Estrogen receptor β in the prefrontal cortex mediates stress-induced anxiety-like behaviors in female mice.

Females are more likely to develop an anxiety disorder following exposure to stress. We previously identified prefrontal parvalbumin (PV) neurons as a potential cellular mechanism underlying this sex-specific vulnerability. By exposing adult mice to 4 weeks of unpredictable chronic mild stress (UCMS), we revealed a female-specific increase in prefrontal PV neurons activity that we causally related to increased anxiety-like behaviors. Because female prefrontal PV neurons mature during adolescence potentially through an estrogen receptor-beta (ERβ)-dependent mechanism, and because the sex difference in prevalence of anxiety disorders emerges post-puberty, we aimed to determine whether females acquire their sex-specific vulnerability to chronic stress through a pubertal ERβ-dependent mechanism. We used a lentivirus mediated-shRNA approach to knockdown ERβ expression in the prefrontal cortex (PFC) prior to puberty or in adulthood and exposed adult mice to UCMS. Mice were then tested in the open field (OFT) and elevated plus maze (EPM) tests, and the number of PV neurons expressing the marker of chronic activity FosB was counted in the PFC. We observed that prepubertal, but not adult, knockdown of prefrontal ERβ prevented UCMS-induced anxiety in the EPM test and the UCMS-induced hyperactivity of prefrontal PV neurons. While early exposure to surgery resulted in some changes in anxiety-like behaviors in the OFT compared to mice not exposed to early surgery, overall, our data support the idea that the female-specific vulnerability to stress-induced anxiety is acquired at puberty through a mechanism that involves the ERβ. These findings contribute to a better understanding of sex-specific risks to emotional changes after exposure to stress.