Conte Center

Vanderbilt / NIMH Silvio O. Conte Center for Neuroscience Research

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Vanderbilt University
465 21st Avenue South
Nashville, TN 37232
For more information,
please contact Denise Malone.

2008 Pilot Grant Recipients

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David Airey, Ph.D.

Htr2c RNA editing in hippocampus after stress

The Airey project tries to understand how genetic (G) and environmental (E) sources of variation may interact (GXE) to alter RNA editing of the serotonin 2C receptor. To understand GXE effects, it is necessary to measure a trait in genetically defined animals in two or more environments. Airey will measure Htr2c RNA editing in the hippocampus of mice with different allelic combinations of functional SNPs in Tph2 and Slc6a4 in behaviorally stressed and unstressed conditions.

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Alexandre Bonnin, Ph.D.

Consequences of early developmental disruption of 5-HT signaling in thalamocortical and dorsal Raphe axons

We propose to generate transgenic mouse lines to investigate the long term consequences of an early developmental disruption of 5-HT signaling in thalamocortical (TCA) and dorsal Raphe axons (DRA).  A microRNA-based genetic targeting will be used to reduce the endogenous expression of 5-HT1B receptor only in TPH2- and NtnG1-expressing neurons of the dorsal Raphe nuclei and dorsal thalamus respectively. These lines will be used not only to characterize the effects of decreased 5-HT signaling on the formation and guidance of TCAs and DRAs, but also to investigate long-term consequences of these developmental alterations on adult behavior.

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Ana Carneiro, Ph.D.

Discovery of Serotonin Regulatory Genes in Recombinant Inbred Mice

Alterations in whole blood 5-HT levels are associated with a variety of neuropsychiatric disorders, suggesting that conserved molecular mechanisms regulate 5-HT homeostasis in brain and blood.  Genetic variation determining components of 5-HT signaling capacity can be assessed through analysis of platelet and midbrain samples derived from Recombinant Inbred (RI) mice produced in the Collaborative Cross Initiative available at Oak Ridge National Laboratories. An analysis of both platelet and midbrain 5-HT levels in the same mouse strains will clarify the common and distinct genetic determinants of peripheral and central 5-HT homeostasis. Genes that are identified  in  this  effort will be prime targets for more extended funding from the NIH and will elucidate novel candidate genes to explore as disease risk determinants in disorders featuring disrupted 5-HT signaling. 

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Gregg Stanwood, Ph.D.

Interactions between 5-HT6, 5-HT7 and Dopamine D1 Receptors: Implications for the Pathophysiology of Neuropsychiatric Disease

Behavioral and neurobiological interactions between serotonin and dopamine neurotransmitter systems have been appreciated for some time.  These interactions may occur through a variety of cellular mechanisms.  In our pilot project, we will explore whether direct biochemical and/or molecular interactions occur between specific 5-HT and DA receptors.   Through co-immunoprecipitation experiments, we recently discovered that 5-HT6 and 5-HT7 receptors appear to be present within the D1 receptor-containing protein complexes within the brain, and that these associations may be developmentally regulated.  Such interactions provide a novel and direct mechanism by which these receptors may co-regulate each others’ signaling properties, and elucidation of these interactions might lead to a better understanding of the developmental etiology of neuropsychiatric disease.

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Chongbin Zhu, M.D., Ph.D.

Inflammatory Cytokine Modulation of Serotonin Transporters

The role of pro-inflammatory cytokines in the pathogenesis of neuropsychiatric disorders has drawn significant interest over the last decade. Presynaptic, plasmalemmal serotonin (5-HT) transporters (SERT, SLC6A4) clear extracellular 5-HT following vesicular release and thereby impact the temporal dynamics of serotonergic signaling. Inhibition of SERT with serotonin reuptake inhibitors (SSRIs) is a predominant pharmacologic treatment of these disorders. We recently used a serotonergic neuroblastoma (RN46A) as well as mouse brain synaptosomal preparations to establish the ability of interleukin-1β (IL-1β) to enhance SERT activity. Whether presynaptic IL-1 receptor communicates local and systemic inflammatory stress (and perhaps other stressors) via modulation of SERT activity remains unclear. The current proposal are to study the SERT responsiveness of IL-1R constitutive knockout mice and to develop an animal model with constitutive and conditional elimination of IL-1β signaling. The hypothesis is that elimination of IL-1 receptors will eliminate direct and peripheral IL-1β elevations (triggered by LPS) in central SERT activity. The examination of these mice will provide critical preliminary data for an enlarged study examining cytokine-5HT interactions and (2) help advance our understanding of the contribution of modulated 5HT signaling networks to depression-like traits that emerge in sickness syndrome paradigms.