It is important to point out that the term “extinction” is used in several different ways. Extinction may refer to 1) the experimental procedure used to produce a decrement in the fear response; 2) the decremental effect of this procedure upon the fear response; and 3) the theoretical process responsible for that effect. Moreover, extinction can be measured both at the time the fear-inducing cue is presented in the absence of the aversive event and at a later time. We will define the experimental procedure as extinction training, the decrement in the fear response measure during extinction training as within-session extinction, and the decrement measured at some interval after extinction training as extinction retention. The term extinction will be reserved for the theoretical process underlying the loss of the conditioned fear response.
Extinction is known not to result from forgetting because the fear-conditioned response lasts months, even years, in the absence of additional training after fear acquisition4
(). The mechanism of extinction has been the subject of some debate historically. Some theories have described extinction as an “unlearning” process that results when the fear-inducing cue no longer predicts delivery of the aversive event.5
Others have emphasized habituation to the cue as a function of repeated presentation of the cue in the absence of the aversive event.6
However, three major pieces of evidence challenge these views. First, the expression of extinction dissipates (i.e., the extinguished response reappears) over time after extinction training, a phenomenon known as spontaneous recovery7
(). Second, extinguished responses reappear when the subject is tested outside of the context of extinction training, a phenomenon known as renewal8
(). Third, extinguished responses reappear when the subject is exposed to unsignaled presentations of the aversive event after extinction training, a phenomenon known as reinstatement9
(). In each of these cases, the reappearance of extinguished responses in the absence of additional pairings of the cue and the aversive event indicates that the fear response cannot have been unlearned. Habituation to the cue potentially can account for spontaneous recovery and reinstatement because habituation dissipates over time and is disrupted by stressors,10
but habituation cannot easily account for renewal because habituation does not seem to be context specific11,12
(but see McSweeney and Swindell10
for some potentially important exceptions). Thus, it would seem that extinction is a complex phenomenon that is not well characterized as either an erasure of memory or a nonassociative response decrement.
FIG. 1 Behavioral features of extinction. A: Extinction is not the same as forgetting because the acquired fear response does not disappear unless the cue is presented in the absence of shock. B: At relatively extended intervals after extinction, conditioned (more ...)
An alternative class of theories proposes that extinction is a form of new learning that counteracts the expression of the conditioned fear response.13–16
These “inhibitory” theories suggest that fear memories are not erased in extinction but rather are inhibited in a context-dependent manner, such that the subject effectively learns that “now, in this place, the cue no longer predicts the aversive event.” Hence, when the subject is tested in a context different from the one in which extinction training occurred (renewal) or when an interval of time elapses following the completion of extinction training (spontaneous recovery), the status of the cue as a predictor of the aversive event becomes ambiguous and the conditioned fear response returns. These theories emphasize retention of fear memory throughout and beyond extinction training and conceptualize extinction as new learning that suppresses fear responses.
As neuroscientists have begun to investigate extinction, they have been guided by this basic behavioral and theoretical work and have accumulated a body of data that is consistent with an inhibitory account. For example, it has been established that fear extinction, like fear acquisition, is dependent on NMDA receptors (NMDARs) and L-type voltage-gated calcium channels (L-VGCCs)17,18
; is sensitive to modulation of second messenger systems, including kinase and phosphatase activity19
; and may require protein synthesis.20,21
Moreover, some conditioned single unit responses to the fear-eliciting cue within the basolateral amygdala persist through extinction22
and can be modulated by context following extinction training in a cellular correlate of renewal.23
Extinction is postulated to reflect engagement of GABAergic interneurons and/or intercalated cell populations within the amygdala, perhaps under the control of efferent structures such as prefrontal cortex,24
so as to effectively inhibit amygdalar activation by the CS after extinction training.25
Curiously, very recent neurobiological data have emerged in support of a mechanism more consistent with an “unlearning” account of extinction, in which plasticity underlying fear memory is compromised through a process known as synaptic depotentiation. Depotentiation refers to a reversal of long-term potentiation (LTP) when low-frequency or theta-frequency stimulation is applied to afferent pathways shortly following LTP induction. Because LTP of sensory pathways onto principal neurons within the amygdala is a major candidate mechanism for the acquisition and retention of conditioned fear responses,26
processes such as depotentiation that reverse LTP would be hypothesized to erase fear memories. Lin and Gean27
have demonstrated that depotentiation occurs in the amygdala in vitro
and that its induction shares some key features with fear extinction in the behaving animal. For example, both depotentiation and extinction are blocked by NMDAR and L-VGCC channel antagonists as well as inhibitors of calcineurin, a major protein phosphatase.27,28
Both depotentiation and extinction also are associated with an increase in calcineurin protein levels and enzymatic activity within the amygdala, as well as a reversal of fear- or LTP-associated increases in phosphorylated target molecules such as Akt. Finally, depotentiation-inducing low-frequency stimulation of the amygdala in vivo
10 min after fear acquisition blocks the expression of conditioned fear 24 h later, an effect that could be interpreted as a mimicking of extinction.27,28
These findings are impressive but puzzling because it is not clear at the present time how to reconcile them with observations of recovery of fear after extinction through spontaneous recovery, renewal, and reinstatement. Clearly, if treatments could be devised that would lead to an erasure of traumatic fear memories, this could potentially be very significant from a clinical perspective, and for this reason our laboratory currently is trying to tease apart variables that might produce an erasure of fear memory versus those that might lead to an active inhibition of fear memory in animals. For all practical purposes, however, extinction seems to be best characterized as an active inhibition of fear. Consistent with this, most pharmacological treatments that facilitate fear extinction in animals appear to do so by interacting with the major inhibitory neurotransmitter in the mammalian brain, GABA.