Sexually dimorphic interplay between anxiety-related phenotype and fear memory extinction

Abstract

AbstractAbility to efficiently extinguish fear memories is critical for individual well-being, and extinction impairments are commonly observed in a variety of neuropsychiatric conditions. Efficient extinction is also a critical component of exposure therapy, the most widely utilized form of treatment for anxiety and trauma/stressor-related disorders. While individual as well as sex-related differences in extinction are recognized, their neurobiological underpinnings remain unclear. To examine neurobehavioral and molecular features that may contribute to the efficacy of fear memory extinction in genetically similar subjects raised in the same conditions, extinction learning was analyzed in the cohorts of inbred wild-type male and female mice. We showed that unlike memory acquisition, anxiety status of the animals appeared to significantly influence extinction. Interestingly, the effect was sex-specific: the level of anxiety-related behavior inversely correlated with extinction efficacy in male mice only. Significant difference in hippocampal expression of anxiolytic Corticotropin Releasing Hormone Receptor 2 (CRHR2) between the male, but not female animals differing in extinction efficacy, suggests that CRHR2 may serve as a key factor underlying sexually dimorphic interplay between anxiety and fear memory extinction. Our results emphasize the need for tailoring treatment strategies for anxiety and fear-related disorders in accordance with the patient sex and identify specific neurobehavioral and molecular features potentially important for such adjustments.Significance StatementFear memory extinction is a gradual diminishment of fear due to the learning that previously fearful context is now safe. Impaired or inefficient extinction has long been associated with anxiety and trauma/stressor-related disorders. Despite strong interest in therapeutic extinction enhancement, the progress has been limited due to insufficient understanding of the mechanisms regulating extinction efficacy and, especially, their sex-related features. This study showed notable sex differences in relation between fear memory extinction and anxiety-related behavior and identified likely molecular underpinnings of such differences. These findings should significantly improve our understanding of neurobehavioral and molecular factors regulating extinction. Furthermore, they could contribute to novel strategies of extinction augmentation and predictive assessments of extinction efficacy in accordance with the subject’s sex.