Women are 60% more likely than men to experience anxiety disorders and the mechanisms that underlie this sex difference are still not well understood. A common feature of many anxiety disorders is the generalization of fear from threatening contexts to non-threatening contexts, a symptom that often goes untreated. Previous research from our lab has shown that female rats generalize contextual fear at a faster rate than male rats, and this effect can be attributed to estradiol. Specifically, activation of cytosolic estrogen receptor beta (ERβ) within the dorsal CA1 region of the hippocampus (dCA1) and anterior cingulate cortex (ACC), promotes generalized fear. The current study is focused on the mechanisms contributing to estradiol’s ability to induced generalized fear in female rodents. Given the strong influence estradiol has on glutamatergic transmission, we hypothesized that estradiol promotes generalized fear by upregulating glutamate receptors. Using passive avoidance, we examined the effects of NMDA or AMPA receptor antagonists (APV, NBQX) infused into the dCA1 or the ACC of ovariectomized (OVX) female rats receiving estradiol. Our results suggest that AMPA and NMDA receptors are necessary for estradiol-induced fear generalization. We more specifically examined a subtype of NMDA receptors called GluN2B, and found that estradiol acts on the NMDA receptors containing GluN2B subunits to induce generalized fear. These data elucidate some of the mechanisms contributing to increased generalized fear in female rodents, and may provide a better understanding of sex differences in anxiety disorders rates among humans.
Ms. Jordan Adkins
Dr. Aaron Jasnow
Women are more likely than men to suffer from anxiety disorders. A characteristic of many anxiety disorders is generalization of fear responses, resulting in expression of fear to neutral stimuli. We’ve shown that estradiol induces fear generalization in female rats by activation of cytosolic estrogen receptor beta (ERβ) in the dorsal CA1 region of the hippocampus and the anterior cingulate cortex. Here, we examined the role of glutamate receptors in estradiol induced generalization and found that AMPA and NMDA receptors are necessary for this effect. We more specifically examined a subtype of NMDA receptors, GluN2B, and found that estradiol acts on these receptors to induce generalized fear. Understanding the mechanisms of estradiol induced generalization will allow for improved, sex-specific, treatments for many anxiety disorders.