Abstract
A distributed network including prefrontal and hippocampal regions is involved in context-related extinction learning as well as in renewal. Renewal describes the recovery of an extinguished response if the context of extinction differs from the context of recall. Animal studies have demonstrated that prefrontal, but not hippocampal N-methyl-D-aspartate receptor (NMDAR) antagonism disrupted extinction learning and processing of task context. However, human studies of NMDAR in extinction learning are lacking, while NMDAR antagonism yielded contradictory results in other learning tasks. This fMRI study investigated the role of NMDAR for human behavioral and brain activation correlates of extinction and renewal. Healthy volunteers received a single dose of the NMDAR antagonist memantine prior to extinction of previously acquired stimulus-outcome associations presented in either identical or novel contexts. We observed better, and partly faster, extinction learning in participants receiving the NMDAR antagonist compared to placebo. However, memantine did not affect renewal. In both extinction and recall, the memantine group showed a deactivation in extinction-related brain regions, particularly in the prefrontal cortex, while hippocampal activity was increased. This higher hippocampal activation was in turn associated with the participants' body mass index (BMI) and extinction errors. Our results demonstrate potentially dose-related enhancing effects of memantine and highlight involvement of hippocampal NMDAR in context-related extinction learning.
Highlights
Extinction is an important learning phenomenon in everyday life, which allows organisms to adapt their behavior to new situations
Extinction During extinction learning in an identical context (AAA condition), both groups showed prominent activation in dorsolateral prefrontal cortex [Brodmann Area (BA) 46] and orbitofrontal cortex (OFC) (BA10,47) as well as in superior temporal gyrus (STG) (BA22,38)
During extinction learning in a novel context (ABA condition), PLAC participants’ activation patterns were similar to those shown in the familiar context, while MEM participants showed considerably decreased activation
Summary
Extinction is an important learning phenomenon in everyday life, which allows organisms to adapt their behavior to new situations. This adaption involves new inhibitive or integrative learning rather than unlearning (Bouton, 2002; Phelps et al, 2004): Instead of erasing the established memory trace (Bouton, 2002; Quirk and Mueller, 2008), extinction learning presumably forms a new memory trace that competes with the initially acquired trace. The context-dependency of extinction is impressively illustrated by NMDAergic Modulation of Extinction Learning the renewal effect, which describes the recovery of an extinguished response when the test context differs from the extinction context (Bouton and Bolles, 1979). The occurrence of the renewal effect illustrates that the context is integrated in ambiguous situations (Rosas and Callejas-Aguilera, 2006)
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