Behavioral effects of chronic adolescent stress are sustained and sexually dimorphic

Abstract

Evidence suggests that women are more susceptible to stress-related disorders than men. Animal studies demonstrate a similar female sensitivity to stress and have been used to examine the underlying neurobiology of sex-specific effects of stress. Although our understanding of the sex-specific effects of chronic adolescent stress has grown in recent years, few studies have reported the effects of adolescent stress on depressive-like behavior. The purpose of this study was to determine if a chronic mixed modality stressor (consisting of isolation, restraint, and social defeat) during adolescence (PND 37-49) resulted in differential and sustained changes in depressive-like behavior in male and female Wistar rats. Female rats exposed to chronic adolescent stress displayed decreased sucrose consumption, hyperactivity in the elevated plus maze, decreased activity in the forced swim test, and a blunted corticosterone response to an acute forced swim stress compared to controls during both adolescence (PND 48-57) and adulthood (PND 96-104). Male rats exposed to chronic adolescent stress did not manifest significant behavioral changes at either the end of adolescence or in adulthood. These data support the proposition that adolescence may be a stress sensitive period for females and exposure to stress during adolescence results in behavioral effects that persist in females. Studies investigating the sex-specific effects of chronic adolescent stress may lead to a better understanding of the sexually dimorphic incidence of depressive and anxiety disorders in humans and ultimately improve prevention and treatment strategies.

Figure 1

Animals exposed to stress during adolescence displayed abnormal weight gain. Males and females pair housed (Control) or exposed to the chronic mixed-modality stress model (Stress) were compared to determine changes in weight gain due to chronic adolescent stress. (A) Males exposed to stress during adolescence gained less body mass than controls. (B) At the adult terminal collection point, adult males exposed to stress weighed more than age-matched controls (* p < 0.05 Student’s t test). (C) Females exposed to stress during adolescence gained more weight than controls. (D) Adult females exposed to chronic adolescent stress had no changes in weight gain compared to age-matched controls. * p < 0.05 main effect due to stress, # p < 0.05 main effect due to age 2-way ANOVA. Data are presented as mean ± SEM, N = 5–9.

Figure 2

Rats were exposed to an acute stress challenge (30 minute restraint session) followed by rapid decapitation and plasma collection to determine the concentration of corticosterone. (A) Male rats exposed to the acute stress challenge showed plasma corticosterone concentrations indicative of a stress response, but no difference was observed between treatment groups (Control = pair housed controls; Stress = isolation, social defeat, and restraint). (B) In females, the acute stress challenge elicited a blunted corticosterone increase in rats that were previously exposed to chronic adolescent stress compared to the acute stress-induced corticosterone increase for controls. * p < 0.05 main effect due to stress, # p < 0.05 main effect due to age 2-way ANOVA. Data are presented as mean ± SEM, N = 5–11.

Figure 3

The effects of chronic adolescent stress on sucrose consumption were determined using a 48 hour sucrose consumption test. Rats were given free access to identical bottles which contained either tap water or 0.8% sucrose in tap water. Consumption of each liquid was measured at 24 hours and 48 hours and the values averaged for each rat. Male rats exposed to chronic adolescent stress consumed similar amounts of sucrose (A) and water (B) compared to male controls. Female rats exposed to chronic adolescent stress consumed less sucrose than control rats during adolescence and adulthood (C). Water consumption in females exposed to chronic adolescent stress was unaltered compared to female controls (D). * p < 0.05 main effect due to stress, # p < 0.05 main effect due to age 2-way ANOVA. Data are presented as mean ± SEM, N = 5–11.

Figure 4

Stress altered behavior in the elevated plus maze for females. Total arm entries (A) percent time in the open arm (B) and number of rears (C) were not altered by stress in male adolescent rats compared to same sex controls (p > 0.05). Female rats exposed to stress engaged in more total arm entries (D). Percent of time in the open arm was unaffected by chronic adolescent stress in females (E). Females exposed to chronic adolescent stress demonstrated increased rearing behavior (F) compared to same sex controls. * p < 0.05 main effect due to stress, # p < 0.05 main effect due to age 2-way ANOVA. Data are presented as mean ± SEM, N = 5–12.

Figure 5

The effects of chronic adolescent stress on behavior in the forced swim test were assessed and compared to control littermates. In adolescent and adult males, chronic adolescent stress did not alter the latency to float (A), time spent struggling (B), or diving behavior (C) compared to the control group. Females in the stress group exhibited a decreased latency to float (D) and decreased time spent struggling (E) compared to control females. Exposure to stress resulted in increased diving behavior compared to control females (F). These effects in females were observed regardless of age and the behavioral effects were sustained into adulthood for females. * p < 0.05 main effect due to stress, # p < 0.05 main effect due to age 2-way ANOVA. Data are presented as mean ± SEM, N = 5–12.