This project is aimed at investigating the genetic mechanisms that act across lifespan to regulate 5-HT system function and determine how these mechanisms impact postnatal 5-HT modulated behaviors. The basis of these studies is the discovery of a Pet-1 dependent transcriptional program that regulates 5-HT-modulated behaviors and newly developed 5-HT neuron-specific and temporally controlled conditional targeting approaches. Our approaches have enabled an investigation of 5-HT neuron-specific transcriptional mechanisms in purified 5-HT neurons and functional studies of serotonergic genes at any stage of life with reliable spatial and temporal control of gene ablation. Many questions remain unanswered about the mechanisms through which Pet-1 controls 5-HT neuron development and ultimately 5-HT modulated behaviors. For example, although our previous studies have shown that Pet-1 is needed for the coordinate induction of genes (Tph2, AADC, Sert, Vmat2, Htr1A, Htr1B, MaoB) directly responsible for 5-HT synthesis, reuptake, autoinhibition and metabolism it is not known whether Pet-1's function is restricted to these genes. It is also not known whether Pet-1 regulates different sets of genes in different populations of 5-HT neurons and whether it is solely an activator of serotonergic gene expression or whether it, perhaps, also simultaneously represses expression of some genes during the development of 5-HT neurons. Although we have shown that Pet-1 is needed in adult 5-HT neurons for maintenance of Tph2 and Sert the critical periods for Pet-1-directed transcription in essential 5-HT neuron functions such as 5-HT neuron firing and 5-HT modulated behaviors are poorly understood. We will investigate whether transcriptional regulation by Pet-1 is required for control of 5-HT signaling at different stages of life including the neonatal to adolescent period. The neonatal period (P5-P20) is a period in which 5-HT signaling has been shown to be critical for normal adult emotional behaviors while the adolescent period coincides with the onset of 5-HT related disorders such as schizophrenia and stress-related emotional disturbances. Finally, the importance of 5-HT synthesis in neonatal and adult 5-HT neurons for 5-HT modulated behaviors has never been adequately addressed because of the lack of suitable methods. We will use our new temporal conditional targeting approaches to test specific hypotheses about the early postnatal and adulthood requirements for 5-HT synthesis in the behaving mouse. Together, our new aims will investigate the downstream network of Pet-1 regulated genes, the requirements for intrinsic transcriptional mechanisms, and 5-HT synthesis at malleable developmental transition periods that are known to be critical periods for the determination of mental health relevant behaviors.

Public Health Relevance

This research project will continue to elucidate the Pet-1 directed transcriptional regulatory mechanisms that control serotonin system function across life span. We will determine the Pet-1 downstream network and the temporal requirements for Pet-1 directed transcription at neonatal, adolescent and adult stages in the regulation of psychiatric disease relevant behaviors. We will also implement a new targeting approach to determine the importance of neonatal and adult serotonin synthesis in behavior and physiology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH062723-12
Application #
8291975
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Panchision, David M
Project Start
2000-12-01
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
12
Fiscal Year
2012
Total Cost
$392,500
Indirect Cost
$142,500
Name
Case Western Reserve University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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
Issler, Orna; Haramati, Sharon; Paul, Evan D et al. (2014) MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity. Neuron 83:344-60
Spoida, Katharina; Masseck, Olivia A; Deneris, Evan S et al. (2014) Gq/5-HT2c receptor signals activate a local GABAergic inhibitory feedback circuit to modulate serotonergic firing and anxiety in mice. Proc Natl Acad Sci U S A 111:6479-84
Deneris, Evan S; Hobert, Oliver (2014) Maintenance of postmitotic neuronal cell identity. Nat Neurosci 17:899-907
Deneris, Evan S; Wyler, Steven C (2012) Serotonergic transcriptional networks and potential importance to mental health. Nat Neurosci 15:519-27
Hawthorne, Alicia L; Hu, Hongmei; Kundu, Bornali et al. (2011) The unusual response of serotonergic neurons after CNS Injury: lack of axonal dieback and enhanced sprouting within the inhibitory environment of the glial scar. J Neurosci 31:5605-16
Deneris, E S (2011) Molecular genetics of mouse serotonin neurons across the lifespan. Neuroscience 197:17-27
Oh, Eugene; Maejima, Takashi; Liu, Chen et al. (2010) Substitution of 5-HT1A receptor signaling by a light-activated G protein-coupled receptor. J Biol Chem 285:30825-36
Liu, Chen; Maejima, Takashi; Wyler, Steven C et al. (2010) Pet-1 is required across different stages of life to regulate serotonergic function. Nat Neurosci 13:1190-8
Hawthorne, Alicia L; Wylie, Christi J; Landmesser, Lynn T et al. (2010) Serotonergic neurons migrate radially through the neuroepithelium by dynamin-mediated somal translocation. J Neurosci 30:420-30

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