Genes Controlling Assembly and Function of Serotonin Systems

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Description (Provided by Applicant): This proposal seeks the creation of an NIMH Silvio O. Conte Center for Neuroscience Research at Vanderbilt University to investigate "Genes Controlling Assembly and Function of Serotonin Systems". Our central hypothesis is that functional and genetic variation in a tightly controlled network of proteins establishes modulatory capacity of the neuretransmitter serotonin (5HT) during early brain development. These variations have consequences that reverberate throughout life, impacting serotonin neuronal activity and serotonin signaling and ultimately constraining behavioral flexibility that is needed to meet the challenges of daily life. To test this hypothesis and illuminate this network, we have assembled an interdisciplinary team of established researchers at Vanderbilt University (Levitt, Blakely, Sanders-Bush, Emeson, McMahon) and Case Western Reserve (Deneris). Project 1 (Deneris) identifies embryonic and postnatal 5HT neuron transcriptomes and elucidates the serotonergic-specific function of the glucocorticoid receptor in 5HT neuron development, function and contributions to behavior. Project 2 (Levitt) explores the network of signaling pathways supporting the modulatory role of 5HT in the assembly of thalamocortical and raphe circuits. Project 3 (Blakely) investigates the protein network regulating the antidepressant-sensitive serotonin transporter (SERT) and the functional impact of altered PKG/p38 MARK signaling linked to the SERT proteome in novel mouse models. Project 4 (Sanders-Bush) elucidates the genetic underpinnings of 5HT production and signaling as well as 5HT-linked behaviors in the mouse through the analysis of quantitative traits in recombinant-inbred mouse strains. Project 5 (Emeson) utilizes novel transgenic mouse models to explore the biochemical, functional and behavioral capacities linked to editing of 5HT2C receptor RNA. Project 6 (McMahon) examines the molecular network and physiological responses specified by clock genes in both raphe neurons and raphe targets in the hypothalamus linked to the modulation of behavioral rhythms. Our program is supported by Administrative, Bioanalytical, Biobehavioral, and Bioinformatics/Biostatistics Cores as well as a significant investment of the Vanderbilt School of Medicine including staff, facilities and a pilot grant program linked to the goals of the project. Through this program, we seek to illuminate the network of genes and proteins organizing the capacity for 5HT signaling in the mouse and link this information to orthologous gene networks in humans for eventual use in translational programs that target 5HT-linked disorders by the broader neuroscience community. Using web-based tools, scientific symposia, pilot grant programs and community forums, the Vanderbilt Conte Center for Neuroscience Research will seek to disseminate its findings to the general public and excite young minds to sustain exploration in this important area of basic neurobiology underlying mental illness including anxiety, depression, obsessive-compulsive disorder, and autism as well as common and future pharmacotherapies.