Early life environmental and pharmacological stressors result in persistent dysregulations of the serotonergic system.

Peiyan Wong,Ying Sze,Shiwei Cai,Cecilia Chin Roei Chang,Laura Jane Gray,Xiaodong Zhang

doi:10.3389/fnbeh.2015.00094

Abstract

Dysregulations in the brain serotonergic system and exposure to environmental stressors have been implicated in the development of major depressive disorder. Here, we investigate the interactions between the stress and serotonergic systems by characterizing the behavioral and biochemical effects of chronic stress applied during early-life or adulthood in wild type (WT) mice and mice with deficient tryptophan hydroxylase 2 (TPH2) function. We showed that chronic mild stress applied in adulthood did not affect the behaviors and serotonin levels of WT and TPH2 knock-in (KI) mice. Whereas, maternal separation (MS) stress increased anxiety- and depressive-like behaviors of WT mice, with no detectable behavioral changes in TPH2 KI mice. Biochemically, we found that MS WT mice had reduced brain serotonin levels, which was attributed to increased expression of monoamine oxidase A (MAO A). The increased MAO A expression was detected in MS WT mice at 4 weeks old and adulthood. No change in TPH2 expression was detected. To determine whether a pharmacological stressor, dexamethasone (Dex), will result in similar biochemical results obtained from MS, we used an in vitro system, SH-SY5Y cells, and found that Dex treatment resulted in increased MAO A expression levels. We then treated WT mice with Dex for 5 days, either during postnatal days 7–11 or adulthood. Both groups of Dex treated WT mice had reduced basal corticosterone and glucocorticoid receptors expression levels. However, only Dex treatment during PND7–11 resulted in reduced serotonin levels and increased MAO A expression. Just as with MS WT mice, TPH2 expression in PND7–11 Dex-treated WT mice was unaffected. Taken together, our findings suggest that both environmental and pharmacological stressors affect the expression of MAO A, and not TPH2, when applied during the critical postnatal period. This leads to long-lasting perturbations in the serotonergic system, and results in anxiety- and depressive-like behaviors.

Highlights

Increasing evidence suggest that stress is an important factor in the etiology of depression in humans (Hammen, 2005; Clark et al, 2007; Cohen et al, 2007; Heim and Binder, 2012)
Effects of Chronic Mild Stress Applied During Adulthood Exposure to 4 weeks of chronic unpredictable stress (CMS) during adulthood did not affect the behaviors of adult wild type (WT) and tryptophan hydroxylase 2 (TPH2) KI mice, as a two-way ANOVA for the percentage of time spent immobile in the TST only showed a significant main effect of genotype (F(1,24) = 18.4, p < 0.001; Figure 1A)
Concluding Remarks Taken together, our results showed that stressors, be it environmental or pharmacological, would have adverse effects when applied during the critical postnatal period of at least from day 1–14, or perhaps the narrower day 7–11, but not during adulthood

Summary

Introduction

Increasing evidence suggest that stress is an important factor in the etiology of depression in humans (Hammen, 2005; Clark et al, 2007; Cohen et al, 2007; Heim and Binder, 2012). The normal physiological response to stress is the activation of the hypothalamic-pituitary-adrenal (HPA) axis. This results in the production of corticosteroids that bind to and activate mineralocorticoid and glucocorticoid receptors, which give rise to physiological and homeostatic changes downstream (De Kloet, 2004; Smith and Vale, 2006). Early life stress seems to have long-lasting impacts on adult behavior This has been attributed to the fact that the brain and HPA axis of developing animals are more vulnerable to stress-induced pre-programming (Matthews, 2002; Champagne et al, 2009; Huang, 2011; Banerjee et al, 2012)

Methods

Results

Discussion

Conclusion