This report covers the fourth year of operation of the Sackler Institute, established at Columbia April 27^th 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.

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 20^th 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 30^th, 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 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 20^th 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.

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 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

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.

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

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.

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

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.

The G. Harold and Leila Y.

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

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.

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 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.

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 genetictechniques 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.

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.

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.

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
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

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

$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).

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 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 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.