Serotonin and urocortin 1 in the dorsal raphe and Edinger–Westphal nuclei after early life stress in serotonin transporter knockout rats

Rick H.A. van der Doelen, Berit Robroch, Ilse A. Arnoldussen, Maya Schulpen, Judith R. Homberg, Tamas Kozicz

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)345-358
Number of pages14
JournalNeuroscience
Volume340
DOIs
StatePublished - Jan 6 2017
Externally publishedYes

Keywords

  • 5-HT receptor 1A
  • corticotropin-releasing factor receptor
  • depression
  • DNA methylation
  • maternal separation
  • serotonin transporter

ASJC Scopus subject areas

  • Neuroscience(all)

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