Early life adversity and serotonin transporter gene variation interact at the level of the adrenal gland to affect the adult hypothalamo-pituitary-adrenal axis

Abstract

The short allelic variant of the serotonin transporter (5-HTT) promoter-linked polymorphic region (5-HTTLPR) has been associated with the etiology of major depression by interaction with early life stress (ELS). Furthermore, 5-HTTLPR has been associated with abnormal functioning of the stress-responsive hypothalamo-pituitary-adrenal (HPA) axis. Here, we examined if, and at what level, the HPA-axis is affected in an animal model for ELS × 5-HTTLPR interactions. Heterozygous and homozygous 5-HTT knockout rats and their wild-type littermates were exposed daily at postnatal days 2–14 to 3 h of maternal separation. When grown to adulthood, plasma levels of adrenocorticotropic hormone (ACTH), and the major rat glucocorticoid, corticosterone (CORT), were measured. Furthermore, the gene expression of key HPA-axis players at the level of the hypothalamus, pituitary and adrenal glands was assessed. No 5-HTT genotype × ELS interaction effects on gene expression were observed at the level of the hypothalamus or pituitary. However, we found significant 5-HTT genotype × ELS interaction effects for plasma CORT levels and adrenal mRNA levels of the ACTH receptor, such that 5-HTT deficiency was associated under control conditions with increased, but after ELS with decreased basal HPA-axis activity. With the use of an in vitro adrenal assay, naïve 5-HTT knockout rats were furthermore shown to display increased adrenal ACTH sensitivity. Therefore, we conclude that basal HPA-axis activity is affected by the interaction of 5-HTT genotype and ELS, and is programmed, within the axis itself, predominantly at the level of the adrenal gland. This study therefore emphasizes the importance of the adrenal gland for HPA-related psychiatric disorders.

Both maternal care received and genotype influence stress‐related phenotype in female rats

“…However, genotypic variation did not replicate in Study 2, though genetic variation in 5htt was also associated with differential levels of USVs in early life, and differential levels of locomotor activity in adulthood. These results are perhaps not surprising given that 5htt genotype has been shown to affect GR, MR, FKBP5 activity as well as DNA methylation in the CRF gene, all thought to underlie the expression of anxiety behavior (van der Doelen, Calabrese, et al, ; van der Doelen, Deschamps, et al, ; ). Taken together, our findings suggest that the influence of higher levels of maternal care received on offspring anxiety behavior from early life throughout adulthood depend upon 5htt genotype.…”

The Serotonin Transporter and Early Life Stress: Translational Perspectives

“…The basal level (non-stressed) of SERT +/− rodents were compared with the basal level of SERT +/+ rodents (C). The data from stressed groups were compared with the basal levels in same genotype animals .*, these studies all included SERT −/− rats to determine an interaction effect.1, Bartolomucci et al (2010);2, Bodden et al (2015);3, van der Doelen et al (2014a);4, van der Doelen et al (2015);5, van den Hove et al (2011);6, Jansen et al (2010);7, Jiang et al (2009);8, Li et al (1999);9 , Tjurmina et al (2002) .…”

Interacting Neural Processes of Feeding, Hyperactivity, Stress, Reward, and the Utility of the Activity-Based Anorexia Model of Anorexia Nervosa

“…240,261 In animals, early-life stress is recapitulated by early weaning, single housing, or severe food restriction, and the addition of these stressors to the ABA paradigm leads more animals to develop ABA. 262 …”