Abstract
While the neural structures mediating context-related renewal of extinction are well established, the neurotransmitter systems processing renewal remain elusive. Noradrenergic stimulation before extinction improved learning, but did not alter renewal. Since context processing already during initial conditioning can influence renewal, in this fMRI study we investigated how noradrenergic stimulation by a single dose of atomoxetine (ATO) before initial acquisition of a context-related predictive-learning task affects subsequent learning and renewal in humans. ATO participants showing contextual renewal (REN) exhibited a selective extinction learning deficit compared to placebo (PLAC) and ATO participants lacking renewal (ATO NoREN), probably owing to formation of more stable associations during acquisition. New learning and retrieval during the extinction phase as well as initial acquisition were unimpaired. In ATO REN, higher activation in right inferior frontal gyrus (iFG) during acquisition may have supported the formation of more stable associations, while reduced activation in hippocampus and left iFG during extinction was associated with impaired context encoding and response inhibition. During recall, ATO REN showed reduced overall context-dependent renewal associated with higher activation in medial PFC and right hippocampus. The results demonstrate the importance of noradrenergic processing in inferior frontal cortex and hippocampus for human extinction learning, but not necessarily initial conditioning. Since an identical atomoxetine treatment evoked diverging blood-oxygen level dependent (BOLD) activation patterns in REN and NoREN participants, the effect is presumably related to the participants’ preferred processing strategies that may have recruited differentially interconnected networks in which noradrenergic stimulation produced diverging consequences. In the ATO REN group, probably an additive effect of their preferred processing strategy, which pre-activated the noradrenergic system, and the experimental treatment caused a shift beyond the optimal working range of the noradrenergic system, thus modulating BOLD activation in a way that impaired extinction learning and recall.
Highlights
The phenomenon of renewal, next to reinstatement and spontaneous recovery, delivers evidence that extinction constitutes not forgetting, but rather inhibition of a previously acquired response (Bouton, 2002; Phelps et al, 2004)
Based on our previous findings of enhanced extinction learning after atomoxetine administration we hypothesized improved performance in the extinction phase of the task, together with increased activation in hippocampus and inferior frontal gyrus (iFG)
This result indicates that presumably the administration of atomoxetine did not per se affect an individual’s general tendency to show renewal – a finding that corresponds to the renewal behavior of atomoxetine-treated participants in a previous study (Lissek et al, 2015a)
Summary
The phenomenon of renewal, next to reinstatement and spontaneous recovery, delivers evidence that extinction constitutes not forgetting, but rather inhibition of a previously acquired response (Bouton, 2002; Phelps et al, 2004). A recent study demonstrated that renewal during extinction recall is mediated by hippocampus and ventromedial PFC (vmPFC) regions (Lissek et al, 2013): participants who showed renewal during extinction recall exhibited significantly more prominent hippocampal activation during extinction learning than participants who did not show renewal, and higher vmPFC activation during retrieval proper These findings corroborate previous results that found hippocampus and vmPFC participating in context processing (Kalisch et al, 2006; Milad et al, 2007). Another region repeatedly found involved in extinction learning and recall is inferior frontal gyrus (iFG) with Brodmann areas BA 44, 45, and 47 (Lissek et al, 2015a,b; Klass et al, 2017). In particular right-hemispheric iFG has been implicated in processing response inhibition (Garavan et al, 1999; Hampshire et al, 2010), while a lesion study showed that left iFG is critical for response inhibition (Swick et al, 2008)
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