Social isolation is a risk factor for cognitive impairment. Adolescents may be particularly vulnerable to these effects, because they are in a critical period of development marked by significant physical, hormonal, and social changes. However, it is unclear if the effects of social isolation on learning and memory are similar in both sexes or if they persist into adulthood after a period of recovery. We socially isolated male and female 129Sv/Ev mice throughout adolescence (postnatal days 29-56), provided a 2-week resocialization recovery period, and then tested spatial learning and cognitive flexibility in the active place avoidance task. After behavioral testing, mice were injected with 5'-bromo-2'-deoxyuridine (BrdU) so that lasting effects of social isolation on cell proliferation in the dentate gyrus could be examined. Tissue was also stained for doublecortin (DCX). We found that in males, isolation led to a modest impairment in the rate of initial spatial learning, whereas in females, initial learning was unaffected. However, when the location of the shock zone was switched during the conflict variant of the task, cognitive flexibility was impaired in females only. Similarly, social isolation reduced cell proliferation and the number of immature neurons in the ventral dentate gyrus only in females. Together, these findings indicate that social isolation during adolescence differentially impairs spatial processing in males and females, with effects that persist into adulthood.
© 2025 Hanif et al.; Published by Cold Spring Harbor Laboratory Press.