Sex differences, gonadal hormones and the fear extinction network: implications for anxiety disorders

After a brief overview of the fear extinction network, we summarize what is currently known about sex differences in fear extinction and the influence of gonadal hormones on the fear extinction network. We then go on to propose possible mechanisms by which sex hormones, such as estrogen, may influence neural plasticity within the fear extinction network. We end with a discussion of how knowledge to be gained from developing this line of research may have significant ramifications towards the etiology, epidemiology and treatment of anxiety disorders.There are now substantial data indicating that structural, cellular and molecular differences exist between the male and female brains in regions that are important for cognition, memory and affect, such as the hippocampus, amygdala and prefrontal cortex. Some of these differences may have clinical relevance, as marked disparities in disease incidence, manifestation, prognosis and treatment have been observed between the sexes. For example, men have a higher prevalence of conditions that emerge early in development, such as autism, attention deficit hyperactivity disorder and schizophrenia. Women, on the other hand, have a higher prevalence of disorders that emerge in adolescence or adulthood, such as major depression and anxiety disorders. Surprisingly, very little is known about the neural mechanisms that underlie the expression of sex differences in psychiatric disorders. A 2001 report by the Institute of Medicine highlighted the need to conduct scientific studies at the cellular, molecular and whole organism level that take into account sex as a variable to investigate the neural mechanisms that lead to epidemiological differences in psychiatric disorders.The need to examine sex differences in the network mediating fear learning and its extinction can be surmised from two different perspectives. From a clinical perspective, we need to understand what contributes to the significant epidemiological differences in psychi