The GABAergic system in prefrontal cortex and hippocampus modulates context-related extinction learning and renewal in humans

Abstract

Context-related extinction learning and renewal in humans is mediated by hippocampal and prefrontal regions. Renewal is defined as the reoccurrence of an extinguished response if the contexts present during extinction learning and recall differ. Animal studies implicate hippocampal γ-aminobutyric acid (GABA) A receptors in extinction and renewal. However, human studies on GABAergic mechanisms in extinction learning are lacking. In this fMRI study, we therefore investigated the role of the GABAergic system in context-related extinction learning and renewal. Participants treated with the GABA A agonist lorazepam prior to extinction learning were impaired in encoding changed associations during extinction learning, regardless of context, and in retrieving extinction associations during recall. In contrast, retrieval of associations learned during acquisition was largely unaffected, which led to reduced genuine renewal, since acquisition associations were retrieved context-independently. These deficits, which were presumably due to weak encoding of extinction associations, were related to altered BOLD activation in regions relevant for context processing and retrieval, as well as response selection: reduced activation in bilateral PFC and hippocampus during extinction learning and recall, and increased ventromedial/orbitofrontal cortex activation during recall. Our findings indicate that the GABergic system is involved in context-related extinction learning and recall in humans, by modulating hippocampus-based context processing and PFC-based processing of changed associations and subsequent response selection.

Left Inferior Frontal Gyrus Participates in Mediating the Renewal Effect Irrespective of Context Salience

“…Pronounced context-related activation in hippocampus during extinction and recall is regularly found when comparing REN to NoREN groups in the predictive learning task (Lissek et al, 2013(Lissek et al, , 2016(Lissek et al, , 2018, consistent with studies on fear extinction and recognition tasks that found hippocampal activation necessary for the encoding of context information (Corcoran et al, 2005;Ji and Maren, 2007;Lambert et al, 2017). Bilateral posterior hippocampus activation is frequently observed associated with renewal (Lissek et al, 2013(Lissek et al, , 2016(Lissek et al, , 2018, and lacking activation or deactivation in this region may accompany reduced or lacking renewal (Lissek et al, 2017(Lissek et al, , 2018. Hippocampal activation in the SWITCH group in the present study is consistent with these findings: during extinction and recall in the REG session, where in contrast to the REN group they did not show renewal, their level of hippocampal activity was partially lower than in REN since context processing had a lower priority.…”

“…In contrast, a ratio value of −1 indicates that every response of this type occurred during AAA recall and none during ABA recall, suggesting rather weak memory for AAA extinction associations, with preserved memory for ABA extinction associations, but without context consideration. Higher ratios thus signal a higher probability of genuine renewal (for details on the calculation see Lissek et al, 2017).…”

“…Another prefrontal region potentially important for renewal is inferior frontal gyrus (iFG)-an area which in our previous studies was occasionally found activated during extinction learning and recall (e.g., Lissek et al, 2017Lissek et al, , 2019, and whose involvement in renewal is as yet unexplored. IFG is assumed to mediate response inhibition (Konishi et al, 1999), necessary during operant/instrumental extinction learning (Bouton et al, 2016).…”

“…Correspondingly, interindividual differences in the propensity to show renewal reflect in differential activation of the hippocampus and ventromedial PFC during a non-fear related predictive learning task: previous studies consistently found pronounced differences in hippocampal blood-oxygen level-dependent (BOLD) activation during acquisition and extinction between participants with and without a propensity for renewal (e.g., Lissek et al, 2013Lissek et al, , 2016, linking higher hippocampal activity to subsequent renewal. Besides, these studies showed that ventromedial PFC was involved during extinction learning and extinction recall (Lissek et al, 2013(Lissek et al, , 2017) in the predictive learning task. Activity in ventromedial PFC during extinction learning in a novel context was positively correlated with renewal rates, suggesting that higher activation during encoding of these new associations entailed better assignment of the associations to their respective contexts during recall (Lissek et al, 2015a).…”

Distinct Neuronal Populations Contribute to Trace Conditioning and Extinction Learning in the Hippocampal CA1

“…As new learning occurs, subjects will suppress their conditioned response to the previously predictive tone or light. Extinction learning has also been shown to be NMDA receptor dependent 28 , and requires the involvement of hippocampal inhibitory neurons 29 and adult neurogenesis 30 .…”