This report covers the fifth 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 10 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. 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. An additional gift is supporting a special project on the early developmental role of serotonin transporter function.

The administrative structure and faculty of the institute over the past year were as follows:

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. A financial report is available separately.

There were 7 excellent applications for the Sackler Award this year and we were able to fund three (one at $50,000 and two at 25,000/yr each). Dr. Amir Levine, a research associate in the center for Neurobiology and Behavior was awarded the full stipend for his project on molecular mechanisms that contribute to the epidemiological finding that the earlier in life the exposure to drug abuse takes place, the greater the likelihood of becoming addicted. Dr. Levine proposed that “Since addiction, like memory storage, requires the synthesis of new proteins, this difference between adult and young brains is likely to be regulated at the level of gene expression through chromatin modulation.” Based on preliminary findings he proposes to investigate transcription activators such as CREB and fosB.

Dr. Rachel Marsh, a postdoctoral fellow in the NIMH funded Developmental Psychobiology training program, with which the Sackler Institute is closely affiliated, was awarded an NIMH K01 Mentored Research Scientist Development Award shortly after her selection for a Sackler Award by our committee. She was then funded at half the full level, to support a research technician for her studies. She will be working with Bradley Peterson in her project on the possible functional impairment of the frantostriatal brain circuitry of patients with Bulimia Nervosa that underlie abnormalities in habit learning, self-regulatory and impulse control recently described in some patients.

The third award, also at the half-stipend level, was given to Dr. Philip Grieve, assistant professor of Biomedical Engineering in the Department of Pediatrics, for his project to use his novel measure of spatial and temporal EEG integration, during sensory processing in young children (0-3) at risk for autism (younger siblings), in age matched, low-risk controls and in autistic children 3-6 years of age. This novel method of computerized EEG analysis, devised by Dr. Grieve, assesses the ‘coherence' of brain activity (timing, integration and gating) that is highly likely to be sensitive to the known brain abnormalities of autism (local over-connectivity and long distance under-connectivity) and their associated information processing deficits. The long term aim of this work is to enable early diagnosis and treatment and thus lead to better long term outcome. Funding for these 3 projects begins July 1, 2006

With a Sackler Foundation gift, the special project on the Early Developmental Role of Serotonin Transporter Function was begun in the spring of '05. Five interlocking research projects are aimed at understanding the unique roles of serotonin in the developing brain that underlie two recent clinical findings: the paradoxical increased vulnerability to depression when serotonin transporter gene function is reduced in individuals with certain gene variants, the adverse clinical responses of children and adolescents to selective serotonin receptor inhibitor (SSRI) drugs, as well as newborns exposed in utero by SSRI treatment of maternal depression.

(1) Experimental studies in mice by Drs. Gingrich and Ansorge have found a paradoxical increase in vulnerability to depression-like behaviors following both targeted serotonin transporter gene deletion and treatment of infant /juvenile mice from 3-21 days postnatal with SSRI drugs. Their most recent findings have implicated changes in serotonin neuron function in locus coeruleus, somatosensory cortex and corpus collosum in adult brains of these mice. These studies have led to the recent award of a project grant from the NIMH. (2) 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. Collection of blood DNA began May 2005 and 145 samples have been collected thus far. Our collection first concentrates on subjects who have undergone MRI. (3) Drs. Fifer and Monk are collecting data on fetal behavior and autonomic function in utero, in newborns and in early infancy following maternal treatment with SSRI's during pregnancy. (4) Dr. Raymond Stark and Marianne Garland in the department of Neonatology, have found in their pregnant baboon model, that both placental transport and fetal metabolism reduce fetal SSRI levels to well below those in the mother, while PET studies show intense levels of binding to placental serotonin transporter. This preliminary data enabled Dr. Stark to obtain an NIH “innovation” (R-21) grant to extend these studies over the next 3 years. (5) Drs. Myers and Brunelli, working in a rodent model, found increases in pain threshold, isolation distress and body weight, but no effects in motor or reflex systems in rat pups following maternal SSRI treatment. After acute treatment with SSRI's in juvenile/adolescent rat pups, significant increases in impulsive behavior were observed. An NIMH grant proposal based on these findings is currently under review. (More detailed information can be found in the sections for individual faculty members and in the addendum provided by Dr. Stark on page 31).

This spring we had a number of guest speakers and visiting scientists who gave talks and seminars at the institute. On January 12, 2006, visiting scientist Dario Maestripieri gave a research seminar entitled “ Maternal Attachment in Human and nonhuman Primates” and on March 23, 2006 Susan Anderson visited the department and gave a talk entitled “Brain Development, Stress and Antidepressants“. On May 4, 2006, Thomas O'Conner visited our department and gave us a presentation entitled “Early Experience and Human Development: Theory, Evidence and Implications ” followed by Carol Shively on May 11, 2006 with her presentation on "Socially-Induced Depression in Adult Female Cynomolgus Monkeys”. On June15, 2006 Bryan Kolb spoke at our fellows seminar on "Pre and Postnatal Factors in Brain Development and Plasticity”.

At the 2005 annual meeting of the International Society for Developmental Psychobiology, the Sackler Institute funded a symposium titled “Developing a Framework for Development” in which Dr. Hofer and two other scientists discussed their approaches to building a new general theory of development. Sackler funding also supported travel for students from Canada, Europe, New Zealand and Australia to attend this meeting.

Sponsored Symposia : At the 21^st annual meeting of the Winter Conference in Developmental Psychobiology, we co-sponsored, with the Cornell Sackler, two symposia: “Attention, Memory and Emotion” and “fMRI Studies of Language Development”.

A ‘Mini-Grant' of $6,000 was awarded to Dana Byrd, a post-doctoral fellows in our NIMH-funded training program for her current study entitled “Infant Neuro-Developmental Markers of Cerebellar-Mediated Psychiatric Disorders”

Dr. Thomas Jessell, Chief – Dissecting Interneuron Circuits That Coordinate Locomotion

Local interneuron circuits have a major role in the coordination of motor behaviors. The simple repetitive movements that underlie locomotion are generated by localized neural networks known as central pattern generators (CPGs). These circuits provide a modelsystem for studying how neuronal networks generate simple behaviors. The local interneuron circuits that contribute to the vertebrate locomotor CPG reside in the spinal cord and generate the elemental patterns of motor activity that underlie swimming and walking movements. Little is known, however, about the organization of the locomotor CPG circuit in walking mammals, in part because of the difficulty in identifying and manipulating its intrinsic interneuronal components.

One potential strategy for selective manipulation of defined sets of CPG interneurons has emerged from our studies on interneuron subtypes and their progenitors in the developing spinal cord. Like motor neurons, spinal interneurons can be distinguished by the restricted expression of homeodomain transcription factors. We have found that graded sonic hedgehog signaling specifies four cardinal sets of ventral interneurons-V0, V1, V2, and V3 neurons-each with a different intraspinal projection pattern and target connectivity. Genetic and physiological studies performed with the lab of Martyn Goulding (Salk Institute for Biological Studies) have shown that V0 interneurons have a key role in establishing left-right alternation in motor activity, and thus are critical elements of the interneuronal circuitry that directs locomotor behavior.

Yet the classical physiological descriptions of spinal interneurons indicate a greater diversity than is revealed by these four cardinal interneuron subsets. In recent studies, we have found that these major interneuron classes can be further subdivided, on the basis of transcription factor expression, into more discrete neuronal classes. The selectivity of transcription factor expression by subsets of interneurons thus provides a powerful and systematic way of assessing local interneuronal function, through
the neuronal subtype-restricted expression of toxins that kill neurons or ion channel proteins that regulate their activity. In this way, it should be possible to dissect the core logic of the interneuronal circuits that gate sensory-motor transmission and
generate the rhythm and pattern of motor output. More generally, our findings point to the utility of transcription factors as genetic entry points for the functional analysis of brain circuits and mammalian behavior.

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.

Dasen, J.S., Tice, B.C., Brenner-Morton, S. and Jessell, T.M. (2005). A Hox regulatory network establishing motor neuron pool identity and target muscle connectivity. Cell 123, 477-491.

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.

Huber, A.B., Kania, A., Tran, T.S., Gu, C., de Marco, N., Lieberam, I., Johnson, D., Jessell, T.M., Ginty, D.D., and Kolodkin, A.L. (2005). Distinct roles for secreted semaphorin signaling in spinal motor axon guidance. Neuron, 48, 949-964.

Mukouyama, Y.-S., Deneen, B., Lukaszewicz, A., Novitch, B.G., Wichterle, H., Jessell, T.M., and Anderson, D.J. (2006). Olig2⁺ neuroepithelial motor neuron progenitors are not multipotent stem cells in vivo. Proc. Natl. Acad. Sci. USA, 1551-1556.

Chen, A.I., de Nooij, J.C. and Jessell, T.M. (2006). Graded activity of transcription factor Runx3 specifies the laminar termination pattern of sensory axons in the developing spinal cord. Neuron 49, 395-408.

Chen, C.-L., Broom, D.C., Liu, Y., de Nooij, J.C., Li, Z., Cen, C., Samad, O.A., Jessell, T.M., Woolf, C.J., and Ma, Q. (2006). Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain. Neuron 49, 365-377.

Kramer, I., Sigrist, M., de Nooij, J.C., Taniuchi, I., Jessell, T.M., and Arber, S. (2006). Runx transcription factor signaling contributes to the emergence of specific sensory neuron subpopulations. Neuron 49, 379-393.

Patel, S.D., Ciatto, C., Chen, C.P., Bahana, F., Rajebhosale, M., Arkus, N., Schieren, I., Jessell, T.M., Honig, B., Price, S.R., and Shapiro, L. (2006). Crystal structures of type II cadherin ectodomains: Implications for the functional specificity of classical cadherins. Cell 124, 1255-1268.

Research support from HHMI is focused on the inductive interactions that control neural identity in the spinal cord.

Overlap: There is no direct overlap between HHMI funding and the experiments outlined in this proposal.

The aim of this project is to study the mechanisms by which the diversity of different motor neuron subpopulation are generated.

Overlap: There is no overlap between this grant and the current application.

The aim of this projects is to define the molecular cascades and gene networks involved in the determination of two defined neuronal cell types.

Overlap: There is no overlap between this grant and the current application.

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.