Etienne L. Sibille Assistant Professor, Psychiatry University of Pittsburgh Phone: 412-624-0804 Fax: 412-624-9910 Email: sibilleel@upmc.edu W1656 Biomedical Science Tower

Ph.D., Cornell University Medical College Research Interests Major depression is believed to result from a complex polygenic mechanism with contributing environmental factors, but no gene mutations or specific molecular and/or neural disruptions have been identified as causative factors. To address past difficulties at identifying biological markers, we are applying genome-wide investigational strategies that are aimed at reducing the complexity of the disease in order to explain part of its variance and initiate a molecular characterization of putative subtypes, or molecular endophenotypes of depression. These studies are conducted in the human postmortem brain. Novel leads are expected to generate hypotheses that will be tested in genetic mouse models. Aging leads to a variety of morphological and functional changes in the brain, and is associated with increased risk for specific psychiatric, neurological and cognitive disorders. However, the mechanisms underlying normal aging likely differ from those associated with pathological conditions and are still poorly understood. We have previously identified a robust “molecular signature” of aging in the human brain, consisting of life-long progressive changes in expression levels of several hundred genes. To identify genes and pathways that correspond to particular behavioral, cognitive or physiological characteristics of aging, we are investigating behavioral and genomic correlates of aging in the context of targeted genetic manipulations in the mouse, with a focus on the serotonin neurotransmitter system. Trainees in the laboratory have the opportunity to participate in a number of research projects investigating relationships between genes and behavior, in the context of depression and aging. To achieve these goals, we combine genetic, genomic, molecular biology, behavioral and bioinformatic approaches. Specific projects may include: identification of mechanisms of aging in the CNS that are common between mice and humans, characterization of the role of serotonin receptors in aging and mood disorders, genetic and pharmacological modeling in the mouse of aspects of human mood disorders, bioinformatic analysis of gene co-expression and transcription factor networks, regional and cellular characterization of altered gene and protein expression in the mammalian brain (human and mouse). Recent Publications E. Sibille1,4,†, J. Su1, S. Leman6, A.M. Le Guisquet6, Y. Ibarguen-Vargas6, J. Joeyen-Waldorf1, C.A. Glorioso4, G. Tseng2, M. Pezzone3, R. Hen5 and C. Belzung6, †. Reduced Longevity and Anticipated Brain Molecular Aging in Mice Lacking the Serotonin-1B Receptor. Submitted. Erraji-Benchekroun, L., Underwood, M.D., Arango, V.,Galfalvy, H., Pavlidis, P., Smyrniotopoulos, P., Mann, J.J., and E. Sibille. Molecular aging in human prefrontal cortex is selective and continuous throughout adult life. Biological Psychiatry (2005) In press. Pavlidis, P., Qin, J., V.Arango, V., Mann, J.J., and E. Sibille. Statistical analysis of Gene Ontology classes as a tool for understanding gene expression changes in the aging human brain. Neurochemical Research (2004) 29(6):1213-22. Sibille E., V. Arango, H. Galfalvy, P.Pavlidis, S.Ellis, and J.J. Mann. Genomic analysis of depression and suicide in human prefrontal cortex. Neuropsychopharmacology (2003) 29(2):351-61. Sibille, E. and R.Hen. Combining Genetic and Genomic Approaches to Study Mood Disorder. European Neuropsychopharmacology (2001) 11:413-21. Sibille, E., Pavlides, C., Benke, D. and M.Toth. Genetic inactivation of the 5-HT1A receptor results in downregulation of major GABAA receptor  subunits, reduction of GABAA receptor binding, and benzodiazepine-resistant anxiety. Journal of Neuroscience (2000) 20:2758-2765.