Prenatal alcohol exposure and chronic mild stress differentially alter depressive- and anxiety-like behaviors in male and female offspring

Abstract

Background: Fetal Alcohol Spectrum Disorder (FASD) is associated with numerous neurobehavioral alterations, as well as disabilities in a number of domains, including a high incidence of depression and anxiety disorders. Prenatal alcohol exposure (PAE) also alters hypothalamic-pituitary-adrenal (HPA) function, resulting in increased responsiveness to stressors and HPA dysregulation in adulthood. Interestingly, data suggest that pre-existing HPA abnormalities may be a major contributory factor to some forms of depression, particularly when an individual is exposed to stressors later in life. We tested the hypothesis that exposure to stressors in adulthood may unmask an increased vulnerability to depressive- and anxiety-like behaviors in PAE animals.

Methods: Male and female offspring from prenatal alcohol (PAE), pair-fed (PF), and ad libitum-fed control (C) treatment groups were tested in adulthood. Animals were exposed to 10 consecutive days of chronic mild stress (CMS), and assessed in a battery of well-validated tasks sensitive to differences in depressive- and/or anxiety-like behaviors.

Results: We report here that the combination of PAE and CMS in adulthood increases depressive- and anxiety-like behaviors in a sexually dimorphic manner. PAE males showed impaired hedonic responsivity (sucrose contrast test), locomotor hyperactivity (open field), and alterations in affiliative and nonaffiliative social behaviors (social interaction test) compared to control males. By contrast, PAE and, to a lesser extent, PF, females showed greater levels of "behavioral despair" in the forced swim test, and PAE females showed altered behavior in the final 5 minutes of the social interaction test compared to control females.

Conclusions: These data support the possibility that stress may be a mediating or contributing factor in the psychopathologies reported in FASD populations.

Fig. 1

Experimental design.

Fig. 2

Effects of prenatal group and sex on plasma corticosterone (ng / ml). Data represent mean basal corticosterone (ng / ml) before (Day 1) and on the last day (Day 10) of CMS exposure in (A) males and (B) females. * denotes significantly different from PF and C animals. # denotes significantly different from PAE and C rats. & denotes significantly different between Days among PAE rats. n’s = 8 to 10 for each condition; p’s < 0.05.

Fig. 3

Effects of prenatal group and sex on behavior in the sucrose contrast test. Data represent the amount of sucrose consumed by body weight on Days 4 (“Pre”; 2.1% sucrose concentration) and 5 (“Post”; 15% sucrose concentration) in (A) males and (B) females exposed to chronic mild stress.* denotes a significant difference in consumption across days for all prenatal groups. & denotes significant difference in consumption across days for PF and C. # indicates that precontrast, PAE males consumed significantly more sucrose than PF and C males. n’s = 8 to 10 for each condition; p’s < 0.05.

Fig. 4

Effects of prenatal group and sex on duration of immobility in the forced swim test. Data represent the time (s) spent immobile in (A) males and (B) females on Day 1 and Day 2. * denotes PAE significantly different from C animals. # denotes PAE and PF significantly different from C animals. & denotes that C males significantly more immobile than C females. n’s = 8 to 10 for each condition; p’s < 0.05.

Fig. 5

Effects of prenatal group and sex on locomotor activity in the open field. Data represent the total distance traveled (cm) in (A) males and (B) females during a 5-minute testing period across 3 consecutive days of testing. # denotes significantly different from C animals. n’s = 8 to 10 for each condition; p’s < 0.05.

Fig. 6

Effects of prenatal group and sex on the duration of behaviors in the social interaction test. Data represent the duration(s) of affiliative and nonaffiliative behaviors among (A) males and (B) females in the first (0 to 5 minutes) and third (11 to 15 minutes) intervals of a 15-minute test. * denotes significantly different from PF and C animals. n’s = 8 to 10 for each condition; p’s < 0.05.

Fig. 7

Effects of prenatal group and sex on the frequency of behaviors in the social interaction test. Data represent the frequency of affiliative and nonaffiliative behaviors among (A) males and (B) females in the first (0 to 5 minutes) and third (11 to 15 minutes) intervals of a 15-minute test. & denotes significantly different than affiliative behaviors in the third interval. n’s = 8 to 10 for each condition; p’s < 0.05.