Serotonin and urocortin 1 in the dorsal raphe and Edinger-Westphal nuclei after early life stress in serotonin transporter knockout rats.
The interaction of early life stress (ELS) and the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) has been associated with increased risk to develop depression in later life. We have used the maternal separation paradigm as a model for ELS exposure in homozygous and heterozygous 5-HTT knockout rats and measured urocortin 1 (Ucn1) mRNA and/or protein levels, Ucn1 DNA methylation, as well as 5-HT innervation in the centrally projecting Edinger-Westphal (EWcp) and dorsal raphe (DR) nuclei, both implicated in the regulation of stress response. We found that ELS and 5-HTT genotype increased the number of 5-HT neurons in specific DR subdivisions, and that 5-HTT knockout rats showed decreased 5-HT innervation of EWcp-Ucn1 neurons. Furthermore, ELS was associated with increased DNA methylation of the promoter region of the Ucn1 gene and increased expression of 5-HT receptor 1A in the EWcp. In contrast, 5-HTT deficiency was associated with site-specific alterations in DNA methylation of the Ucn1 promoter, and heterozygous 5-HTT knockout rats showed decreased expression of CRF receptor 1 in the EWcp. Together, our findings extend the existing literature on the relationship between EWcp-Ucn1 and DR-5-HT neurons. These observations will further our understanding on their potential contribution to mediate affect as a function of ELS interacting with 5-HTTLPR.
Department of Anatomy, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Rick H A
RHA
van der Doelen
Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Berit
B
Robroch
Department of Anatomy, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Ilse A
IA
Arnoldussen
Department of Anatomy, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Maya
M
Schulpen
Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Judith R
JR
Homberg
Department of Anatomy, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Pediatrics, Hayward Genetics Center, Tulane University, New Orleans, LA, USA. Electronic address: Tamas.Kozicz@radboudumc.nl.
Tamás
T
Kozicz
D000818:Animals; D019175:DNA Methylation; D065847:Dorsal Raphe Nucleus / Q000254:growth & development / Q000378:metabolism*; D065839:Edinger-Westphal Nucleus / Q000254:growth & development / Q000378:metabolism*; D005260:Female; D008297:Male; D008426:Maternal Deprivation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000069458:Ranolazine; D055647:Rats, Transgenic; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D013315:Stress, Psychological / Q000378:metabolism*; D054832:Urocortins / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D018019:Receptors, Corticotropin-Releasing Hormone; D011965:Receptors, Glucocorticoid; C482440:Sert1 protein, rat; C000607145:Ucn protein, rat; D054832:Urocortins; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D000069458:Ranolazine
5-HT receptor 1A; DNA methylation; corticotropin-releasing factor receptor; depression; maternal separation; serotonin transporter