No abstract

In this review we propose that the fear extinction model can be used as an experimental tool to cut across symptom dimensions of multiple anxiety disorders to enhance our understanding of the psychopathology of these disorders, and potentially facilitate the detection of biomarkers for the same. We evaluate evidence for this proposition from studies examining the neurocircuitry underlying fear extinction in rodents, healthy humans and clinical populations. Furthermore, we assess the potential use of the fear extinction model to predict vulnerability for anxiety and treatment response, and to improve existing, or lead to developing novel, treatments. Finally, we suggest potential directions for future research that will help to further validate extinction as a biomarker for anxiety across diagnostic categories, and that will help to bridge the gap between basic neuroscience and clinical practice.

Background Fear extinction is a laboratory model of fear inhibition and is the basis of exposure therapy for anxiety disorders. Emerging evidence from naturally cycling female rodents and women indicates that estrogens are necessary to the consolidation of fear extinction. Hormonal contraceptives (HCs) inhibit estrogen production, yet their effects on fear extinction are unknown. Methods We used a cross-species translational approach to investigate the impact of HCs and estradiol supplementation on fear extinction in healthy women (n=76) and female rats (n=140). Results Women using HCs exhibited significantly poorer extinction recall compared to naturally cycling women. The extinction impairment was also apparent in HC-treated female rats and was associated with reduced serum estradiol levels. The impairment could be rescued in HC-treated rats either by terminating HC treatment after fear learning or by systemic injection of estrogen-receptor agonists prior to fear extinction, all of which restored serum estradiol levels. Finally, a single administration of estradiol to naturally cycling women significantly enhanced their ability to recall extinction memories. Conclusions Together, these findings suggest that HCs may impact women’s ability to inhibit fear, but that this impairment is not permanent and could potentially be alleviated with estrogen treatment.