Polan, H. J. & Kandel, E. R. 2005. Toward a Neurobiology of Psychotherapy: Basic Science and Clinical Applications. J Neuropsychiatry Clin Neurosci, 17:145-58.

Lepp, N. & Polan, H. J. Maternal separation and handling in infancy alter preweanlings’ secure base behaviors. Developmental Psychobiology, in revision.

C. Kellendonk, E. Simpson, H. J. Polan, G. Malleret, H. Moore & E. Kandel. Transient up-regulation of dopamine D2 receptors in the striatum leads to cognitive deficits. Cell, In revision.

11 Masson, J., Darmon, M., Conjard, A., Chuhma, N., Ropert,N., Thoby-Brisson, M., Foutz, A.S., Parrot, S., Miller, G.M., Jorisch, R., Polan, H. J., Hamon, M., Hen, R., and Rayport. S. Mice lacking brain/kidney phosphate-activated glutaminase (GLS1) have impaired glutamatergic synaptic transmission, altered breathing, disorganized goal- directed behavior and die shortly after birth. Submitted.

Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA (2004) Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science 306:879-881.

Compan V, Zhou M, Grailhe R, Gazzara RA, Martin R, Gingrich JA, Dumuis A, Brunner D, Bockaert J, Hen R (2004) Attenuated response to stress and novelty and hypersensitivity to seizures in 5-HT4 receptor knockout mice. J. Neurosci, 24:412-419.

Ten VS, Wu EX, Tang H, Bradley-Moore M, Fedarau MV, Ratner VI, Stark RI, Gingrich JA, Pinsky DJ (2004) Later measures of brain injury after neonatal hypoxia-ischemia in mice. Stroke, 35:2183-2138.

Ansorge, M, Zhou, M, Lira, A, Hen, R, Gingrich, JA (2004) Early life blockade of the 5- HT transporter alters emotional behavior in adult mice. Science 306 (5697):879-81.

Zhuang X, Masson J, Gingrich JA, Rayport S, Hen R (2005) Targeted gene expression in dopamine and serotonin neurons of the mouse brain. J Neurosci Methods. 143(1): 27-32.

Grant Support (dollar figures are per year)

“Fetal Origins of Disease: Markers, Modulators, Mechanisms” Principal Investigator: Myers, M.M. Role: PI (25%) $342,163 Agency: NIEHS Type: R01 (ES11596) Period: 08/01/01 – 06/31/06 These are animal model and human infant studies that focus on changes in cardiovascular function, glucose regulation, and gene expression associated with variations in early life growth and nutrition.

"Research Training in the Psychobiological Sciences" Principal Investigator: Hofer, M.A. Co-Director: Myers, M.M.(5%) $250,066 Agency: NIMH Type: T32 (MH018264) Period: 07/01/03 - 06/30/08 Postdoctoral research training grant for MD and PhDs in Psychobiology.

“Perinatal Assessment of At-Risk Infants” Principal Investigator: Fifer, William P. Co-Investigator: Myers, M.M. (15%) $97,000 Agency: NICHD Type: R01 (HD 32774) Period: 07/01/05 - 06/30/06

12 These studies focus on making cardiorespiratory measurements in groups of human fetuses and newborns who are at risk for developing subsequent neurologic damage and/or Sudden Infant Death Syndrome.

“Northern Plains Perinatal and Infant Health Consortium” Principal Investigator: Elliot, A. (U. of South Dakota) Co-Investigator: Myers,M.M. (5%) $125,000 Agency: NICHD Type: U01 (HD45935) Period: 10/01/03-9/30/06 This is planning grant to design multi-site investigations of the effects of maternal alcohol consumption on stillbirths and sudden infant death syndrome.

“Spontaneous arousals in “CHIME” Infants at Risk for SIDS” Principal Investigator: Darnall, R.A. (Dartmouth) Co-Investigator: Myers, M.M. (5%) $379,054 Agency: NICHD Type R01 (HD045653) Period: 01/15/04-12/31/06 This grant will characterized and quantify spontaneous arousals during sleep from data previously recorded as part of a large home monitoring grant (CHIME).

“Effects of Early SSRI Exposure on Neurobehavioral Development” Principal Investigator: Myers, M.M. Role: (PI) (5%) $75,000 Agency: Sackler Institute for Developmental Psychobiology at Columbia Type: Private This project will characterize early behavioral and physiological effects of exposure to SSRIs in rats.

"Research Training in the Psychobiological Sciences" Principal Investigator: Hofer, Myron A. Co-Director: Myers, M.M. $250,066 Agency: NIMH Type: T32 (MH018264) Period: 07/01/03 - 06/30/08 Postdoctoral research training grant for MD and PhDs in Psychobiology.

"Developmental Dopaminergic Excess, Environmental Stress, and the Pathogenesis of Schizophrenia" Principal Investigator: Polan, Jonathan Agency: Lieber Center for Schizophrenia Research $80,000 per year Period: 7/1/04 -6/30/06

Conte Center for the Neuroscience of Mental Disorders Role: Co-PI Gingrich, Jay (20%) $50,000 Type: (P50MH066171-01A1) (Laruelle) Period: 07/01/04-06/30/09 Our component of this Center uses mice partially deficient in neuregulin subtypes as an animal model of schizophrenia.. There is no overlap with present application

13 Epigenetic mechanisms: Paternal Age and Disease . Principal Investigator: Gingrich, Jay Agency: NIMH Type: (R21 MH073794-01) Period: 03/17/05-02/28/07 $150,000 2 year project to investigate the role of aberrant sperm methylation as a mechanism for the risk advanced paternal age poses for their offspring to several diseases, including schizophrenia. There is no overlap with present application.

Serotonin Transporter Research Project – Molecular Genetic Mechanisms. Principal Investigator: Gingrich, Jay Agency: Sackler Institute Type: (Private) Period: 07/1/04-06/30/06 $75,000 To investigate the developmental effects of serotonin transporter dysregulation on brain development. There is no overlap with present application.

“NRG1 mutant mice as a model of the negative symptoms of schizophrenia” Postdoctoral Recipient: Merker, Rob Mentor: Gingrich, Jay Agency: NIMH Type: NRSA Period: 10/01/04-09/30/05 $65,000 The project examines the social drive, olfaction, and SVZ neurogenesis fo mice with reduced NRG1 lg Isoform mice. There is no overlap with present application.

“Role of Cortical 5-HT2A receptor expression in hallucinogen function“ Principal Investigator: Gingrich, Jay Agency: Whitehall Foundation Type: Private Period: 1/01/05 -12/30/07 $75,000 A 3 year project to identify the role of cortical 5-HT2A receptors in the mechanism of action of LSD-like hallucinogens. There is no overlap with present application.

“Role of Cortical 5-HT2A receptors in impulsivity and aggression” Principal Investigator: Gingrich, Jay Agency: American Foundation for Suicide Prevention $20,000 Type: Private Period: 02/1/05-01/31/06 To examine the role of serotonin 5-HT2A receptors as possible mediators of impulsivity and aggression with the goal of identifying medications that may reduce these characteristics in susceptible individuals. There is no overlap with present application.

“Consequences of SERT Inhibition during Development on Adult Behavior and Neurophysiology” Principal Investigator: Ansorge, Mark Mentor: Gingrich, Jay Agency: NIMH Type: NARSAD Period: 07/15/05-07/14/07

14 $30,000 2 year project to investigate the disruption of SERT function during critical developmental periods may alter the trajectory of the central nervous system development in ways that influences affective function later in life. There is no overlap with present application.

3. Clinical Research Division

Dr. Myrna Weissman - Clinical Epidemiology Studies of Genetic Risk and Biological Markers in the Development of Mood and Anxiety Disorders

We have a number of studies involving clinical sample collection for genetic, high risk, and longitudinal studies of mood and anxiety disorders. Our overall goal has been to understand the patterns, timing and risk for mood and anxiety disorders across generations. We have followed and clinically characterized the samples of patients at risk for these disorders and have followed them from childhood to adulthood. We have used genetic, neuropsychological, neurophysiologic and neuroimaging studies to better understand the pathophysiology and neural circuitry of these disorders.

A major focus includes a three generation study of offspring at high and low risk for depression. The study has had four waves of assessments for over 20 years. A fifth wave is underway. The fourth wave of assessments found high rates of psychiatric disorders, particularly anxiety disorders in the prepubertal grandchildren with two generations of major depression. Among the grandchildren with a depressed grandparent and parent there was over a five fold increase risk of anxiety disorders and over a five fold risk of any disorder. The pattern that we have observed in these grandchildren (the third generation) paralleled what we found in the parents (the second generation) when they were followed from childhood to adulthood and in the grandparents (the first generation) who retrospectively reported their childhood conditions when we first surveyed them as adult (Weissman et al 2005). The 20 year follow up of the second generation found continuing recurrent depression in the high risk group and an increase in medical problems and mortality as they enter middle age (Weissman et al, in press).

In collaboration with Dr. Bradley Peterson we are now conducting functional and anatomical magnetic imaging studies of these generations and are developing hypothesis about brain endophenotypes using the EEG and startle data. We have now completed about 160 MRIs and this work will be progressing for another two years. The results of the EEG showed that offspring with both parents having a major depression had the greater alpha asymmetry at the medial sites with relatively less activity over the right central and parietal regions, when compared to the offspring with having one or no parents with depression. Alpha asymmetry is indicative of right parietotemporal hypoactivity, previously reported for depressed adolescents and adults, and heightened anterior to posterior gradient of alpha are present in high risk offspring having parents concordant for major depression (Bruder et al 2005).

15 The startle response studies found that startle discriminated between low and high risk groups. In the probands’ children, the high risk group showed increased startle magnitude throughout the fear-potentiated startle test. In the probands’ grandchildren, a gender-specific abnormality was found in the high risk group, with high risk girls, but not boys, exhibiting elevated startle magnitude throughout the procedure. Increased startle reactivity in threatening contexts, previously found in patients with anxiety disorder and in children of parents with an anxiety disorder, may constitute a vulnerability marker for major depression. Both the EEG and the startle could be endophenotypes (Grillon et al 2005).

We have been interested in the work of Caspi et al who showed that functional polymorphism in the promoter region of the serotonin transporter gene moderated the effect of life events on developing depression; i.e. the effects of the genes were conditional on exposure to an environmental risk. Our findings suggest another point of heterogeneity in depression. The development of depression in a young person may be conditional on both the parent and grandparent having a moderate to severe depression. These effects may be independent of environmental confounders. Whether these generations also carry the functional polymorphism is an interesting unanswered question. We do have data on life events. We are using Sackler funds to test these hypotheses. We received IRB approval in May 2005 and have become the genetic studies. Our collection first concentrates on subjects who have undergone MRI. With the receipt of an NARSAD Distinguished Investigator Award in June 2005 we have added a study to include gene expression analysis. There is evidence that RNA variation that may predispose individuals to complex genetic disorders like major depression may also perturb gene expression. We now plan to have interrogate gene expression in peripheral blood cells. Our hypothesis is that genes that may be undergoing altered expression in the central nervous system due to genetic or environmental factors may also show altered expression in the periphery. We are awaiting IRB approval.

We have followed up previous findings on the high familiality of recurrent major depression beginning before the age of 30. As participants in a multi-site study to identify major depression susceptibility gene, the collection of about 1000 sib pairs with recurrent early onset major depression has been completed. Biological material and clinical data is being shared with the scientific community. Data analyses of this study are underway (Holmans et al 2004). This renewal of this grant has been approved for 4 more years and will be funded in 9/05 to follow up findings and collect an additional sample.

Work is ongoing to understand the genetic basis of fear and anxiety disorders in humans by identifying variants forms of genes that may contribute to pathological anxiety state. The basic idea is that learned innate fear are tractable target for genetic analysis in mice and humans; that there are similarities in fear conditioning circuitry between animal models and humans; that genes involved in the pathway associated with fear in mice may be involve in the development of human anxiety disorders. Candidate genes that are identified from the study of learned and innate fear will be tested in a sample of normal humans with various degrees of fear conditioning, following startle test. These genes may also be related to human anxiety disorders. We 16 are collecting samples of patients with panic disorders, social anxiety disorders, and normal controls. We have collected over 400 cases and are beginning to test candidate gene. This work is supported by an NIMH Program Project grant between Eric Kandel, Rene Hen, Conrad Gilliam, Abby Fyer, and Myrna Weissman.

We have used the Sackler funds to encourage young investigators to further develop the data from our clinical sample. Adriana Feder, MD has completed her study on twenty-four-hour cortisol secretion patterns in prepubertal children with depression, anxiety and healthy controls in a longitudinal clinical follow up into young adulthood. Findings indicate that prepubertal children with major depression, as well as children who are at risk for developing major depression by young adulthood, show abnormalities in their 24-hour cycle of cortisol secretion. In addition, Dr. Feder has conducted a pilot study of children of depressed mothers. The sample for this study comes from an urban primary care practice serving low-income, predominantly immigrant Hispanic families from the Caribbean islands and Central America, with adults who speak primarily Spanish. Fifty-eight children from 35 families were studied. Compared with children of non-depressed mothers, children of depressed mothers had increased lifetime prevalence of depressive disorders, separation anxiety disorder and disruptive behavior disorders, including attention deficit-hyperactivity disorder and oppositional defiant disorder. Her findings suggest that psychiatric disorders, in particular disruptive behavior disorders, may be even more prevalent in these children than in children from less economically disadvantaged depressed mothers.

Sanjay Mathew, MD, partially funded by the Sackler Foundation, has just completed a neuroimaging study using proton magnetic resonance spectroscopy (H- MRS), on a sample of adolescent-onset depressives followed into adulthood. Dr. Mathew investigated hippocampal metabolite concentrations in adults who had been diagnosed approximately 20 years previously with adolescent-onset major depressive disorder (MDD). Clinical outcomes of this cohort showed significant rates of persistent psychopathology, including recurrent MDD, bipolar I or II disorder, OCD and varied phobic disorders. There were no overall mean group differences in individual hippocampal metabolites or laterality indices. However, the NAA laterality index significantly discriminated (p < .001) the two remitted patients from all others by revealing a much greater right- to left-sided concentration. Favorable outcome for adolescent-onset MDD was strongly associated with a relative right-sided lateralization in hippocampal NAA, independent of current psychotropic medication usage.

Yoko Nomura, Ph.D. is following up our efforts to identify multitude risk factors for early onset depression. Working in collaboration with William P. Fifer, Ph.D. she is studying pathways to psychiatric and medical comorbidity. Exposure to perinatal problems and social adversity in conjunction with maternal depression may explain the increased risk of behavioral, emotional, and medical problems in offspring in their infancy, childhood, and adulthood. Individuals with psychiatric illness such as depression who have a comorbid medical problem have increased functional impairment, more frequent use of health care services, and a higher prevalence of suicidal ideation. Elucidation of the mechanism through which the phenomenon occurs, through examination of problems across the life cycle (birth, infancy, childhood, and

17 adulthood), will help clarify the temporal sequences of the selected comorbid medical illness (allergies, headaches, and heart disease). Her first analysis found that low birth weight increased the risk of major depression and suicidal ideation in adulthood. This effect was moderated by maternal depression.

Publications (2004/2005)

Bass J, Neugebauer R, Clougherty KF, Verdeli H, Wickramaratne PJ, Ndogoni L, Speelman L, Weissman MM, Bolton P. Randomized controlled trial of group interpersonal psychotherapy for depression in rural Uganda: 6-month outcomes. British J Psychiatry. Submitted, 2005

Blanco C, Clougherty KF, Lipsitz KF, Mufson L, Weissman MM. Interpersonal Psychotherapy. In Gabbard G, Beck J, Holmes J (eds.) Journal of Psychotherapy Integration (Special Series): Integrating between-session homework activities into different psychotherapies. Concise Oxford Textbook of Psychotherapy. Gabbard, GO, Beck J, Holmes JA. In press, 2005.

Blanco C, and Weissman MM. Interpersonal Psychotherapy. In Gabbard GO, Beck JS, Holmes J (eds) Oxford Textbook of Psychotherapy, Oxford University Press, NY 2005, pp. 27-34.

Bruder GE, Tenke CE, Warner V, Nomura Y, Grillon C, Hille J, Leite P, Weissman MM. Electroencephalographic measures of regional hemispheric activity in offspring at risk for depressive disorders. Biol Psychiatry 57:328-335, 2005.

Das AK, Gameroff M, Pilowsky D, Blanco C, Feder A, Gross R, Lantigua R, Shea S, Olfson M, Weissman MM. Screening for bipolar disorder in primary care patients. JAMA 293:956-963, 2005

Das AK, Olfson M, McCurtis HL, Weissman MM. Depression in African Americans: Barriers to detection and effective management in primary care. JFP. In press, 2005.

Grillon C, Warner V, Hille J, Merikangas KR, Bruder GE, Tenke CE, Nomura Y, Leite P, Weissman MM. Families at high and low risk for depression: A three-generation startle study. Biol Psychiatry 57:953-960, 2005.

Gross R, Das AK, Weissman MM. Letter to editor: Bipolar Disorder. N Engl J Med 351:2454-2455, 2004.

Gross R, Olfson M, Gameroff MJ, Carasquillo O, Shea S, Feder A, Lantigua R, Fuentes M, Weissman MM. Social anxiety disorder in primary care. Gen Hosp Psychiatry 27:161-168, 2005.

Gross R, Olfson M, Gameroff MJ, Carasquillo O, Shea S, Feder A, Lantigua R, Fuentes M, Weissman MM. Depression and glycemic control in primary care patients with diabetes J Gen Intern M ed 20:460-466, 2005.

18 Gur M, Miller L, Warner V, Wickramaratne P, Weissman MM. Maternal depression and the intergenerational transmission of religion. J Nerv Ment Dis 193(5): 338-345, 2005.

Hamilton SP, Slager SL, Baisre de Leon A, Heiman GA, Klein DF, Hodge SE, Weissman MM, Fyer AJ, Knowles JA. Evidence for genetic linkage between a polymorphism in the Adenosine 2A receptor (ADORA2A) and panic disorder. Neuropsychopharmacology 29:558-565, 2004.

Lewis-Fernandez R, Das AK, Alfonso C, Weissman MM, Olfson M. Depression in US Hispanics: diagnostic and management considerations in family practice. JABFP. In press, 2005.

Markowitz JC, Weissman MM. Interpersonal psychotherapy: principles and applications. World Psychiatry 3(3): 136-139, 2004.

Olfson M, Das AK, Gameroff M, Pilowsky D, Feder A, Gross R, Lantigua R, Shea S, Weissman MM. Manic depression in primary care. Am J Psychiatry. In press, 2005. Oquendo MA, Lizardi D, Greenwald S, Weissman MM, Mann JJ. Rates of lifetime suicide attempt relative to rates of lifetime major depression in different ethnic groups in the United States. Acta Psychiatr Scand 110(6):446-451, 2004.

Weissman MM. The epidemiology of bipolar disorder. In Goodwin F, Jamison K (eds.), Manic Depressive Illness, Oxford University Press. In press, 2005.

Weissman MM. Epidemiologic Phenotype Hunting: Panic Disorder and Interstitial Cystitis. In Eaton W (ed) Medical and Psychiatric Comorbidity Over the Course of Life, APPI, Washington DC. In press, 2005.

Weissman MM. Book Review on What Works for Whom? Roth A & Fonagy P. Guilford Press, 2004. Psychological Medicine. In press, 2005.

Weissman MM, Blom MBJ. Interpersonal Psychotherapy. In R.M. Murray, K. Kendler, P. McGuffin, S. Wessely, D. Castle (eds.) Essentials of Psychiatry, Cambridge University Press, UK. In press, 2005.

Weissman MM, Neria Y, Das A, Feder A, Blanco C, Lantigua R, Shea S, Gross R, Gameroff MJ, Pilowsky D, Olfson M. Gender differences in PTSD among primary care patients following the World Trade Center attacks. Gender Med 2(2):76-87, 2005.

Weissman MM, Wickramartne P, Nomura Y, Warner V, Pilowsky D, Verdeli H. Offspring of depressed parents: 20 years later. Am J Psychiatry. In press, 2005.

Weissman MM, Wickaramartne PJ, Nomura Y, Warner V, Verdeli H, Pilowsky DJ, Grillon C, Bruder G. Families at high and low risk for depression: A three generation study. Arch Gen Psychiatry 62: 29-36, 2005.

19 Grant Support (dollar figures are per year)

Myrna M. Weissman, Ph.D. 5 RO1 MH60912-04 (Weissman) 09/1/05 - 08/31/09 NIH/NIMH $1,618,341 Genetics of Early-Onset Major Depression A six-site cooperative project to collect a large sample of subjects with early-onset MDD obtaining clinical data and genetic samples aiming to map genes giving a susceptibility to MDD. This is a renewal of a collaborative study.

2 RO1 MH28274-26 (Weissman) 07/08/02 to 06/30/06 NIH/NIMH $265,160 Genetic Studies of Depressive Disorders This is a project to understand the etiology of panic disorder using a broad range of novel and advanced genetic and epidemiologic approaches. A competing continuation has been submitted.

5 R01 MH63852-04 (Weissman) 07/19/01 to 06/30/06 NIMH $776,539 Children of Depressed Mothers: a STAR*D Ancillary Study The overall aim is to study the impact of a reduction of maternal depressive symptoms on childrens psychiatric symptoms and social functioning as an ancillary study to the Sequenced Treatment Alternatives to Relieve Depression study (STAR*D).

2 T32 MH16434-21 (Shaffer) 07/01/00 to 06/30/05 NIH/NIMH $488,000 Research Training in Child Psychiatry The Child Psychiatry Research Training Program trains postdoctoral psychiatrists, psychologists, and others to become independent investigators in the field of child and adolescent psychopathology. The grant supports ten M.D. and/or Ph.D. trainees for up to three years.

P30 MH071478 (Shaffer) 06/1/04 to 05/31/09 $1,274,194 ACISR for Pediatric Psychiatry Disorders The proposal outlines four cores that will work with another towards the following goals: 1) to promote and develop efficacy studies in disorders of interest to investigators of the Center where the evidence-based support for interventions remains substantially deficient and where "export" into the field would be premature. 2) To study of transportability and effectiveness of interventions or methods of evaluation for which there is substantial evidence-based support, to real world settings. 3) To identify problems in the methods used in intervention research with children and adolescents. 4) To work with basic-scientists to investigate whether state of the art imaging and genotyping methods can be used to identify the mediators of treatment response. 5) To train new intervention researchers; and 6) To take a scientific and advocacy leadership role in promoting and disseminating intervention research. The Principal Research Core

20 (M. Weissman), will set the research agenda for the center.

5 R01 MH 36197-20 (Weissman) 01/01/03 -12/31/08 NIH/NIMH $620,928 Children at High and at Low Risk for Depression Overall aim of this study is to understand the long term temporal sequence and familial patters of mood and other disorders from childhood to adulthood in offspring at high and low risk for depression. The study now includes three generations. The aims during this project period are (1) to complete data analyses of the 4 th wave of assessments; (2) acquire and analyze both anatomical and functional MRI in 214 subjects; (3) conduct data analyses integrating clinical, psychophysiological, and neuroimaging studies.

1 P01 MH60970-02 (Weissman) 12/1/02-11/30/06 NIH/NIMH $237,374 (Project 4 only) (Weissman is PI of Project 4 “Clinical Studies of Human Anxiety) (Program Project Grant in collaboration with C. Gilliam, E. Kandel, R. Hen, and A. Fyer) Molecular Genetic Studies of Fear and Anxiety This is a program project to study the molecular and genetic basis of amygdala- regulated fear and anxiety in mice and humans. Several fear conditioning paradigms will be studied in both mice and humans, along with selected anxiety related traits and disorders in humans. Genes that alter fear-conditioning phenotypes in mice will be analyzed for trait-related DNA sequence variation in humans who score at the phenotypic extremes for the matched paradigm. Genes shown to alter other anxiety measurements in mice will be analyzed for trait or disorder-related variation in humans with a variety of anxiety-related temperaments and disorders.

1 P60 MD000206-02(Carrasquillo) 10/01/02-9/30/07 NIH/NCMHHD $75,651 Core Only Columbia Center for the Health of Urban Minorities - Core 7 (Olfson) The overall aim of the Mental Health Research Core is to facilitate the development and research evaluation of mental health interventions for low income minority populations

Josiah P Macy Foundation (Weissman) 07/01/03-06/30/06 $200,000 Bridging the Gap Between Research and Clinical Practice in Modern Psychotherapy The overall goal is to decrease the considerable gap that now exists between the availability of evidence based treatments (EBT), particularly psychotherapy, and training of clinical practitioners, in psychiatry, psychology, and social work, who actually provide psychotherapy to the patients.

NARSAD Distinguished Investigator Award 5/1/05-04/30/06 (Weissman) $100,000 Three Generations at Risk for Depression: Genetic Studies To collect RNA for gene expression studies in collaboration with Steven P. Hamilton, M.D, Ph.D.

21 4. Developmental Neuro-imaging Laboratories

Dr. Bradley Peterson – Normal Brain Development and the Neural Basis of Psychiatric Disorders

Funded Projects Dr. Peterson received funding for a midlevel Career Development Award that will support a portion of his salary for research and mentoring activities.

Dongrong Xu, Ph.D., received a 2-year NARSAD Young Investigator Award to study nerve fiber tracts in adolescents with Bipolar Disorder using Diffusion Tensor Imaging.

Collaboration with Drs. Myrna Weissman of the Sackler Institute has continued in our funded R01, and we have thus far successfully scanned 155 individuals in a large, 3- generational cohort that has been followed by Dr. Weissman over the past 20 years. Individuals in all 3 generations who are at either high or low risk for major depressive illness are being studied with MRI and with neuropsychological tasks designed to test the integrity of neural systems thought to be dysfunctional in depression. Data analyses are underway in preparation for the first report on the imaging data collected from this cohort.

On a funded R01, we have begun recruitment and imaging of newborn infants exposed prenatally to crack cocaine, narcotics, or marijuana. We are using MRI to assess brain structure, connectivity, and neurometabolites in these drug-exposed infants compared with unexposed controls. We have established recruitment sites in drug treatment centers and obstetric clinics throughout the greater New York metropolitan area.

On another funded R01, we are analyzing MRI data from 620 MRI scans obtained in children and adults who have Tourette syndrome, OCD, or ADHD, or who are healthy comparison subjects. Brain-based correlates of morphological measures with performance on cognitive tasks, with brain activity on fMRI scans, and genetic variation are being assessed. A number of papers pertaining to this work have been published in the past year or are in press. Of particular note perhaps is that the paper of Dr. Marsh on memory systems in persons with Tourette’s that was published in the Archives of General Psychiatry was one of ten studies cited by the NIMH director as notable science in his spring 2005 report.

Other In July 2005, Dr. Peterson was promoted to full Professor of Psychiatry with Tenure.

Publications von Plessen K, Wentzel-Larsen T, Hugdahl K, Feineigle P, Klein J, Staib L, Leckman JF, Bansal R, Peterson BS. Altered interhemispheric connectivity in individuals with Tourette syndrome. Am J Psychiatry, 161:2028-2037, 2004.

22 Marsh R, Alexander GM, Packard MG, Zhu H, Wingard JC, Quackenbush G, Peterson BS. Habit learning in children and adults with Tourette Syndrome: A translational neuroscience approach to a developmental psychopathology. Arch Gen Psychiatry, 61:1259-1268, 2004.

Kim DJ, Yoon SJ, Choi B, Kim TS, Woo YS, Kim W, Myrick H, Peterson BS, Choi YB, Kim YK, Jeong J. Increased fasting plasma ghrelin levels during alcohol abstinence. Alcohol Alcohol, 40:76-9, 2005.

Bansal R Staib LH, Whiteman R, Wang YM, Peterson BS. ROC-based assessments of 3D cortical surface-matching algorithms. Neuroimage, 24:150-62, 2005.

Raz A, Lieber B, Soliman F, Buhle J, Posner J, Peterson BS, Posner MI. Ecological nuances in functional magnetic resonance imaging (fMRI): psychological stressors, posture, and hydrostatics. Neuroimage 25:1-7, 2005.

Sukhodolsky DF, Rosario-Campos MC, Scahill L, Katsovich L, Pauls DL, Peterson BS, King RA, Lombroso PL, Findley D, Leckman JF. Adaptive and family functioning in children with Obsessive-Compulsive Disorder with and without Attention- Deficit/Hyperactivity Disorder. Am J Psychiatry, 162:1125–1132, 2005.

Peterson, BS. Clinical neuroscience and imaging studies of core psychoanalytic constructs. Clin Neurosci Res, 4:349–365, 2005.

Marsh R, Alexander GM, Packard MG, Zhu H, Peterson BS. Perceptual-motor skill learning in Tourette syndrome. Evidence for multiple procedural learning and memory systems. Neuropsychologia, 43: 1456-1465, 2005.

Posner J, Russell J, Peterson BS. The circumplex model of affect: an integrative approach to affective neuroscience, cognitive development, and psychopathology. Develop Psychopath, in press.

Zhuang J, Hrabe J, Branch CA, Kangarlu A, Bansal R, Peterson BS. Correction of eddy current distortions in diffusion tensor images using the known direction and strength of diffusion gradients. Magn Reson Med, in press.

Gorman DA, Zhu H, Anderson GM, Davies M, Peterson BS. Iron indices in Tourette Syndrome and their association with basal ganglia and regional cortical volumes. Am J Psychiatry, in press.

Bloch MH, Peterson BS, Scahill L, Otka J, Katsovich L, Zhang H, Leckman JF. Clinical predictors of future tic and OCD severity in children with Tourette Syndrome. Arch Ped Adolesc Med, in press.

Bloch MH, Leckman JF, Zhu H, Peterson BS. Caudate volumes in childhood predict symptom severity in adults with Tourette Syndrome. Neurology, in press.

23 Margolis A, Donkervoort M, Kinsbourne M, Peterson BS. Interhemispheric connectivity in adults with Tourette Syndrome. Neuropsychology, in press.

Amat JA, Bronen R, Saluja S, Zhu H, Gorman DA, Peterson BS. Evidence for cerebral inflammatory processes in children with Tourette syndrome, OCD, or ADHD. Am J Psychiatry, in press.

Blumberg HP, Krystal JH, Bansal R, Kaufman J, Martin A, Dziura J, Durkin K, Martin L, Gerard E, Charney DS, Peterson BS. Evidence of aberrant neurodevelopment of ventral prefrontal cortex in Bipolar Disorder: influences of rapid-cycling and pharmacotherapy. Biol Psychiatry, in press.

Blumberg HP, Fredericks C, Wang F, Kalmar J, Spencer L, Papademetris X, Pittman B, Martin A, Peterson BS, Fulbright R, Krystal JH. Preliminary evidence for persistent abnormalities in amygdala volumes in adolescents with bipolar disorder. Bipolar Disorders, in press.

Marsh R, Zhu H, Schultz R, Quackenbush G, Royal J, Skudlarski P, Gore JC, Peterson BS. A developmental fMRI study of self-regulatory control. Hum Brain Mapping, in press.

Plessen KJ, Bansal R, Zhu H, Whiteman R, Amat J, Quackenbush GA, Martin L, Durkin K, Blair C, Royal J, Hugdahl K, Peterson BS. Hippocampus and amygdala morphology in Attention-Deficit/Hyperactivity Disorder. Arch Gen Psychiatry, in press.

Grant Support

2002 NIMH MH36197 Children at High and Low Risk for Depression (M. Weissman. & B. Peterson, Co-PI’s) 20% Effort. To identify the brain-based correlates of children and adults at high or low risk for depressive illness using anatomical and functional MRI. 1/1/03-12/31/08 Initial Annual Cost $635,513 Total Direct Cost $3,258,079 Total Cost $4,593,000

2004 NIDA DA017820 MRI of Infants Exposed Prenatally to Drugs of Abuse (B. Peterson, PI) 25% Effort. To define the effects of drugs of abuse on brain structure and metabolite concentrations, as well as the behavioral correlates of those effects, in infants and children who have been exposed to drugs of abuse during fetal development. 4/01/04-3/31/09 Annual Direct Cost $499,938 Total Direct Cost $2,497,828 Total Cost $3,636,292

24 2004 NIMH MH068318 Neuroanatomical MRI Studies of Childhood Disorders (B. Peterson, PI) 30% Effort. To understand normal brain development and the neural basis of childhood neuropsychiatric disorders using anatomical MRI. 7/01/04-6/30/09 Annual Direct Cost $499,999 Total Direct Cost $2,499,995 Total Cost $4,000,427

2004 NIMH MH070424 WTC Impact, Familial Transmission and Child PTSD (C. Hoven, PI) 15% Effort. We will use MRI to study the effects of trauma on the CNS in children and their parents who resided in close proximity to the World Trade Center on 9/11/01. We will be scanning 80 representative children and their parents who were evacuated from the site after the disaster, as well as 80 matched control children and their parents who were not in physical proximity to the trauma. Role: Director of the MRI research component of the project. 4/04/04-4/03/05 Annual Direct Cost $426,563 Total Direct Cost $426,563 Total Cost $ 601,611

2004 NIMH ACISR for Pediatric Psychiatry Disorders (D. Shaffer, PI) 3% Effort. The proposal outlines four cores that will work with one another to promote and develop efficacy studies in disorders of interest to investigators of the Center where the evidence-based support for interventions remains substantially deficient and where “export” into the field would be premature and to work with basic scientists to investigate whether state of the art imaging and genotyping methods can be used to identify the mediators of treatment response. 06/01/04 – 05/31/09 Annual Direct Cost $260,870 Total Direct Cost $1,304,354 Total Cost $1,839,139

2005 NIMH 2T32 MH16434 Research Training in Child Psychiatry (D. Shaffer, PI) 5% Effort. The Child Psychiatry Research Training Program trains postdoctoral psychiatrists, psychologists, and others to become independent investigators in the field of child and adolescent psychopathology. The grant supports ten M.D. and/or Ph.D. trainees for up to three years. 07/01/05 - 06/30/10 Annual Direct Cost $579,380

2005 NIMH K02 74677-01MRI In Childhood Neuropsychiatric Disorders (B. Peterson, PI) 95% Effort. This is a midlevel Career Development Award to use Magnetic Resonance Imaging (MRI) methodologies to identify the neurobiological basis of developmental neuropsychiatric disorders, particularly in: (1) Disorders of impulse control, including Tourette’s syndrome, Obsessive-Compulsive Disorder, and Attention-Deficit/Hyperactivity Disorder; 2) Conditions that confer risk for disturbances in development of the neonatal brain, including premature birth and prenatal exposure to drugs of abuse; and 3) Affective Disorders. A substantial

25 portion of his work also involves the development of new methods for processing MRI data and for translational research involving behavioral neuroscience paradigms within the MRI scanner, as well as mentoring junior investigators in the application of neuroimaging methodologies to the study of childhood psychiatric disorders.

5. Sackler Awardee

Jonathan Polan

In the past year, I showed that a mouse generated in this lab to model schizophrenia by over-expressing the dopamine D2 receptor in the striatum acquires its adult phenotype of working memory and social interaction deficits during pre- or early postnatal development. To model the “double hit” hypothesis of schizophrenia I am investigating the interaction of prenatal restraint stress with the genetic vulnerability. My hypothesis is that the transgenic animals that were prenatally stressed will demonstrate a synergism between the genetic vulnerability and the environmental manipulation by developing more severe shizophrenia-like symptoms than either stressed or transgenic animals alone. The data so far show an effect of prenatal stress, validating the method. Because a large number of litters is needed to show a statistical effect of the interaction of the stress and the transgene, I anticipate having evidence for or against the interaction hypothesis in the next several months.

At the same time, I generated another transgenic mouse model of dopamine-related psychopathology, which over-expresses the gene for catechol-O-methyl transferase (COMT), an enzyme responsible for the metabolism of dopamine at brain synapses. I already have more than 5 founder animals, which are being mated. These matings will produce adult offspring for molecular biological and behavioral phenotypic analysis in 60 days. Like the excess D2 receptor animal, the COMT transgene is restricted to the forebrain and under temporal control by a molecular switch, which can be turned off at will.

These two transgenic animal models should provide complementary views of the developmental psychopathology involving forebrain dopamine systems. In conjunction with my work on these two animal models, I collaborated on a study of humans which showed that working memory is impaired by a combination of genetic polymorphisms that over-express the D2 receptor.

In a separate project, which directly extends my prior work in the Sackler Laboratory on early mother/infant attachment, I found genetic effects on maternally directed orienting behaviors (MDOBS), the neonatal behaviors that I identified as the formative stage of filial attachment in rats. The new study, in collaboration with Stephen Rayport’s lab at Columbia, identified MDOBs in neonatal mice and showed that mice lacking the gene for phosphate activated glutaminase, an enzyme that is key to the function of the neurotransmitter glutamate, have MDOB deficits, the severity of which are a function of the gene dose. I.e., heterozygotes have a mild deficit and survive, whereas homozygotes (knockouts) have severe deficits and do not survive past 2 days. This 26 study establishes the cross-species generality of MDOBs, genetic and neurochemical links to their development, and suggests their functional importance.

Mark Ansorge

The Sackler funding has provided valuable resources to support our research examining the effect of developmental serotonin transporter blockade on behavior, physiology and anatomy. We have used the funds to perform crucial experiments that increase our knowledge, leading to a publication in Science with one other manuscript in preparation. The Sackler support of my salary has allowed us to develop pilot data, refine our hypotheses and consequently prepare and submit two RO1 applications. These grants have received very promising reviews and will likely be funded in 2006.

We want to highlight the fact that the Sackler funding has been instrumental for our laboratory. The award has allowed me to begin to establish a career path in one of the most competitive and interesting areas of developmental psychobiology. Moreover, our work has inspired several collaborations with researchers in both the clinical and preclinical realms that will hopefully bring additional interest to these important developmental questions.

General Progress. The findings on which our original proposal was based - pharmacological inhibition of serotonin transporter function during early development produces abnormal emotion-related behaviors in the adult, mimicking the phenotype of mice with a genetic deletion of the serotonin transporter - have been published in Science (Ansorge et al., 2004). When we wrote the original proposal, it was not clear whether any chronic Fluoxatine (FLX) treatment would produce the observed altered emotional behavior 10 weeks after the treatment was stopped. We therefore determined the effect of chronic (21 days) FLX exposure in the adult and could show that it has no long lasting effect on exploratory or affective behavior 10 weeks later indicating that the effects of FLX in early development, post-natal (PN-FLX) are not age independent withdrawal symptoms. Another important finding is that Serotonin transporter knockout (SERT KO) mice display a progressive motor coordination deficit. This phenotype could potentially interact with the emotional phenotype and complicate the analysis and the interpretation of our results. Importantly, we could dissociate the motor and the emotional phenotype by showing that PN-FLX treatment has no effect on motor coordination, whereas chronic SERT blockade during the adult.

Progress towards developing an inducible SERT knockout mouse. We have generated mice that express the tetracycline transactivator protein (tTA) under the control of the SERT promoter using a knock-in strategy. This knock-in mutation inactivates the endogenous SERT gene. The tTA in the SERT locus drives expression of genes under the control of the tetO minimal promoter with raphé-specific patterns of expression.

27 Progress towards determining the specificity of SERT disruption to produce altered adult affective behavior. We have generated mice, treated in early development (post-natal days 2-21) with saline (control), FLX (active control, 10 mg/kg), citalopram (an SRI, 10 mg/kg), clomipramine (a tricyclic with SRI activity, 20 mg/kg), and desipramine (an NRI without SRI activity, 10 mg/kg). Following weaning and maturation, the mice will be tested as adults in the behavioral paradigms. In an earlier experiment we could show that tattooing has no effect on adult emotional behavior. In addition we are currently testing adult wild type and SERT KO mice for their responsiveness to acute and chronic FLX and desipramine. These additional experiments will allow us to draw more informed conclusions and create hypotheses regarding the role of the SERT in mediating the effect of antidepressants and compare it to the effect of those drugs when given during early development. Preliminary results indicate that SERT KO mice are behaviorally insensitive to FLX and desipramine treatment.

Progress towards determining the mechanisms underlying the effect of postnatal SERT disruption on adult behavior. We have found no effect of constitutive genetic SERT disruption on the size or composition of catecholaminergic nuclei (substantia nigra, ventral tegmental area, locus coeruleus), suggesting that the effect on raphé composition is rather specific. At the moment we are performing stereological analysis of the median and dorsal raphé nucleus in PN-FLX treated mice. Furthermore, we have determined the effect of PN-FLX on the structure of the barrel fields in the somatosensory cortex, which is disrupted in SERT KO mice. We found that our PN-FLX treatment does not affect this structure. Having performed these control experiments we will now pursue our proposed gene chip study.

Part III Financial Report

Enclosed

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