Our proposal, "Enduring Effects of Early-Life Serotonin Signaling", explores the hypothesis that tight control of developmental determinants of serotonin (5-HT) signaling is required to achieve normal patterns of behavioral flexibility and to minimize risk for life-long neuropsychiatric disorders. To test our hypothesis, and to identify opportunities for reversal of disrupted early-life 5-HT signaling, we assemble a highly collaborative team of leading neuroscientists with experience in the development and molecular plasticity of 5-HT signaling. In Project 1, Evan Deneris tackles the support that CNS-synthesized 5-HT signaling plays in the elaboration of raphe neuron gene expression that can support stress-modulated, epigenetic programming. In Project 2, Pat Levitt builds upon his group's discovery of the placenta as a major source of forebrain 5-HT during embryonic development, Levitt's efforts assess how placental-specific disruption of 5-HT synthesis and metabolism leads to enduring effects on brain development and function and whether alterations are reversible. In Project 3, Randy Blakely elucidates the molecular and functional consequences, and potential for reversal, of an autism-associated 5-HT transporter (SERT) mutation (SERT Ala56), and how both either/or CNS and peripheral sites of expression contribute to life-long behavioral deficits, while developing novel conditional SERT mutation expression models. In Project 4, Ron Emeson brings his group's advanced understanding in 5HT2c receptor expression and signaling to bear on the timing and regional specificity of stress-dependent 5HT2c editing, elucidating their mechanisms, biochemical and behavioral consequences and possibilities for reversal. Finally, Mark Wallace leads novel education and outreach programs, extending ARRA-funded efforts to enhance community understanding of neuroscience research and mental illness and that train young scientists in the research and outreach missions of the Conte Center.

Public Health Relevance

Serotonin (5-HT) influences a wide variety of behaviors including anxiety, mood, appetite, sleep, and aggression. Disrupted 5-HT signaling is linked to anxiety, depression, suicide, schizophrenia, obsessive compulsive disorder (OCD) and autism. Increasingly, we recognize that 5-HT signaling initiates during embryonic development and involves a dynamic interaction between CNS and peripheral tissues. Our studies represent an integrated analysis, using novel transgenic mouse models, of how embryonic and early postnatal 5-HT signaling dictates enduring facets of physiology whether altered developmental 5-HT signaling leads to permanent or reversible alterations. Finally, we extend the impact of our work beyond the sphere of the academic community, enhancing the training mission and outreach efforts of the Vanderbilt Conte Center.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
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Special Emphasis Panel (ZMH1-ERB-S (02))
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Nadler, Laurie S
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Vanderbilt University Medical Center
Schools of Medicine
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Ulbricht, Randi J; Emeson, Ronald B (2014) One hundred million adenosine-to-inosine RNA editing sites: hearing through the noise. Bioessays 36:730-5
Ciarleglio, Christopher M; Resuehr, Holly E S; Axley, John C et al. (2014) Pet-1 deficiency alters the circadian clock and its temporal organization of behavior. PLoS One 9:e97412
Jackson, Chad R; Capozzi, Megan; Dai, Heng et al. (2014) Circadian perinatal photoperiod has enduring effects on retinal dopamine and visual function. J Neurosci 34:4627-33
Hood, Jennifer L; Morabito, Michael V; Martinez 3rd, Charles R et al. (2014) Reovirus-mediated induction of ADAR1 (p150) minimally alters RNA editing patterns in discrete brain regions. Mol Cell Neurosci 61:97-109
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Deneris, Evan S; Hobert, Oliver (2014) Maintenance of postmitotic neuronal cell identity. Nat Neurosci 17:899-907
Shi, Zhiao; Wang, Jing; Zhang, Bing (2013) NetGestalt: integrating multidimensional omics data over biological networks. Nat Methods 10:597-8
Wu, Hsiao-Huei; Levitt, Pat (2013) Prenatal expression of MET receptor tyrosine kinase in the fetal mouse dorsal raphe nuclei and the visceral motor/sensory brainstem. Dev Neurosci 35:1-16

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