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

Neuroscience. 2017 Jan 6;340:345-358. doi: 10.1016/j.neuroscience.2016.10.072. Epub 2016 Nov 5.


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.

Keywords: 5-HT receptor 1A; DNA methylation; corticotropin-releasing factor receptor; depression; maternal separation; serotonin transporter.

MeSH terms

  • Animals
  • DNA Methylation
  • Dorsal Raphe Nucleus / growth & development
  • Dorsal Raphe Nucleus / metabolism*
  • Edinger-Westphal Nucleus / growth & development
  • Edinger-Westphal Nucleus / metabolism*
  • Female
  • Male
  • Maternal Deprivation
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Ranolazine
  • Rats, Transgenic
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Receptors, Corticotropin-Releasing Hormone / metabolism
  • Receptors, Glucocorticoid / metabolism
  • Serotonin / metabolism*
  • Stress, Psychological / metabolism*
  • Urocortins / genetics
  • Urocortins / metabolism*


  • RNA, Messenger
  • RNA-Binding Proteins
  • Receptors, Corticotropin-Releasing Hormone
  • Receptors, Glucocorticoid
  • Sert1 protein, rat
  • Ucn protein, rat
  • Urocortins
  • Receptor, Serotonin, 5-HT1A
  • Serotonin
  • Ranolazine