Extinction during reconsolidation of threat memory diminishes prefrontal cortex involvement

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.fear | Pavlovian conditioning | defense | learning E fforts to control maladaptive defensive reactions through extinction or exposure therapy are sometimes short-lived because these techniques do not significantly alter the threat memory itself, but rather regulate its expression via the prefrontal cortex's (PFC) inhibition of the amygdala (1, 2). Individual variation in the integrity of this amygdala-prefrontal circuitry has been linked to trait anxiety and posttraumatic stress disorder, suggesting that exposure-based techniques may be least effective in those who suffer from anxiety disorders (3-9).Recently, it has been shown in mice (10, 11), rats (12), and humans (13-16) that precisely timing behavioral extinction to coincide with memory reconsolidation can persistently inhibit the return of defensive reactions (but see refs. 17-19 for a discussion of boundary conditions). Reconsolidation is the state to which memories enter upon retrieval, which makes them prone to interference (20)(21)(22). Behavioral interference of reconsolidation using extinction has been linked to alterations in glutamate receptor function in the amygdala, which plays a critical role in memory plasticity (10,12). These findings are consistent with the suggestion that, in contrast to standar...

Fear Memory

“…The IL vmPFC thus may be viewed as a gate between the conditioning and the extinction of fear learning (421,514,568,580,581). The IL is believed to integrate, through feedback loops, LA/ BLA information with that produced by hippocampal neurons in the generation and extinction of fear responses (116,598,608).…”

Persistence and plasticity in the human memory system: An empirical investigation of the overwriting hypothesis

“…Moreover, our review of the literature indicates that the extant evidence for the theory is remarkably tenuous (see Chapter 2). Although striking performance deficits have been reported in human participants using a procedural sequence learning paradigm (Walker et al, 2003), and a fear-conditioning paradigm (Schiller et al, 2010(Schiller et al, , 2013, these e ects were absent in several subsequent replication attempts (e.g., Chapter 3, Golkar et al, 2012;Kindt & Soeter, 2013), suggesting that either the original e ects were false positives, or the necessary conditions for reliably obtaining reconsolidation e ects have not yet been adequately specified. Either way, future replications are to be encouraged as they are a vital tool for verifying the reliability of previous findings, and/or identifying genuine boundary conditions, both essential ingredients of theoretical progress.…”

Extinction learning, which consists of the inhibition of retrieval, can be learned without retrieval

“…Reconsolidation is viewed as a consequence of the labilization of consolidated memories at the time of the unreinforced retrieval, which renders them open to strengthening and updating (3)(4)(5)(6)(7)(14)(15)(16)(17)(18)(19)(20), whereas extinction is viewed as a form of learning to inhibit retrieval of original memory (8)(9)(10)(11)(12). Pavlov observed more than a century ago (8) that extinguished responses can recover spontaneously with the passage of time, which indicates that extinction does not erase memories.…”