The impact of social stress during adolescence or adulthood and coping strategy on cognitive function of female rats

Abstract

The age of stressor exposure can determine its neurobehavioral impact. For example, exposure of adolescent male rats to resident-intruder stress impairs cognitive flexibility in adulthood. The current study examined the impact of this stressor in female rats. Rats were exposed to resident-intruder stress during early adolescence (EA), mid-adolescence (MA) or adulthood (Adult). They were tested in an operant strategy-shifting task for side discrimination (SD), reversal learning (REV) and strategy set-shifting (SHIFT) the following week. Performance varied with age, stress and coping style. MA and EA rats performed SD and SHIFT better than other ages, respectively. Social stress impaired performance in rats depending on their coping strategy as determined by a short (SL) or long (LL) latency to become subordinate. SL rats were impaired in SD and REV, whereas EA-LL rats were impaired in SHIFT. These impairing effects of female adolescent stress did not endure into adulthood. Strategy set-shifting performance for female adolescents was positively correlated with medial prefrontal cortex (mPFC) activation as indicated by c-fos expression suggesting that this region is engaged during task performance. This contrasts with the inverse relationship between these indices reported for male adolescent rats. Together, the results demonstrate that social stress produces cognitive impairments for female rats that depend on age and coping style but unlike males, the impairing effects of female adolescent social stress are immediate and do not endure into adulthood. Sex differences in the impact of adolescent social stress on cognition may reflect differences in mPFC engagement during the task.

Keywords: Development; Prefrontal cortex; Resident-intruder; Reversal learning; Sex difference; Strategy shifting.

Figure 1

Effect of age, stress and coping strategy on task performance. A) Performance of rats that were exposed to repeated social stress or control manipulation and trained in the operant set shifting task during the week following the last stress/control manipulation. The abscissa indicates task stages of side discrimination (SD), reversal learning (REV) and strategy set-shifting (SHIFT). The ordinate indicates trials to reach criterion. Each bar is the mean of 19 control and 14 stressed EA rats, 18 control and 14 stressed MA rats and 14 control and 13 stressed Adult rats. Vertical lines are S.E.M. @ p<0.05, effect of age; *p<0.05, effect of stress. B) Performance of rats that were exposed to repeated social stress or control manipulation during EA or MA and trained in the operant set shifting task as adults. The abscissa and ordinate are as in A. Each bar is the mean of 7 controls and 7 stressed EA rats and 7 control and 5 stressed MA rats. There were no effects of age or stress on performance at any task stage. C) Performance of rats based on latency clusters. The abscissa and ordinate are as in A. Each bar is the mean of 19 control, 7 SL and 7 LL EA rats, 18 control, 9 SL and 5 LL MA rats and 14 control, 9 SL and 4 LL Adult rats. @ p<0.05, effect of age; *p<0.05, effect of latency cluster, **p<0.005, effect of latency cluster; # p<0.05. D) Correlation between defeat latency and trials to reach criterion in the REV task. Each point represents an individual Adult, EA or MA rat as indicated by the legend. R²=0.15, p<0.02.

Figure 2

Effect of stress and coping strategy on error type. Bars indicate the number of perseverative (P) and regressive (R) errors made by control, SL or LL rats of different age groups during REV. Vertical lines indicate S.E.M., *p<0.05 compared to both control and SL. #p<0.05 compared to SL.

Figure 3

Effect of social stress and coping strategy on PFC c-fos. A) Representative photomicrographs of the mPFC from EA, MA and Adult rats showing c-fos immunoreactive profiles. B) Mean number of c-fos profiles in the PFC of EA, MA and Adult rats that had social stress or control manipulation. The ordinate indicates the mean number of c-fos profiles. Each bar represents the mean of 6 control and 6 stressed EA rats, 7 control and 5 stressed MA rats and 6 control and 5 stressed Adult rats. Vertical lines indicate S.E.M. *p<0.0005 compared to other ages. C) Correlation between c-fos profiles in the PFC and performance in the SHIFT stage. The abscissa indicates the number of PFC c-fos profiles and the ordinate indicates trials to criterion for the strategy set-shifting stage. Each point represents an individual EA, MA or Adult rat as indicated by the legend. R²=0.15, p<0.02.

Figure 4

Effect of social stress on ERK phosphorylation in the PFC. A shows representative Western blots from EA, MA or Adult rats. ERK represented in red fluorescence and P-ERK in green. ERK and P-ERK are detected at the same molecular weight (near 42,44 kD) and simultaneous visualization of both appears as one yellow blot. In order to distinguish both proteins in the figure ERK and P-ERK bands were imaged separately and the P-ERK image was placed above the line of ERK bands and separated by a white line. B) Quantification of P-ERK:ERK ratio. The ordinate indicates the ratio of P-ERK:ERK. Each bar is the mean of 10 control and 12 stressed EA rats, 4 control and 4 stressed MA rats and 9 control and 8 stressed Adult rats. *p<0.005 compared to MA and Adult rats.

Figure 5

Inverse correlation between reversal learning and strategy shifting. The abscissa indicates the number of trials to reach criterion during REV and the ordinate indicates the number of trials to reach criterion in the SHIFT stage. Each point represents an individual Adult, EA or MA rat as indicated in the legend.