Aging is associated with dysregulation of emotional and endocrine responses in a stressful environment. To understand the developmental mechanisms of stress vulnerability with aging, we investigated the effects of repeated stress on behavioral, endocrine, and neural parameters relating to emotional and stress responses in young (3 months old) and aged (24 months old) F344/N male rats. Young and aged rats were either subjected to 1-h restraint stress for 14 consecutive days or left undisturbed. After the procedures, behaviors were examined in open-field and elevated plus-maze tests to evaluate the level of anxiety induced by aging and repeated stress. Following the behavioral tests, serum corticosterone concentrations and c-Fos immunoreactivity throughout the brain in response to acute restraint stress were examined. Control and repeatedly stressed aged rats showed more anxiety-related behaviors than control and repeatedly stressed young rats in both tests. In particular, repeatedly stressed aged rats showed more anxiety-related behaviors in the elevated plus-maze than control aged and repeatedly stressed young rats, although stressed young rats were not different from control young rats. Repeatedly stressed aged rats showed higher serum corticosterone concentrations in response to acute stress than subjects in all other conditions. In c-Fos expression, control aged rats showed decreases in c-Fos-positive cells in response to acute stress in the prefrontal cortex, medial preoptic area, bed nucleus of the stria terminalis, nucleus accumbens, medial amygdaloid nucleus, and CA3 subfield of hippocampus, whereas they showed increases in the dorsal raphe nucleus and parvocellular part of the paraventricular nucleus of the hypothalamus compared to acutely stressed control young rats. These results indicate that repeated stress enhances emotional and stress responses in aged rats but not in young rats, suggesting that aging causes organisms to become vulnerable to stress, which might be mediated by dysfunction of the brain system regulating emotional and stress responses.
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