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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
1P50MH096972-01
Application #
8287862
Study Section
Special Emphasis Panel (ZMH1-ERB-S (02))
Program Officer
Nadler, Laurie S
Project Start
2012-08-22
Project End
2017-06-30
Budget Start
2012-08-22
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$2,149,982
Indirect Cost
$513,665
Name
Vanderbilt University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Bermingham, Daniel P; Blakely, Randy D (2016) Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters. Pharmacol Rev 68:888-953
Zhang, Zhaiyi; Shen, Manli; Gresch, Paul J et al. (2016) Oligonucleotide-induced alternative splicing of serotonin 2C receptor reduces food intake. EMBO Mol Med 8:878-94
Wyler, Steven C; Spencer, W Clay; Green, Noah H et al. (2016) Pet-1 Switches Transcriptional Targets Postnatally to Regulate Maturation of Serotonin Neuron Excitability. J Neurosci 36:1758-74
Whitney, Meredith Sorenson; Shemery, Ashley M; Yaw, Alexandra M et al. (2016) Adult Brain Serotonin Deficiency Causes Hyperactivity, Circadian Disruption, and Elimination of Siestas. J Neurosci 36:9828-42
Robson, Matthew J; Zhu, Chong-Bin; Quinlan, Meagan A et al. (2016) Generation and Characterization of Mice Expressing a Conditional Allele of the Interleukin-1 Receptor Type 1. PLoS One 11:e0150068
Margolis, Kara Gross; Li, Zhishan; Stevanovic, Korey et al. (2016) Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function. J Clin Invest 126:2221-35
Brindley, Rebecca L; Bauer, Mary Beth; Blakely, Randy D et al. (2016) An interplay between the serotonin transporter (SERT) and 5-HT receptors controls stimulus-secretion coupling in sympathoadrenal chromaffin cells. Neuropharmacology 110:438-48
Wu, Hsiao-Huei; Choi, Sera; Levitt, Pat (2016) Differential patterning of genes involved in serotonin metabolism and transport in extra-embryonic tissues of the mouse. Placenta 42:74-83
Goeden, Nick; Velasquez, Juan; Arnold, Kathryn A et al. (2016) Maternal Inflammation Disrupts Fetal Neurodevelopment via Increased Placental Output of Serotonin to the Fetal Brain. J Neurosci 36:6041-9
Ellegood, J; Anagnostou, E; Babineau, B A et al. (2015) Clustering autism: using neuroanatomical differences in 26 mouse models to gain insight into the heterogeneity. Mol Psychiatry 20:118-25

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