Early Life Adversity-induced Defensive Behavior in Females: The Protective Role of Naturally Fluctuating Ovarian Hormones

Abstract

Experiences of early life adversity (ELA), such as childhood maltreatment, neglect, or trauma, are known to increase a person’s risk for developing anxiety disorders in adulthood. In order to investigate how ELA impacts the brain, researchers have developed several animal models. In particular, a previous study from our lab has shown that the maternal separation and early weaning model (MSEW) increases defensive behaviors in adult male mice but not in females. This finding is inconsistent with clinical trends seen in humans, which suggests that the prevalence of anxiety and mood-related disorders is two times greater in females than in males. This inconsistency illuminates a need to further investigate MSEW female mice and to assess the translational validity of MSEW as an ELA model. Other studies have also shown that estrogen levels can influence activity levels and cause molecular and cellular changes on a short time-scale. Therefore, in this study, we characterized the behavioral and neurobiological changes of MSEW C57BL/6J females, while controlling for estrous cycle stages. We found that females of both control and MSEW groups exhibit increased levels of activity during the estrus (high estrogen) stage of the estrous cycle in the open field test. Moreover, MSEW females present increases in defensive behaviors on the wet elevated plus maze and the light dark test, but only when they are tested and compared to controls in the diestrus (low estrogen) stage. These increases in defensive behaviors did not appear in control and MSEW mice during the other stages of the estrous cycle. We also analyzed cellular changes in the vHIP, mPFC, and BLA—three key brain regions associated with defensive behavior regulation in rodents. Specifically, we looked at the densities and c-Fos expression of PV+ inhibitory interneurons in these regions, which have been shown to contribute to changes in neuronal oscillations commonly associated with increases in defensive behavior. We found that there were no differences in PV expression or activation in inhibitory interneurons between the control and MSEW groups, suggesting that the MSEW-induced behavioral changes in diestrus females may be caused by alterations in PV+ cell firing patterns, rather than simple binary on/off changes in firing.