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 #
5P50MH096972-02
Application #
8535200
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
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$2,017,798
Indirect Cost
$460,193
Name
Vanderbilt University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Robson, Matthew J; Quinlan, Meagan A; Margolis, Kara Gross et al. (2018) p38? MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse. Proc Natl Acad Sci U S A 115:E10245-E10254
Brindley, Rebecca L; Bauer, Mary Beth; Walker, L Anne et al. (2018) Adrenal serotonin derives from accumulation by the antidepressant-sensitive serotonin transporter. Pharmacol Res :
Knoll, A T; Jiang, K; Levitt, P (2018) Quantitative trait locus mapping and analysis of heritable variation in affiliative social behavior and co-occurring traits. Genes Brain Behav 17:e12431
Deneris, Evan; Gaspar, Patricia (2018) Serotonin neuron development: shaping molecular and structural identities. Wiley Interdiscip Rev Dev Biol 7:
Stewart, Adele; Davis, Gwynne L; Gresch, Paul J et al. (2018) Serotonin transporter inhibition and 5-HT2C receptor activation drive loss of cocaine-induced locomotor activation in DAT Val559 mice. Neuropsychopharmacology :
Mayer, Felix P; Schmid, Diethart; Owens, W Anthony et al. (2018) An unsuspected role for organic cation transporter 3 in the actions of amphetamine. Neuropsychopharmacology 43:2408-2417
Ritter, K Elaine; Wang, Zunyi; Vezina, Chad M et al. (2017) Serotonin Receptor 5-HT3A Affects Development of Bladder Innervation and Urinary Bladder Function. Front Neurosci 11:690
Kast, Ryan J; Wu, Hsiao-Huei; Williams, Piper et al. (2017) Specific Connectivity and Unique Molecular Identity of MET Receptor Tyrosine Kinase Expressing Serotonergic Neurons in the Caudal Dorsal Raphe Nuclei. ACS Chem Neurosci 8:1053-1064
O'Neil, Richard T; Wang, Xiaojing; Morabito, Michael V et al. (2017) Comparative analysis of A-to-I editing in human and non-human primate brains reveals conserved patterns and context-dependent regulation of RNA editing. Mol Brain 10:11
Sharif, N F; Korade, Z; Porter, N A et al. (2017) Oxidative stress, serotonergic changes and decreased ultrasonic vocalizations in a mouse model of Smith-Lemli-Opitz syndrome. Genes Brain Behav 16:619-626

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