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

Abstract

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.

The impact of early postnatal environmental enrichment on maternal care and offspring behaviour following weaning

“…Therefore maternal care provided by the dam determines the early postnatal environment of the pups (Hellstrom et al 2012). The quantity of pup licking/grooming has been suggested as a reliable measure to assess maternal care (Champagne et al 2003;Hellstrom et al 2012); increased licking/grooming of pups is associated with a reduction in neuroendocrine responses to stress in rat offspring (Liu et al 1997), and this altered response may persist throughout life (Caldji et al 1998).…”

The methylated-DNA binding protein MBD2 enhances NGFI-A (egr-1)-mediated transcriptional activation of the glucocorticoid receptor

“…Chromatin immunoprecipitation (ChIP) assays [21] were performed using the ChIP assay kit protocol (06-599, Upstate Biotechnology), as previously described [10,12,13,22]. Primary antibodies used at empirically optimized concentrations included CREB-binding protein (CBP; Cell Signalling 4772; Beverly, MA), MBD2/3 (Upstate Biotechnology 07-199), and NGFI-A (Rockland Immunochemicals 600-401-693, Gilbertsville, PA).…”

“…Hippocampal cell cultures from ED 19-20 Long-Evans rat fetuses were prepared as previously described [10,23,24]. Two days after seeding, uridine (20 mM) and 5-fluorodeoxyuridine (20 mM) were added to the medium to prevent proliferation of glial cells.…”

“…(b) Role of MBD2 in 5-HT-induced glucocorticoid receptor expression 5-HT binds to 5-HT 7 receptors to activate NGFI-A expression and enhance GR transcription in hippocampal neurons [7,10,13,24,27,28]. We first examined the effect of 5-HT treatment on hippocampal MBD2 expression using primary hippocampal neuronal cultures.…”

“…In vivo and in vitro studies suggest that maternal LG increases GR gene expression in the offspring through a thyroid hormone-dependent increase in 5-hydroxytryptamine (serotonin, 5-HT) activity at 5-HT 7 receptors, and the subsequent activation of cyclic adenosine 3 0 ,5 0 monophosphate (cAMP) and cAMP-dependent protein kinase A activity, and are accompanied by an increased hippocampal expression of a nerve growth factor-inducible protein A (NGFI-A) transcription factor [7 -10]. NGFI-A overexpression increases GR expression at the level of both mRNA and protein in cultured hippocampal neurons [10].…”