Early life 5-HT signaling influences neurodevelopmental trajectories and altered 5-HT signaling has been implicated in the pathogenesis of numerous stress-related psychiatric disorders. What is not clear is how extracellular 5-HT exerts its effects on nervous system development and whether the critical synthetic source of 5-HT is the brain. In Project 1: Early Brain Serotonin and its Lasting Impact on Neuronal Epigenetic Programming, Evan Deneris seeks to determine whether 5-HT synthesized specifically in hindbrain raphe neurons and secreted during fetal and early postnatal life is an important extracellular signal required for early-life epigenetic programming of serotonergic homeostasis and hypothalamic-pituitary-adrenal (HPA) axis stress circuitry. To investigate this hypothesis, Deneris seeks to apply his recently developed temporally controlled targeting approaches to knock out the gene, tryptophan hydroxylase 2, responsible for synthesis of brain 5-HT. Tph2 will be targeted during fetal and early postnatal life to reduce brain 5-HT synthesis but not synthesis of 5-HT from exogenous sources such as the placental or gut. The targeting of Tph2 at different stages of early life enables Deneris to investigate a series of questions that have been difficult or impossible to address with previous approaches aimed at determining the developmental impact of brain 5 HT synthesis.
In Specific Aim 1, Deneris will target Tph2 during fetal life and during the critical early postnatal period to investigate a potential role for 5-HT as an autocrine signal required for homeostatic maintenance of intrinsic 5-HT neuron transcriptional programs, intrinsic 5-HT neuron biochemical and physiological properties and RNA editing patterns.
In Specific Aim 2, Deneris seeks to initiate a novel study of the previously unexplored serotonergic epigenome and determine how it impacts stress-related behaviors. Tph2 targeted mice will be used to determine the impact of early-life 5-HT on long lasting programming of histone acetylation/methylation marks and DNA promoter methylation patterns in serotonergic genes and serotonergic histone deacetylase (HDAC) expression. 5-HT neuron-type targeting of HDAC2, an HDAC strongly expressed in developing 5-HT neurons, will be used to determine how alterations in the serotonergic epigenome impacts 5-HT neuron function and stress-related behaviors.
In Specific Aim 3, Deneris'team will utilize his powerful 5-HT neuron-type genetic strategies to directly test the long standing hypothesis that 5 HT produced in the brain is a developmental transducer of early life experience and is required to epigenetically program development of the HPA axis and protect against the effects of early life stress.

Public Health Relevance

Early life 5-HT signaling is thought to interact with exposure to stress related environmental factors to epigenetically program adolescent and adult emotional reactivity. Our research is aimed at determining the impact of fetal and early postnatal 5-HT, produced specifically in the brain, in the epigenetic programming of 5-HT neuron homeostasis and HPA axis development. Our hypothesis is that alterations in this layer of gene regulation is influenced by 5-HT and is involved in the pathogenesis of stress-related psychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
1P50MH096972-01
Application #
8441969
Study Section
Special Emphasis Panel (ZMH1-ERB-S (02))
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
$329,535
Indirect Cost
$14,001
Name
Vanderbilt University Medical Center
Department
Type
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

Showing the most recent 10 out of 48 publications