Plasticity Related To Extinction

In a recent human study, Bechara et al. (1999) used the association between monochrome color slides as CS and a startling loud and obnoxious sound as US to examine fear conditioning and extinction of fear responding (scored via changes in skin conductance responses) in patients with ventro-

Figure 3: Mean percent changes in synaptic efficacy (measured by changes in the amplitude of prefrontal response) induced by thalamic stimulation in mice. A. During re-exposure to a tone CS, initially paired with footshock. Thalamic high-frequency stimulation (HFS) induced potentiation of synaptic efficacy (Pre-CS), the level of which was reduced (but remained above the baseline) during re-exposure to the CS. B. Despite this potentiation, the expression of traumatic memory (assessed by freezing) was similar to those of conditioned mice that did not receive HFS (NHFS). Adopted from Herry and Garcia (2002) with permission.

Figure 3: Mean percent changes in synaptic efficacy (measured by changes in the amplitude of prefrontal response) induced by thalamic stimulation in mice. A. During re-exposure to a tone CS, initially paired with footshock. Thalamic high-frequency stimulation (HFS) induced potentiation of synaptic efficacy (Pre-CS), the level of which was reduced (but remained above the baseline) during re-exposure to the CS. B. Despite this potentiation, the expression of traumatic memory (assessed by freezing) was similar to those of conditioned mice that did not receive HFS (NHFS). Adopted from Herry and Garcia (2002) with permission.

medial prefrontal cortex lesions. All patients acquired CS-associated skin conductance responses that were similar in magnitude to the responses displayed by control subjects. These responses progressively extinguished, with a rate similar to the control group, during the phase of repeated CS-alone presentations (Fig. 4). This finding reveals that neurons within the medial prefrontal cortex are not required for the acquisition of extinction.

Animal studies, both in mice (Vouimba et al., 2000) and rats (Gerwitz et al., 1997; Quirk et al., 2000), have also led to an identical conclusion. In these studies, an explicit CS (a light or a tone) was paired with footshock US, and prefrontal lesions (either dorsal or ventral area of the medial prefrontal cortex) were made before of after this fear conditioning. Neither lesion location was found to disrupt the rate of extinction. There are,

Figure 4: Magnitude of skin conductance responses (SCR) during habituation, CS-US association (conditioning), and CS-no US learning (extinction 1 and 2). The SCR generated by control and prefrontal patients (lesion location in VMF cortex shown in A) during the conditioning phase were significantly higher than those generated during the habituation or extinction phase (shown in B; all p values < 0.001). The two groups did not differ from each other. Adopted from Bechara et al. (1999) with permission.

Figure 4: Magnitude of skin conductance responses (SCR) during habituation, CS-US association (conditioning), and CS-no US learning (extinction 1 and 2). The SCR generated by control and prefrontal patients (lesion location in VMF cortex shown in A) during the conditioning phase were significantly higher than those generated during the habituation or extinction phase (shown in B; all p values < 0.001). The two groups did not differ from each other. Adopted from Bechara et al. (1999) with permission.

however, two exceptions showing retardation of extinction following either electrolytic (Morgan and LeDoux, 1995) or 6-hydroxydopamine (Morrow et al., 1999) lesions of the medial prefrontal cortex. However, this phenomenon was observed in the second study only with a high US intensity (0.8 mA versus 0.4 mA).

Although most of these studies have clearly shown that prefrontal lesions do not interfere with extinction of fear responding, analyses of neuronal activity within the medial prefrontal cortex have indicated the occurrence of specific plasticity related to extinction. In humans, two studies in which subjects were scanned before and after treatment for PTSD indicate such changes. In the first study, Levin et al. (1999) observed, in one PTSD patient, that treatment by eye movement desensitization and reprocessing is associated with increased activity in two areas: the anterior cingulate gyrus and the left frontal lobe. Note that the patient was also on an antidepressant treatment (with a selective serotonergic reuptake inhibitor, SSRI) throughout the study. In the second study, Fernandez et al. (2001) found in one subject that pharmacological treatment (with a SSRI)-inducing extinction of behavioral activity in response to trauma reminders was associated with a conversion from depression to potentiation of neuronal activity in the medial prefrontal cortex. Although requiring replication, these two human studies suggest that successful treatments for PTSD are associated with potentiation of neuronal activity within the medial prefrontal cortex. Similar changes in plasticity were also observed in the original animal study (Herry et al., 1999). This study showed that extinction of a freezing response during repeated presentations of a tone CS, previously paired with footshock, initially suppressed the CS-induced depression in prefrontal synaptic efficacy within the medial prefrontal cortex, with further presentations resulting in LTP-like changes.

Contrary to lesion findings, the above data on neuronal activity plasticity suggest a possible role of the medial prefrontal cortex in the acquisition of extinction. Another recent study in which an acceleration of extinction was observed by pairing infralimbic tetanic stimulation with CS-alone presentations also supports this view (Milad and Quirk, 2002). However, other recent analyses of prefrontal synaptic plasticity (Herry and Garcia, 2002) are in agreement with lesion studies, rejecting any implication of prefrontal neuronal activity in fear inhibition during extinction. In this latter study, behavioral data indicate that all mice completely extinguished their freezing response toward a tone CS following 16 trials of CS-alone presentation. However, examination of individual changes in synaptic efficacy within the medial prefrontal cortex revealed two sub-groups of mice. One sub-group displayed maintenance of depression in response to

CS, whereas disappearance of this depression (with total restoration of baseline levels) characterized the other group. Despite this electrophysiological difference, the two sub-groups similarly extinguished their fear responding (Fig. 5). Likewise, mice receiving tetanic thalamic stimulation before extinction or thalamic low-frequency stimulation during extinction developed LTP and LTD, respectively, that did not affect the within-session rate of extinction (Herry and Garcia, 2002).

Figure 5: Mean percentage of changes in synaptic efficacy during re-exposure of mice to a tone CS (in A), initially paired with footshock. CS-alone presentations induced decreased synaptic efficacy (trials 1-4), which, during trials 13-16, was still present in half of animals (sub-group 1), while the other half exhibited a return to baseline synaptic efficacy (sub-group 2). However, mice in both sub-groups exhibited similar extinction of freezing behavior (in B). Adopted from Ilerry and Garcia (2002) with permission.

Figure 5: Mean percentage of changes in synaptic efficacy during re-exposure of mice to a tone CS (in A), initially paired with footshock. CS-alone presentations induced decreased synaptic efficacy (trials 1-4), which, during trials 13-16, was still present in half of animals (sub-group 1), while the other half exhibited a return to baseline synaptic efficacy (sub-group 2). However, mice in both sub-groups exhibited similar extinction of freezing behavior (in B). Adopted from Ilerry and Garcia (2002) with permission.

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