Estrous Cycle Impacts Fear Extinction and Relapse in Female Adolescent Rats

Abstract

Adolescent male rodents and humans exhibit impairments in extinguishing learned fear. Here, we investigated whether female adolescent rats exhibit such impairments and if extinction is affected by the estrous cycle as in adults. Following fear conditioning to a discrete cue, female adolescent Sprague Dawley rats were extinguished either around the onset of puberty, when estrous cycling begins, or across different stages of the estrous cycle. Both extinction retention and renewal (a form of relapse) were assessed. Peri-pubertal females had comparable freezing during extinction training and tests of extinction retention and fear renewal as age-matched males. They were noted to generally be in metestrus, a low estradiol phase, at extinction training. Postpubertal females that received extinction training in proestrus (high estradiol phase), but not metestrus (low estradiol phase), had lower freezing during extinction training and retention than males; males exhibited more freezing during a renewal test than both groups of females. Our findings suggest that female adolescent rats have reduced fear during extinction training and retention compared to males only when extinguished in a high-estradiol phase. These findings suggest fear inhibition fluctuates across the estrous cycle in adolescence, and estradiol may protect females against impairments in fear extinction during this developmental period.