Modulation of Fear Extinction by Stress, Stress Hormones and Estradiol: A Review

Fear acquisition and extinction are valid models for the etiology and treatment of anxiety, trauma- and stressor-related disorders. These disorders are assumed to involve aversive learning under acute and/or chronic stress. Importantly, fear conditioning and stress share common neuronal circuits. The stress response involves multiple changes interacting in a time-dependent manner: (a) the fast first-wave stress response [with central actions of noradrenaline, dopamine, serotonin, corticotropin-releasing hormone (CRH), plus increased sympathetic tone and peripheral catecholamine release] and (b) the second-wave stress response [with peripheral release of glucocorticoids (GCs) after activation of the hypothalamus-pituitary-adrenocortical (HPA) axis]. Control of fear during extinction is also sensitive to these stress-response mediators. In the present review, we will thus examine current animal and human data, addressing the role of stress and single stress-response mediators for successful acquisition, consolidation and recall of fear extinction. We report studies using pharmacological manipulations targeting a number of stress-related neurotransmitters and neuromodulators [monoamines, opioids, endocannabinoids (eCBs), neuropeptide Y, oxytocin, GCs] and behavioral stress induction. As anxiety, trauma- and stressor-related disorders are more common in women, recent research focuses on female sex hormones and identifies a potential role for estradiol in fear extinction. We will thus summarize animal and human data on the role of estradiol and explore possible interactions with stress or stress-response mediators in extinction. This also aims at identifying time-windows of enhanced (or reduced) sensitivity for fear extinction, and thus also for successful exposure therapy.