Abstract
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.
Highlights
Classical fear conditioning is an influential experimental model to study emotional learning and memory
There is increasing evidence that the monoamines, i.e., NA, DA, and 5-HT, which are involved in the stress response, have roles in fear extinction: projections from noradrenergic, dopaminergic, and serotonergic fibers reach the main structures of the fear extinction network, the amygdala, the hippocampus, and the prefrontal cortex
We found an interaction between stress exposure and natural E2-status within women: in mid-cycle women, extinction recall was better when fear acquisition had been preceded by stress, whereas the inverse was true in early follicular women
Summary
Classical fear conditioning (consisting of fear acquisition and extinction) is an influential experimental model to study emotional learning and memory. There is increasing evidence that the monoamines, i.e., NA, DA, and 5-HT, which are involved in the (firstwave) stress response (see ‘‘Features and mediators of the stress response’’ Section), have roles in fear extinction: projections from noradrenergic, dopaminergic, and serotonergic fibers reach the main structures of the fear extinction network, the amygdala, the hippocampus, and the prefrontal cortex.
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