Abstract
Extinction of a cued-fear memory within the reconsolidation window has been proposed to prevent fear reacquisition by reconsolidation interference. This ‘retrieval-extinction’ procedure has received interest for its therapeutic potential to reduce the impact of fear memories on behavior. To fully exploit its therapeutic potential, it is critical to understand the mechanisms that underlie the ‘retrieval-extinction’ effect. If the effect depends upon reconsolidation of the original memory, then it would be predicted that destabilization, induced by prediction error, would be critical for observing the effect. Here, the dependency of the retrieval-extinction effect on memory destabilization or prediction error was investigated in pavlovian cued-fear conditioned adult male rats. The requirement for memory destabilization, and thus reconsolidation, for the retrieval-extinction effect was subsequently investigated using region-specific pharmacological blockade of dopamine D1-receptors. Intra-basolateral amygdala antagonism of dopamine D1-receptors did not prevent the reacquisition of fear associated with the retrieval-extinction procedure. The requirement for prediction error was assessed by using a reinforced or non-reinforced memory retrieval trial before extinction, compared to a no-retrieval, extinction-only control. Both the reinforced (no prediction error) and non-reinforced retrieval sessions led to a decrease in fear reacquisition, suggesting that engagement of prediction error does not influence the occurrence of retrieval-extinction. Together, these data suggest that retrieval-extinction does not require memory destabilization, since behavioral or pharmacological interventions that prevent destabilization did not disrupt any capacity to attenuate fear.
Highlights
Behavioral responses to conditioned stimuli (CSs) can be reduced through extinction training or the manipulation of memory reconsolidation
Antagonism of intra-BLA D1R signaling does not prevent the retrieval-extinction effect Based on the potential recruitment of dopaminergic signaling for aversive learning [16] and the proposed role of the BLA in unsigned neural encoding of prediction error [22], we targeted the BLA dopamine D1Rs to test whether they were required for the retrieval-extinction effect (Fig. 1a)
This design allowed the assessment of the acute effect of Sch administration on the expression of cued-fear (Fig. 1c), which revealed no differences between groups in fear expression (Drug: F < 1)
Summary
Behavioral responses to conditioned stimuli (CSs) can be reduced through extinction training or the manipulation of memory reconsolidation. Both approaches are used to treat anxiety disorders such as post-traumatic stress disorder, but each has limitations. Extinction training is associated with the risk of fear memory return through renewal, reinstatement, reacquisition, or spontaneous recovery of the original ‘CS-US’ association [2, 3]. Pharmacological blockade of memory restabilisation is hypothesized to persistently weaken or even erase the original memory [4]. Disruption of reconsolidation depends critically upon the induction of memory destabilization [5, 6], with the specific conditions likely depending on factors including memory age and strength [7]
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