The candidate (Mark Alter) completed M.D./Ph.D. training in the Medical Scientist Training Program (MSTP) at the University of Pittsburgh in 1999 with a Ph. D. in immunology. He completed residency training in the """"""""Triple Board"""""""" program at Brown University with combined training in pediatrics, psychiatry, and child &adolescent psychiatry in 2004. Recent research in the laboratory of Rene Hen at the Center for Neurobiology &Behavior at Columbia University has stimulated interest in the neurobiological mechanisms underlying individual differences in emotional development and their relationship to childhood emotional disorders. Dr. Alter is particularly interested in epigenetic influences on gene expression and behavior. Epigenetics refers to mechanisms outside (""""""""epi"""""""") the actual genetic sequence that influence gene regulation. Epigenetic influences are thought to be strongest during early development and in rodents have been shown to be impacted by differences in maternal care. Thus, understanding these influences is of direct relevance to emotional disorders in children. To study the relationship of epigenetics to emotional development, Dr. Alter has used genetically identical animals to examine individual variability in emotional behavior. By studying genetically identical animals he brings focus on epigenetic influences. Using this model, he sees stable differences in emotional behavior between individual genetically identical animals. He implicates epigenetic influences on gene expression and emotion by demonstrating that by using only the pattern of gene expression in the hippocampus, a brain region important in emotional regulation, he is able to correctly predict emotional differences of individual animals. In this proposal, Dr. Alter seeks to better understand the relationship of his findings to individual variability in emotional behavior. Specifically he plans to 1) characterize individual variability in emotional behavior across the lifespan in genetically identical animals 2) relate gene expression patterns in the hippocampus to differences in emotional behavior and 3) examine epigenetic programming of genes related to emotional development. This research will likely lead to improved treatment, diagnostics, and identification of children at risk for psychopathology. Completion of his aims will require intimate knowledge of 1) mouse behavior and 2) genomics, areas in which Dr. Alter has limited background. The proposed plan provides Dr. Alter with a period o f mentored research to gain expertise in these areas. Expertise gained during this mentored period will provide Dr. Alter with the experience necessary to attain his long-term goal of developing an independent, multidisciplinary research program with an emphasis on translating increased understanding of epigenetic mechanisms related to emotional development into improved diagnostics and novel therapies for childhood emotional disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Clinical Investigator Award (CIA) (K08)
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Molecular Neurogenetics Study Section (MNG)
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Rosemond, Erica K
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University of Pennsylvania
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Samuels, Benjamin A; Leonardo, E David; Dranovsky, Alex et al. (2014) Global state measures of the dentate gyrus gene expression system predict antidepressant-sensitive behaviors. PLoS One 9:e85136
Nesbitt, Addie May I; McCurdy, Richard D; Bryant, Sharell M et al. (2014) Total levels of hippocampal histone acetylation predict normal variability in mouse behavior. PLoS One 9:e94224
Alter, Mark D (2013) Studying gene expression system regulation at the program level. PLoS One 8:e61324
Gandal, Michael J; Nesbitt, Addie May; McCurdy, Richard M et al. (2012) Measuring the maturity of the fast-spiking interneuron transcriptional program in autism, schizophrenia, and bipolar disorder. PLoS One 7:e41215
Alter, Mark D; Kharkar, Rutwik; Ramsey, Keri E et al. (2011) Autism and increased paternal age related changes in global levels of gene expression regulation. PLoS One 6:e16715
Alter, Mark D; Gilani, Ahmed I; Champagne, Frances A et al. (2009) Paternal transmission of complex phenotypes in inbred mice. Biol Psychiatry 66:1061-6
Alter, Mark D; Hen, Rene (2009) Is there a genomic tone? Implications for understanding development, adaptation and treatment. Dev Neurosci 31:351-7