NMDA receptor-mediated processing in inferior frontal gyrus facilitates acquisition and extinction learning and strengthens renewal.

While the renewal effect of extinction is considered to be invoked by attention to context during the extinction phase, there is also evidence that processing during initial learning (acquisition) may be important for later renewal. A noradrenergic agonist and a dopaminergic antagonist, administered before acquisition, did not affect renewal, however, the effects of NMDAergic neurotransmission in this regard are as yet unknown. In a previous study, administration of a single dose of the NMDA agonist d-cycloserine (DCS) before extinction learning facilitated extinction in the context of acquisition (AAA), but had no effect upon renewal. In the present fMRI study, DCS was administered prior to the initial acquisition of a predictive learning task, in order to investigate whether NMDA receptor (NMDAR) stimulation at this timepoint will modulate overall learning as well as the level of renewal, while increasing activation in the extinction- and renewal-relevant brain regions of inferior frontal gyrus (iFG) and hippocampus (HC). DCS facilitated acquisition, as well as extinction learning in the context of acquisition (AAA), and raised the level of ABA renewal. While BOLD activation during acquisition did not differ between treatment groups, activation in bilateral iFG showed a double dissociation during processing of AAA extinction trials, with DCS-mediated higher activation in right iFG and deactivation in left iFG. In contrast, placebo showed higher activation in left iFG and deactivation in right iFG. During the test (recall) phase, left iFG and right anterior hippocampus activation was increased in DCS participants who showed renewal, with activation in this region correlating with the ABA renewal level. The results demonstrate that NMDA receptor stimulation can facilitate both initial learning and extinction of associations, and in this way has an impact upon the resultant level of renewal. In particular NMDAergic processing in iFG appears relevant for the facilitation of AAA extinction and ABA recall in the test phase.

The DA-antagonist Tiapride affects context-related extinction learning in a predictive learning task, but not initial forming of associations, or renewal.

Renewal describes the recovery of an extinguished response if the contexts of extinction and recall differ, highlighting the context dependency of extinction. Studies demonstrated dopaminergic (DA) signalling to be important for context-related extinction learning with and without a fear component. In a previous study in humans, administration of the dopamine D2/D3 antagonist tiapride prior to extinction impaired extinction learning in a novel, but not a familiar context, without affecting renewal. In a further study, context processing during initial acquisition of associations was shown to be related to renewal. In this human fMRI study we investigated the potential role of DA signalling during this initial conditioning for the learning process and for renewal. While tiapride, administered prior to the start of learning, did not affect initial acquisition and renewal, extinction learning in a novel context was impaired, associated with reduced BOLD activation in vmPFC, left iFG and ACC - regions mediating response inhibition and selection from competing options using contextual information. Thus, different timepoints of administration of tiapride (before initial conditioning or extinction) had largely similar effects upon extinction and renewal. In addition, retrieval of previously acquired associations was impaired, pointing towards weaker association forming during acquisition. Conceivably, effects of the DA blockade are associated with the challenge present in the respective task rather than the administration timepoint: the cognitive flexibility required for forming a new inhibitory association that includes a novel element clearly requires DA processing, while initial forming of associations, or of inhibitory associations without a new element, apparently rely less on the proper function of the DA system.

The effects of dopaminergic D2-like receptor stimulation upon behavioral and neural correlates of renewal depend on individual context processing propensities.

Renewal is defined as the recovery of an extinguished response when the contexts of extinction and recall differ. Prominent hippocampal activity during context-related extinction can predict renewal. Dopaminergic antagonism during extinction learning impaired extinction and reduced hippocampal activation, without affecting renewal. However, to what extent dopaminergic stimulation during extinction influences hippocampal processing and renewal is as yet unknown. In this fMRI study, we investigated the effects of the dopamine D2-like agonist bromocriptine upon renewal in an associative learning task, in hippocampus and ventromedial PFC. We observed significant differences between bromocriptine (BROMO) and placebo (PLAC) treatments in the subgroups showing (REN) and lacking (NoREN) renewal: the renewal level of BROMO REN was significantly higher, and associated with more prominent hippocampal activation during extinction and recall, compared to PLAC REN and BROMO NoREN. Results suggest that an interaction between D2like-agonist-induced enhancement of hippocampal activity and a pre-existing tendency favoring context processing contributed to the higher renewal levels. In contrast, ventromedial prefrontal activation was unchanged, indicating that increased hippocampal context processing and not prefrontal response selection constituted the central driving force behind the high renewal levels. The findings demonstrate that hippocampal dopamine is important for encoding and providing of context information, and thus crucially involved in the renewal effect.

d-Cycloserine facilitates extinction learning and enhances extinction-related brain activation.

Extinction learning is modulated by N-methyl d-aspartate receptors (NMDAR) particularly in prefrontal and hippocampal brain regions. The use of of NMDA agonists in exposure therapy of anxiety disorders has been investigated in various patient groups. Behavioral results showed beneficial effects of pre-learning administration of the partial NMDAR agonist d-Cycloserine (DCS) on therapy success. However, the impact of DCS upon non-fear-related contextual extinction, and associated recruitment of extinction-relevant brain regions is as yet unknown. In the present fMRI study, healthy human participants performed a context-related associative learning and extinction task. A single dose of DCS, administered prior to extinction learning, enhanced extinction learning performance in an identical context, and increased activation in prefrontal, temporal as well as hippocampal/insular regions, compared to placebo controls. In contrast, DCS did not affect extinction learning in a novel context, nor the renewal effect, which describes the recovery of an extinguished response if the context of extinction differs from the context of recall. Our findings demonstrate a specific involvement of prefrontal and hippocampal NMDAR in the modification of established stimulus-outcome associations in identical contexts and thus their role in behavioral flexibility, underlining their potential for enhancing AAA extinction learning.

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

The renewal effect of extinction demonstrates the context-dependency of extinction learning. It is defined as the recovery of an extinguished response occurring when the contexts of extinction and recall differ. Behavioral studies showed that modulating context relevance can strengthen context-specific responses. In our fMRI study, we investigated to what extent a modulation of context salience can alter renewal levels and provide additional information about the neural basis for renewal. In a within-subjects design, participants completed two sessions of an associative learning task in randomized order. In the salient condition (SAL), a context was presented alone at the start of each trial, before being presented together with the stimulus. The regular condition (REG) contained no context-alone phase. In about one-third of participants (SWITCH), the context salience modulation significantly increased renewal rates in the SAL compared to the REG condition. The other participants showed either renewal (REN) or no renewal (NoREN) in both conditions. The modulation did not significantly affect learning performance during the initial forming of associations or extinction learning. In the SWITCH group, activation in left opercular inferior frontal gyrus (iFG) during the recall phase was associated with a renewal effect, together with activity in the bilateral posterior hippocampus and ventromedial prefrontal cortex (vmPFC). Also during the extinction phase, left opercular iFG activation was higher in groups exhibiting renewal in recall, irrespective of the context salience modulation. Besides confirming the participation of vmPFC in extinction recall, our findings provide novel insights regarding an as yet undetected, potentially important role for renewal-supporting processes in left iFG during extinction learning and recall, which are presumably based on the region's proposed function of evaluating competing response options under conditions of ambiguity.

Test-retest reliability of response recovery after discrimination reversal learning.

In one human predictive learning experiment, we demonstrated that an individual's propensity for response recovery following discrimination reversal learning is stable over time. Participants received four sessions of training with the first three sessions being separated by one week each, while the last session was conducted after a delay of four weeks. During each session, participants initially received discrimination training (E+, F-) in one context, followed by discrimination reversal training (E-, F+) in another context. Sessions each completed with a test, in which the stimuli were presented in the context of initial acquisition. Each test revealed response recovery according to the initially acquired stimulus-outcome contingencies. Furthermore, the strength of response recovery was correlated across sessions that were separated by one week (Sessions 1 and 2), and across sessions separated by four weeks (Sessions 3 and 4). Overall, intra-individual test behavior was stable in 87 % of participants across two sessions, and in 79 % of participants across four sessions. Our results indicate that inter-individual differences in response recovery are a reliable phenomenon, which is a finding that is not accounted by current theories of context-dependent learning.

Effects of Noradrenergic Stimulation Upon Context-Related Extinction Learning Performance and BOLD Activation in Hippocampus and Prefrontal Cortex Differ Between Participants Showing and Not Showing Renewal.

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.