Prenatal stress programs neuroendocrine stress responses and affective behaviors in second generation rats in a sex-dependent manner

Natalia J Grundwald,Paula J Brunton

doi:10.1016/j.psyneuen.2015.08.010

Abstract

An adverse environment in early life is often associated with dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis and higher rates of mood disorders in adulthood. In rats, exposure to social stress during pregnancy results in hyperactive HPA axis responses to stress in the adult offspring and heightened anxiety behavior in the males, but not the females. Here we tested whether, without further intervention, the effects of prenatal stress (PNS) in the first filial generation (F1) are transmitted to the F2 generation via the maternal line. F1 control and PNS female rats were mated with control males and housed under non-stress conditions throughout pregnancy. HPA axis responses to acute stress, anxiety- and depressive-like behavior were assessed in the adult F2 offspring.ACTH and corticosterone responses to an acute stressor were markedly enhanced in F2 PNS females compared with controls. This was associated with greater corticotropin releasing hormone (Crh) mRNA expression in the paraventricular nucleus and reduced hippocampal glucocorticoid (Gr) and mineralocorticoid receptor (Mr) mRNA expression. Conversely, in the F2 PNS males, HPA axis responses to acute stress were attenuated and hippocampal Gr mRNA expression was greater compared with controls.F2 PNS males exhibited heightened anxiety-like behavior (light-dark box and elevated plus maze) compared with F2 control males. Anxiety-like behavior did not differ between F2 control and PNS females during metestrus/diestrus, however at proestrus/estrus, F2 control females displayed a reduction in anxiety-like behavior, but this effect was not observed in the F2 PNS females. Heightened anxiety in the F2 PNS males was associated with greater Crh mRNA expression in the central nucleus of the amygdala compared with controls. Moreover, Crh receptor-1 (Crhr1) mRNA expression was significantly increased, whereas Crhr2 mRNA was significantly decreased in discrete regions of the amygdala in F2 PNS males compared with controls, with no differences in the F2 females. No differences in depressive-like behavior (sucrose preference or forced swim test) were observed in either sex. In conclusion, the effects of maternal stress during pregnancy on HPA axis regulation and anxiety-like behavior can be transmitted to future generations in a sex-dependent manner. These data have implications for human neuropsychiatric disorders with developmental origins.

Highlights

Maternal exposure to stress during pregnancy can have wideranging and long-lasting effects on the offspring’s brain and behavior
In our rat model of prenatal stress, we have demonstrated that increased anxiety-like behavior in the adult male offspring is associated with increased corticotropin-releasing hormone (Crh) receptor-1 (Crhr1) and decreased Crhr2 mRNA expression in the amygdala (Brunton et al, 2011)
We describe for the first time, sex-dependent transgenerational transmission of prenatal stress effects via the maternal line on HPA axis regulation and anxiety-like behavior in rats

Summary

Introduction

Maternal exposure to stress during pregnancy can have wideranging and long-lasting effects on the offspring’s brain and behavior. The phenomenon of ‘fetal programming’ of the brain by prenatal stress is well established in rodents and is generally associated with heightened anxiety- and depressive-like behaviors and augmented stress responses (Abe et al, 2007; Brunton and Russell, 2010; Mueller and Bale, 2008; Vallee et al, 1997), though some effects are sex-dependent (for review see (Brunton, 2010; Weinstock, 2007)). The neuroendocrine stress axis, the hypothalamo-pituitary-adrenal (HPA) axis, is susceptible to fetal programming by prenatal stress (Maccari et al, 2014) and the resultant HPA axis dysfunction may underpin altered affective traits and an increased propensity for developing psychiatric disorders (Wingenfeld and Wolf, 2011). Impaired central glucocorticoid negative feedback regulation of the HPA axis may explain enhanced HPA axis responses to stress in prenatally stressed offspring and is supported by findings of reduced hippocampal expression of mRNA for mineralocorticoid receptor (Mr) in our model or both glucocorticoid receptor (Gr) and Mr in other models of prenatal stress (Maccari et al, 2014)

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