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Extinction during reconsolidation of threat memory diminishes prefrontal cortex involvement
Contributed by Joseph E. LeDoux, October 30, 2013 (sent for review August 13, 2013)

Significance
An advantage of targeting reconsolidation to control reactions to learned threats is that the memory appears to be persistently altered, not inhibited. When these memories are diminished through extinction, the amygdala’s representation remains largely intact and the prefrontal cortex inhibits its expression, thus allowing the learned responses to recover. Targeting reconsolidation, therefore, should eliminate the necessity of prefrontal inhibition. We tested this hypothesis by contrasting standard extinction with extinction occurring during reconsolidation. We observed that behavioral interference of reconsolidation appears to bypass the prefrontal circuitry of extinction, inducing a more persistent loss of learned responses. Application of this strategy, which targets underlying learned threat processes, to fear and anxiety disorders may provide a more effective approach to treatment.
Abstract
Controlling learned defensive responses through extinction does not alter the threat memory itself, but rather regulates its expression via inhibitory influence of the prefrontal cortex (PFC) over amygdala. Individual differences in amygdala–PFC circuitry function have been linked to trait anxiety and posttraumatic stress disorder. This finding suggests that exposure-based techniques may actually be least effective in those who suffer from anxiety disorders. A theoretical advantage of techniques influencing reconsolidation of threat memories is that the threat representation is altered, potentially diminishing reliance on this PFC circuitry, resulting in a more persistent reduction of defensive reactions. We hypothesized that timing extinction to coincide with threat memory reconsolidation would prevent the return of defensive reactions and diminish PFC involvement. Two conditioned stimuli (CS) were paired with shock and the third was not. A day later, one stimulus (reminded CS+) but not the other (nonreminded CS+) was presented 10 min before extinction to reactivate the threat memory, followed by extinction training for all CSs. The recovery of the threat memory was tested 24 h later. Extinction of the nonreminded CS+ (i.e., standard extinction) engaged the PFC, as previously shown, but extinction of the reminded CS+ (i.e., extinction during reconsolidation) did not. Moreover, only the nonreminded CS+ memory recovered on day 3. These results suggest that extinction during reconsolidation prevents the return of defensive reactions and diminishes PFC involvement. Reducing the necessity of the PFC–amygdala circuitry to control defensive reactions may help overcome a primary obstacle in the long-term efficacy of current treatments for anxiety disorders.
Footnotes
- ↵1To whom correspondence may be addressed. E-mail: daniela.schiller{at}mssm.edu, liz.phelps{at}nyu.edu, or ledoux{at}cns.nyu.edu.
Author contributions: D.S., J.E.L., M.H.M., and E.A.P. designed research; D.S. and J.W.K. performed research; D.S., J.W.K., and E.A.P. analyzed data; and D.S., J.W.K., J.E.L., and E.A.P. wrote the paper.
The authors declare no conflict of interest.
Freely available online through the PNAS open access option.
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