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.

Stress-related psychiatric diseases are nearly twice as prevalent in women compared to men. We recently showed in male rats that the resident-intruder model of social stress differentially engages stress-related circuitry that regulates norepinephrine-containing neurons of the locus coeruleus (LC) depending on coping strategy as determined by the latency to assume a defeat posture. Here, we determined whether this social stress had similar effects in female rats. LC afferents were retrogradely labeled with Fluorogold (FG) and rats had one or five daily exposures to an aggressive resident. Sections through the nucleus paragigantocellularis (PGi), a source of enkephalin (ENK) afferents to the LC, and central nucleus of the amygdala (CeA), a source of corticotropin-releasing factor (CRF) afferents to the LC, were processed for immunocytochemical detection of c-fos, a marker of neuronal activity, FG and ENK or CRF. Like male rats, female rats defeated with a relatively short latency (SL) in response to a single resident-intruder exposure and showed significant c-fos activation of LC neurons, PGi-ENK LC afferents and CeA-CRF LC afferents. With repeated exposure, some rats exhibited a long latency to defeat (LL). LC neurons and CeA-CRF LC afferents were activated in SL rats compared to control and LL whereas PGi-ENK LC afferents were not. Conversely, in LL rats, PGi-ENK LC and CeA-CRF LC afferents were activated compared to controls but not LC neurons. CRF type 1 receptor (CRF1) and μopioid receptor (MOR) expression levels in LC were decreased in LL rats. Lastly, electron microscopy showed a relative increase in MOR on the plasma membrane of LL rats and a relative increase in CRF1 on the plasma membrane of SL rats. Together, these results suggest that as is the case for males, social stress engages divergent circuitry to regulate the LC in female rats depending on coping strategy, with a bias towards CRF influence in more subordinate rats and opioid influence in less subordinate rats.

Background

The research goal was to determine whether social stress differentially impacts on behavior and brain physiology during critical windows in adolescent development. Early adolescent (EA), mid‐adolescent (MA) and adult rats were exposed to 7 days of a social stressor, the resident‐intruder paradigm. Social stress had divergent effects on behavior in EA and adult rats, promoting active coping behaviors in EA rats and decreasing active coping behaviors in adult rats as determined by the defensive burying test and response to swim stress. Mid‐adolescent rats exposed to social stress showed no changes in the behavioral endpoints. Effects of social stress in EA rats was not mimicked by chronic restraint stress. Because the locus coeruleus (LC)‐norepinephrine system has been implicated in certain active coping behaviors, LC neuronal activity was recorded in EA rats exposed to social stress and matched controls. LC spontaneous firing rates were higher in EA rats exposed to social stress. Moreover, intra‐LC infusion of the CRF antagonist, DPheCRF12‐41, inhibited LC neurons of stressed rats but not controls. These data suggest that exposure to social stress in early adolescence promotes tonic secretion of CRF into the LC to activate this system. This CRF‐induced activation of the LC‐norepinephrine system may underlie the promotion of active‐coping behaviors noted in socially stressed EA rats.MH058250

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