The Effect of Temporary Amygdala Inactivation on Extinction and Reextinction of Fear in the Developing Rat: Unlearning as a Potential Mechanism for Extinction Early in Development

Kim, Jee Hyun; Richardson, Rick

doi:10.1523/jneurosci.4736-07.2008

Cited by 103 publications

(120 citation statements)

References 42 publications

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“…This resistance of extinction to spontaneous recovery, reinstatement, and renewal suggests that extinction training at this developmental stage may evoke a process akin to unlearning of the original fear memory, as opposed to the formation of a new competing safety memory. Consistent with this interpretation, extinction learning in these pre-weanling animals does not depend upon engagement of the IL, but instead appears to be amygdala-dependent (Kim et al, 2009;Kim and Richardson, 2008). This suggests that early-life extinction may effectively yield fear erasure.…”

Section: Developmental Changes In Fear-learning Circuitssupporting

confidence: 60%

Sensitive Periods in Affective Development: Nonlinear Maturation of Fear Learning

Hartley

Lee

2014

Neuropsychopharmacol

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At specific maturational stages, neural circuits enter sensitive periods of heightened plasticity, during which the development of both brain and behavior are highly receptive to particular experiential information. A relatively advanced understanding of the regulatory mechanisms governing the initiation, closure, and reinstatement of sensitive period plasticity has emerged from extensive research examining the development of the visual system. In this article, we discuss a large body of work characterizing the pronounced nonlinear changes in fear learning and extinction that occur from childhood through adulthood, and their underlying neural substrates. We draw upon the model of sensitive period regulation within the visual system, and present burgeoning evidence suggesting that parallel mechanisms may regulate the qualitative changes in fear learning across development.

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Section: Developmental Changes In Fear-learning Circuitssupporting

confidence: 60%

Sensitive Periods in Affective Development: Nonlinear Maturation of Fear Learning

Hartley

Lee

2014

Neuropsychopharmacol

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“…Preweanling-aged rats (17-d-old), however, did not display these phenomena. Extinction in 24-d-old rats, moreover, involved the core brain regions of the extinction circuitry in adults (i.e., the amygdala and the vmPFC), whereas in 17-d-old rats extinction engaged the amygdala but not the vmPFC (31,32).…”

Section: Discussionmentioning

confidence: 91%

Extinction during reconsolidation of threat memory diminishes prefrontal cortex involvement

Schiller

Kanen²,

LeDoux

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

264

254

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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...

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“…One plausible explanation for the absence of an action of PEPA on reextinction is as follows. Several studies suggest that the BLA is not required for reextinction Kim and Richardson, 2008).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Discrimination of Extinction and Reconsolidation of Contextual Fear Memory by a Potentiator of AMPA Receptors

Yamada

Zushida

Wada

et al. 2009

Neuropsychopharmacol

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Conditioned fear memory, once formed through fear conditioning, is modulated by reexposure of individuals to a conditioned stimulus. The reexposure reactivates the fear memory, which induces reconsolidation of the memory first, and then extinction of the fear response. Both attenuating the former and facilitating the latter are effective in reducing the fear response, and these findings are potentially translatable to the enhancement of exposure therapy for complex anxiety disorders. Currently, there is no drug that is established to modulate either reconsolidation or extinction selectively, which are thought to be independent processes. Here, we report that an extinction-facilitating AMPA potentiator, 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide (PEPA), does not act on the reconsolidation of fear memory formed by contextual fear conditioning in mice. The freezing rates observed in contextually conditioned mice following short reexposure (3 min) to the context were not influenced by intraperitoneal or intra-amygdala administration of PEPA. The same short reexposure to the context enhanced freezing responses in mice that were similarly administered D-cycloserine (DCS), a drug that facilitates both extinction and reconsolidation, and this enhancement of freezing responses in mice intraperitoneally administered DCS was abolished by propranolol, a drug that suppresses reconsolidation. At the same doses used in the short reexposure experiments, PEPA and DCS facilitated extinction of the fear response induced by long reexposure to the context and suppressed reinstatement of the conditioned fear memory. PEPA and DCS did not affect reextinction. These results suggest that PEPA acts on extinction of contextual fear memory without having detectable influences on its reconsolidation.

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The Effect of Temporary Amygdala Inactivation on Extinction and Reextinction of Fear in the Developing Rat: Unlearning as a Potential Mechanism for Extinction Early in Development

Cited by 103 publications

References 42 publications

Sensitive Periods in Affective Development: Nonlinear Maturation of Fear Learning

Sensitive Periods in Affective Development: Nonlinear Maturation of Fear Learning

Extinction during reconsolidation of threat memory diminishes prefrontal cortex involvement

Pharmacological Discrimination of Extinction and Reconsolidation of Contextual Fear Memory by a Potentiator of AMPA Receptors

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