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Scientific Understanding of Consciousness |
Disruption of Reconsolidation Erases Fear Memory Trace
Science 21 September 2012: Vol. 337 no. 6101 pp. 1550-1552 Disruption of Reconsolidation Erases a Fear Memory Trace in the Human Amygdala Thomas Agren, Jonas Engman, Andreas Frick, Johannes Björkstrand, Elna-Marie Larsson, Tomas Furmark, Mats Fredrikson 1Department of Psychology, Uppsala University, SE-751 42 Uppsala, Sweden. 2Department of Radiology, Oncology and Radiation Science, Uppsala University, SE-751 42 Uppsala, Sweden. [paraphrase] Memories become labile when recalled. In humans and rodents alike, reactivated fear memories can be attenuated by disrupting reconsolidation with extinction training. Using functional brain imaging, we found that, after a conditioned fear memory was formed, reactivation and reconsolidation left a memory trace in the basolateral amygdala that predicted subsequent fear expression and was tightly coupled to activity in the fear circuit of the brain. In contrast, reactivation followed by disrupted reconsolidation suppressed fear, abolished the memory trace, and attenuated fear-circuit connectivity. Thus, as previously demonstrated in rodents, fear memory suppression resulting from behavioral disruption of reconsolidation is amygdala-dependent also in humans, which supports an evolutionarily conserved memory-update mechanism. Anxiety disorders are common, and they cause great suffering and high societal costs. The etiology involves amygdala-dependent memory mechanisms that link stressful events to previously neutral stimuli, and the amygdala has been demonstrated to be hyperresponsive across the anxiety disorders. Pharmacological and behavioral treatments of anxiety reduce symptomatology and amygdala activity but have limited success because relapses occur. However, fear memories may be erased by recalling them and preventing their reconsolidation. In rodents, the amygdala seems vital for fear memory reconsolidation, but this has not been investigated in humans. Fear conditioning, in which a previously neutral stimulus turns into a conditioned stimulus (CS) through pairings with an aversive stimulus, forms a memory trace in the amygdala. Memory activation produces behavioral and autonomic fear reactions, such as skin conductance responses (SCRs) frequently used to measure fear learning. Studies in animals and anxiety patients demonstrate that extinction weakens, but does not erase, fear memories. In rodents and humans alike, extinction attenuates conditioned fear expression through prefrontal inhibition. Fear can return after stress, be renewed when altering the environmental context, or reoccur with the passage of time By activating memories and disrupting their reconsolidation, through protein synthesis blockade local in the amygdala or through systemic administration of β-adrenergic receptor antagonists, fear memories are inhibited. Fear memory reconsolidation can also be disrupted behaviorally. In humans, extinction performed within the reconsolidation interval also inhibited fear, whereas extinction training performed outside of the reconsolidation interval spared the memory and fear returned. In animals, the neural functions enabling fear memory formation and reconsolidation are located in the amygdala. In humans, lesion and brain imaging studies confirm that the amygdala is a key area for fear memory encoding. Finally, we evaluated if activation of the fear memory in the amygdala was linked to activity in other nodes of the fear network by calculating the covariation between memory-associated amygdala activity and activity in the remaining network. Our amygdala seed of interest correlated strongly with activity bilaterally in the insula, hippocampus, and the midline anterior cingulate cortex and significantly more so in the 6 hours than in the 10 min group. No clusters showed a better correlation with the amygdala seed in the 10 min group. This suggests that the amygdala could be the primary site of memory plasticity, but also influence reconsolidation by affecting other regions of the fear network. The amygdala could thus play a modulatory, rather than a solitary, role in human fear reconsolidation processes. In summary, whereas the amygdala memory representation after activation and undisrupted reconsolidation predicted return of fear and was functionally coupled to other nodes of the brain’s fear network, disruption of reconsolidation significantly weakened the amygdala memory and its coupling, rendering it unrelated to both recall and return of fear. We conclude that extinction training initiated during reconsolidation abolishes fear expression by erasing a memory trace in the amygdala. Reactivated fear memories are sensitive to behavioral disruption, and the amygdala proves to be a key neurobiological substrate for this process also in humans. This mechanism holds great clinical promise in anxiety treatment in order to dissociate fear from cognitive memory. [end of paraphrase]
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