Short- and long-term effects of stress during adolescence on emotionality and HPA function of animals exposed to alcohol prenatally

Abstract

Prenatal alcohol exposure (PAE) is associated with extremely high rates of psychopathologies, which may be mediated by the hypothalamic-pituitary-adrenal (HPA) dysregulation observed in exposed individuals. Of relevance, PAE carries an increased risk of exposure to stressful environments throughout life. Importantly, stressful experiences during adolescence increase vulnerability to psychopathologies. However, little is known about how adolescent stressful experiences in the context of PAE-induced HPA dysregulation may further alter the developmental trajectory and potentially contribute to the disproportionally high rate of psychopathologies observed in this population. Here we investigate the short- and long-term effects of adolescent chronic mild stress (CMS) on the emergence of anxiety-/depressive-like behaviors (open-field and forced swim test - FST) and on HPA activity (corticosterone and type 1 CRH receptor - CRHR1) in PAE male and female rats. Under non-CMS conditions, open field results indicate that PAE induced inappropriate behavior (increased time in center) in males and females, with increased activity in female adolescents, but anxiety-like behavior in adult PAE females. Conversely, FST results indicate that PAE induced depressive-like behavior in adolescent males. Exposure to CMS resulted in increased activity in adolescent males and anxiety-like behaviors in adult females. Moreover, PAE and/or CMS altered corticosterone and CRHR1 expression in the mPFC and amygdala. Together, these results suggest that PAE and adolescent CMS induce dynamic neurobehavioral alterations that manifest differently depending on the age and sex of the animal. These results highlight the importance of using both sexes as well as an ontogenetic approach when investigating the effects of environmental adversity.

Keywords: Adolescence; Anxiety-like behavior; CRHR1; Chronic mild stress; Depressive-like behavior; Prenatal alcohol exposure.

Fig. 1

Effects of PAE on the open field test in rats tested pre-CMS exposure. Circles represent mean ± SEM of the time in the center (A–B), total distance traveled (C–D), or frequency of rearing in the open field (E–F) (males: n=32–34 for all groups; females: n = 25–32 for all groups).

Fig. 2

Short- and long-term effects of PAE and adolescent CMS in the open field. Bars represent mean ± SEM of the time in the center of the open field (A–D), total distance traveled in the open field (E–H), or, frequency of rearing in the open field (I–L). † indicates a significant main effect of prenatal treatment, where all PAE animals are different from control animals; § indicates a significant main effect of CMS exposure, where all animals exposed to CMS are different from animals not exposed to CMS; for A, # indicates that PAE non-CMS is different from control non-CMS based on a priori comparisons; for E, # indicates that PAE CMS is different from PAE non-CMS based on a priori comparisons (n = 6–10 for all groups).

Fig. 3

Short- and long-term effects of PAE and adolescent CMS in the FST. Bars represent mean ± SEM of time immobile in the FST. † indicates a significant main effect of prenatal treatment, where all PAE animals are different from control animals; § indicates a significant main effect of CMS exposure, where all animals exposed to CMS are different from animals not exposed to CMS (n = 6–10 for all groups).

Fig. 4

Short- and long-term effects of PAE and adolescent CMS on amygdala CRHR1 mRNA expression. Bars represent the mean ± SEM (mean gray value) of CRHR1 mRNA expression in the basolateral (A–D) and medial (E–H) amygdala nuclei. † indicates a significant main effect of prenatal treatment, where all PAE animals are different from control animals; § indicates a significant main effect of CMS exposure, where all animals exposed to CMS are different from animals not exposed to CMS; for B, # indicates that control CMS and PAE non-CMS are different from control non-CMS based on a priori comparisons; for E, # indicates that PAE CMS is different from PAE non-CMS based on a priori comparisons; and for G and H, # indicates that PAE non-CMS is different from control non-CMS based on a priori comparisons (n = 5–10 for all groups).

Fig. 5

Short- and long-term effects of PAE and adolescent CMS on mPFC CRHR1 mRNA expression. Bars represent the mean±SEM (mean gray value) of CRHR1 mRNA expression in the anterior cingulate (A–D), prelimbic (E–H), and infralimbic (I–L) cortices. † indicates a significant main effect of prenatal treatment, where all PAE animals are different from control animals; § indicates a significant main effect of CMS exposure, where all animals exposed to CMS are different from animals not exposed to CMS; for D and F, # indicates that control CMS is different from control non-CMS based on a priori comparisons (n = 6–10 for all groups).