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.
Highlights
Human and animal research on extinction learning has identified amygdala, insula, prefrontal cortex and hippocampus as important regions participating in both fear extinction (Herry et al 2010; Sehlmeyer et al 2009), and nonfear related extinction (Todd et al 2014)
In this study we investigated the effects of GABA A agonism upon context-related extinction learning without a fear component and upon renewal during recall of extinction memory
To the best of our knowledge, this study is the first to investigate the effects of GABA A agonism upon brain activation patterns in non-fear-related associative extinction learning in healthy humans, demonstrating that deficits related to manipulations of the GABAergic system are not restricted to fear extinction in animals
Summary
Human and animal research on extinction learning has identified amygdala, insula, prefrontal cortex and hippocampus as important regions participating in both fear extinction (Herry et al 2010; Sehlmeyer et al 2009), and nonfear related extinction (Todd et al 2014). The level of context processing in an individual can be inferred from their retrieval performance after extinction learning in a context different from that present during recall. In many cases, such a paradigm induces renewal, which is defined as the reoccurrence of a previously extinguished response if the contexts of extinction learning and recall differ (Bouton and Ricker 1994). The prerequisites for renewal to occur, e.g. context encoding during extinction learning and context retrieval in subsequent recall, were found mediated by hippocampus and vmPFC, respectively, suggesting that these regions have a crucial role in evoking renewal (Lissek et al 2013). Already during initial conditioning or acquisition, hippocampal activation is more prominent in participants who later show renewal (Lissek et al 2016), a finding that underlines the important
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