Role of noradrenergic arousal for fear extinction processes in rodents and humans

Abstract

Fear extinction is a learning mechanism that is pivotal for the inhibition of fear responses towards cues or contexts that no longer predict the occurrence of a threat. Failure of fear extinction leads to fear expression under safe conditions and is regarded to be a cardinal characteristic of many anxiety-related disorders and post -traumatic stress disorder. Importantly, the neurotransmitter noradrenaline was shown to be a potent modulator of fear extinction. Rodent studies demonstrated that excessive noradrenaline transmission after acute stress opens a time window of vulnerability, in which fear extinction learning results in attenuated long-term extinction success. In contrast, when excessive noradrenergic transmission subsides, well-coordinated noradrenaline transmission is necessary for the formation of a long-lasting extinction memory. In addition, emerging evidence suggests that the neuropeptide corticotropin releasing hormone (CRF), which strongly regulates noradrenaline transmission under conditions of acute stress, also impedes long-term extinction success. Recent rodent work -using sophisticated methods -provides evidence for a hypothetical mechanistic framework of how noradrenaline and CRF dynamically orchestrate the neural fear and extinction circuitry to attenuate or to improve fear extinction and extinction recall. Accordingly, we review the evidence from rodent studies linking noradrenaline and CRF to fear extinction learning and recall and derive the hypothetical mechanistic framework of how different levels of noradrenaline and CRF may create a time window of vulnerability which impedes successful long-term fear extinction. We also address evidence from human studies linking noradrenaline and fear extinction success. Moreover, we accumulate emerging approaches to non-invasively measure and manipulate the noradrenergic system in healthy humans. Finally, we emphasize the importance of future studies to account for sex (hormone) differences when examining the interaction between fear extinction, noradrenaline, and CRF. To conclude, NA's effects on fear extinction recall strongly depend on the arousal levels at the onset of fear extinction learning. Our review aimed at compiling the available (mainly rodent) data in a neurobiological framework, suited to derive testable hypotheses for future work in humans.