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

Abstract

Ability 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.

Brain-based transcriptomic architecture associated with high and low efficacy of fear extinction learning

“…The molecular analysis performed here was based on the behavioral results of our previously reported characterization of fear extinction in mice (Bonilla et al, 2023a). In brief, Pavlovian contextual fear conditioning using cohorts of ~14-weekold inbred C57BL/6J male and female animals (40 mice/sex) was performed to induce fear memory acquisition.…”

“…Molecular analysis performed in this study utilized mice selected from the cohorts of 40 male and 40 female animals that underwent Pavlovian contextual fear conditioning and extinction reported in Bonilla et al, 2023a). 3 + 3 male and 3 + 3 female mice that exhibited the lowest (LE) and the highest (HE) levels of fear extinction learning efficacy (lowest and highest efficacy extinction learners), however, similar levels of fear memory acquisition, were chosen for hippocampal transcriptomics reported here.…”

“…Total fear extinction was determined by scoring freezing events on the final (6 th ) day of the extinction training. Fear extinction efficacy was calculated for each animal as a percentage difference between fear responses exhibited/measured during Pavlovian fear conditioning testing session and during the final (6 th ) session of fear extinction training (fear memory acquisition scores and fear extinction scores for all (40 mice/sex) tested animals can be found in Bonilla et al, 2023a).…”

“…It remains unclear why some individuals of any sex exhibit strong and efficient extinction allowing to successfully inhibit/diminish fearful memories, while in others, such memories remain mostly intact and can severely affect person's mental health (Holmes and Singewald, 2013;Stout et al, 2018;King et al, 2018;Lebois et al, 2019). Uncovering molecular basis of the inter-individual and sex-related differences in extinction would be important for both understanding the mechanism of fear extinction as well as developing better therapeutic strategies, including novel pharmacological treatments, for a variety of neuropsychiatric conditions linked to extinction impairments, such as anxiety disorders, phobias, and PTSD (Green, 2013;Morrison and Ressler, 2014;Kelmendi et al, 2016;Krystal et al, 2017;Lebois et al, 2019) Recently, we reported analysis of neurobehavioral factors that could influence fear extinction in male and female wild-type mice (Bonilla et al, 2023a). In that study, we used groups of inbred animals of the same age raised in the same conditions, 4 to minimize effects of the differences in genetic background-, age-and maintenance on mouse' behavior.…”