Abstract
The neurobiological basis of early life stress (ELS) impact on vulnerability to alcohol use disorder is not fully understood. The effect of ELS, adult ethanol consumption and single housing, on expression of stress and DNA methylation regulatory genes as well as blood corticosterone levels was investigated in the hypothalamus and pituitary of adult out-bred Wistar rats subjected to different rearing conditions. A prolonged maternal separation (MS) of 360 min (MS360) was used to study the effect of ELS, and a short MS of 15 min (MS15) was used as a control. Voluntary ethanol drinking was assessed using a two-bottle free choice paradigm to simulate human episodic drinking. The effects of single housing and ethanol were assessed in conventional animal facility rearing (AFR) conditions. Single housing in adulthood was associated with lower Crhr1 and higher Pomc expression in the pituitary, whereas ethanol drinking was associated with higher expression of Crh in the hypothalamus and Crhr1 in the pituitary, accompanied by lower corticosterone levels. As compared to controls with similar early life handling, rats exposed to ELS displayed lower expression of Pomc in the hypothalamus, and higher Dnmt1 expression in the pituitary. Voluntary ethanol drinking resulted in lower Fkbp5 expression in the pituitary and higher Crh expression in the hypothalamus, independently of rearing conditions. In rats exposed to ELS, water and ethanol drinking was associated with higher and lower corticosterone levels, respectively. The use of conventionally reared rats as control group yielded more significant results than the use of rats exposed to short MS. Positive correlations, restricted to the hypothalamus and ELS group, were observed between the expression of the hypothalamus-pituitary-adrenal receptor and the methylation-related genes. Promoter DNA methylation and expression of respective genes did not correlate suggesting that other loci are involved in transcriptional regulation. Concluding, single housing is a confounding factor to be considered in voluntary ethanol drinking paradigms. ELS and ethanol drinking in adulthood exert independent effects on hypothalamic and pituitary related genes, however, in a manner dependent on the control group used.
Highlights
Clinical studies point to early life stress (ELS) as a risk factor for psychiatric disorders, including alcohol use disorder (AUD) (Enoch, 2011)
The effect of single housing and ethanol drinking on gene expression, DNA methylation and corticosterone levels was examined in conventionally reared animal facility rearing (AFR) rats in order to understand how different housing paradigms affect the HPA axis
Voluntary ethanol intake was associated with higher Crh expression in the hypothalamus (Figure 3C), and Crhr1 expression in the pituitary (Figure 3A), in comparison with water drinking AFR rats
Summary
Clinical studies point to early life stress (ELS) as a risk factor for psychiatric disorders, including alcohol use disorder (AUD) (Enoch, 2011). The main system regulating the stress response is the hypothalamus-pituitary-adrenal (HPA) axis, a complex molecular pathway including feedback regulatory interactions between the hypothalamus, the pituitary gland, and the adrenal glands (Figure 1) (Tsigos and Chrousos, 2002). Through synergistic positive reinforcing interaction between CRH and AVP, and CRH actions on the CRH receptor (CRHR1), CRH and AVP stimulate the secretion of adrenocorticotropin hormone (ACTH) from the pituitary (Tsigos and Chrousos, 2002). Corticosterone binds to the glucocorticoid receptor (NR3C1) in the brain and inhibits the CRH release through an inhibitory feedback loop (Brunton, 2013). The FK506 Binding Protein 5 (FKBP5) by changing the conformation of the receptor complex can reduce the sensitivity of NR3C1 to corticosterone and the efficiency of the negative feedback on the HPA axis (Binder, 2009). In addition to CRH and AVP, oxytocin (OXT) moderates the release of ACTH and corticosterone by either altering sensitivity to the feedback mechanism or by decreasing CRH release (Petersson et al, 1999)
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