Maternal licking regulates hippocampal glucocorticoid receptor transcription through a thyroid hormone-serotonin-NGFI-A signalling cascade

Philos Trans R Soc Lond B Biol Sci. 2012 Sep 5;367(1601):2495-510. doi: 10.1098/rstb.2012.0223.


Variations in parental care direct phenotypic development across many species. Variations in maternal pup licking/grooming (LG) in the rat regulate the development of individual differences in hypothalamic-pituitary-adrenal responses to stress. The adult offspring of mothers that show an increased frequency of pup LG have increased hippocampal glucocorticoid receptor (GR) expression and more modest pituitary-adrenal responses to stress. This parental effect is mediated by the epigenetic programming of a GR exon 1 promoter (exon 1(7)) through the binding of the transcription factor nerve growth factor-inducible factor A (NGFI-A). In this paper, we report that: (i) the association of NGFI-A with the exon 1(7) GR promoter is dynamically regulated by mother-pup interactions; (ii) this effect is mimicked by artificial tactile stimulation comparable to that provided by pup LG; (iii) that serotonin (5-HT) induces an NGFI-A-dependent increase in GR transcription in hippocampal neurons and NGFI-A overexpression is sufficient for this effect; and (iv) that thyroid hormones and 5-HT are key mediators of the effects of pup LG and tactile stimulation on NGFI-A binding to the exon 1(7) GR promoter in hippocampus. These findings suggest that pup LG directly activates 5-HT systems to initiate intracellular signalling pathways in the hippocampus that regulate GR transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal*
  • Early Growth Response Protein 1 / metabolism
  • Exons
  • Female
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Hippocampus / physiology
  • Lentivirus / genetics
  • Lentivirus / metabolism
  • Male
  • Maternal Behavior*
  • Primary Cell Culture
  • Promoter Regions, Genetic
  • Protein Binding
  • Rats
  • Rats, Long-Evans
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism*
  • Serotonin / genetics
  • Serotonin / metabolism*
  • Signal Transduction*
  • Thyroxine / genetics
  • Thyroxine / metabolism
  • Transcription, Genetic*
  • Triiodothyronine / genetics
  • Triiodothyronine / metabolism


  • Early Growth Response Protein 1
  • Egr1 protein, rat
  • Receptors, Glucocorticoid
  • Triiodothyronine
  • Serotonin
  • Thyroxine