Gender Specific Effect of Neonatal Handling on Stress Reactivity of Adolescent Rats

Early neonatal handling of rat pups produces dampened hypothalamic‐pituitary‐adrenal axis reactivity to stress in adult male offspring. However, less is known about whether there is a similar effect for females. Although, most studies of neonatal handling have examined subsequent effects during adulthood, adolescence is an important developmental stage for stress responsivity. To address these issues, the effect of neonatal handling on the endocrine stress response and brain activity of male and female rats was determined in response to acute restraint stress during adolescence. Consistent with previous findings in adult males, neonatal handling reduced restraint stress‐induced hormone levels in adolescent males. However, in contrast, we found elevated plasma hormone concentrations in handled females. A gender‐specific handling effect on brain activity was also evident, with significantly increased stress‐induced activation of the posterior cingulate cortex of handled females, as measured by c‐ fos mRNA expression. The striking gender difference in the effect of early neonatal handling provides evidence that this must be considered as an important variable in subsequent stress responsivity induced by early manipulations.