Plasticity Related To Traumatic Memory

Abnormal traumatic recall and fear responding (e.g. increased heart rate and blood pressure) can occur in PTSD patients in the absence of CS (e.g. intrusive memories, recurrent dreams, and "flashbacks" of the traumatic event). This suggests the potential existence of abnormalities in the circuits implicated in the emotional regulation of memory (e.g. the prefrontal cortex and the amygdala). Experimentally, traumatic memory is activated and expressed during exposure of PTSD patients to a provocative stimulus (e.g. traumatic pictures and sounds in combat veterans; Prins et al., 1995), or when an aversive CS is presented to a previously conditioned individual (both animals and humans). In this latter case, animals (Gerwitz et al., 1997; Morrow et al., 1999; Quirk et al., 2000) or humans (Bechera et al., 1999) with lesions of the medial prefrontal cortex have been found to express normal traumatic memory. The only exception concerns lesions located in the more dorsal part of the medial prefrontal cortex, for which potentiation of conditioned fear behavior (freezing responses) has been reported both in rats (Morgan and LeDoux, 1995) and mice (Vouimba et al., 2000). Although these results are far from uniform, it has been repeatedly suggested that a class of prefrontal neurons modulates fear responding via their inhibitory connections with amygdalar neurons that are involved in the expression of traumatic memory (LeDoux, 1993, Devinsky et al., 1995; Vouimba et al., 2000; Vermetten and Bremner, 2002). Consequently, damage to this class of prefrontal neurons produces potentiation of certain emotional responses (but also see Holson, 1986; Jaskiw and Weinberger, 1992; Frysztak and Neafsey, 1994). However, this potentiation remains difficult to explain, especially in the light of data from neuroimaging and electrophysiological studies reporting the absence of prefrontal neuronal activity effects on expression of traumatic memory (particularly before any acquisition of CS-no US association).

Firstly, in humans, Bremner and colleagues have reported consistent neuroimaging data demonstrating changes in blood flow in the medial prefrontal cortex (Brodmann's area 25) in PTSD patients. In particular, this group (Bremner et al., 1997, 1999) showed that exposure to traumatic conditioned stimuli (e.g. war sounds such as helicopter sounds, explosions, and machine gun fire) results in a decreased blood flow bilaterally in the medial prefrontal cortex in these patients (Fig. 1). This observation was also confirmed in a more recent study using war sounds as a provocation of PTSD symptoms (Fernandez et al., 2001). In general, it is admitted that neuronal firing (or synaptic efficacy) and blood flow increments or decrements are tightly paired (Kety and Schmidt, 1945). Hence, a decreased blood flow in bilateral medial prefrontal cortex may correspond to a decreased neuronal firing or synaptic efficacy. If decreased prefrontal activity (Brodmann's area 25) results in reduced inhibitory effects on amygdalar neurons involved in the expression of traumatic memory, increased prefrontal activity in the same area during similar provocation of PTSD symptoms should alter the expression of fear responses. However, two other neuroimaging studies, using helicopter sounds, explosions, and machine gun fire as provocative stimuli, have provided contrasting data. In one of these studies, no differences in prefrontal activation (Brodmann's

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Figure 1: Scanning of the brain of a patient with combat-related PTSD during exposure to traumatic CS (combat-related sounds). The CS triggered expression of traumatic memory (e.g. increased heart rate and blood pressure), which was associated with decreased blood flow in the medial prefrontal cortex (arrow). From Bremner et al. (1999) with permission.

area 25) were found between combat veterans with and without PTSD or noncombattant controls (Liberzon et al., 1999). In the other study, it was observed that these stimuli produce an increased, instead of decreased, activity in the same frontal area (Zubieta et al., 1999). However, in addition to these different patterns of changes in neuronal activity in the medial prefrontal cortex, all of these studies reveal similar war sounds-associated distresses (scored via psychophysiological measures, such as increased skin conductance and heart rate). Therefore, similar symptom provocation paradigms can induce contrasting effects on neuronal activity in the medial prefrontal cortex, indicating a dissociation between the evoked direction of activity (decrease or increase or even no change) and the expression of traumatic memory. Additional studies are still needed to better understand this divergence in humans.

Secondly, animal studies examining the effects of aversive CS on prefrontal neuronal activity have also led to contradictory results concerning the medial prefrontal cortex (lesions of which produced either no change or potentiation of freezing behavior, as seen above). Garcia et al. (1999) and Milad and Quirk (2002) measured changes in spontaneous activity in the medial prefrontal cortex during re-exposure of animals (mice and rats, respectively) to a tone initially paired with foot shock. In the first study, animals were conditioned with "light-tone" presentations signaling the omission of shock (conditioned inhibition procedure) or without this procedure ("light-tone" unpaired, the tone being always reinforced). During conditioning tests (i.e. expression of traumatic memory), the "light-tone" paired group displayed less freezing than the "light-tone" unpaired group, indicating the acquisition of conditioned inhibition. Analyses of changes in multi-unit activity in the dorso-medial prefrontal cortex showed a greater decrease in the activity in the "light-tone" paired group than in the other group, with a strong correlation found between the magnitude of expression of traumatic memory (freezing behavior) and the decrease in prefrontal activity. However, in the second study (Milad and Quirk, 2002), the authors reported the absence of changes in unit firing rate in the same area during the expression of freezing behavior to the tone CS. This divergence is probably due to different experimental conditions. Moreover, prefrontal cells displaying CS-evoked decreased activity are not easily encountered, and once encountered (see Fig. 2, next page), they rapidly switch from depression to normal activity (R. Garcia, unpublished observation). Despite this divergence between the observations of Garcia et al. (1999) and Milad and Quirk (2002), these findings yield at least one common point of convergence. Indeed, here also, as with the neuroimaging studies, one can conclude that levels of neuronal activity in the medial prefrontal cortex do not affect the magnitude of conditioned fear responses. Consequently, during post-conditioning CS presentation, prefrontal neuronal activity does not profoundly alter the activity of amygdalar neurons involved in the expression of traumatic memory expression.

This conclusion is also supported by synaptic plasticity studies. In particular, these studies have shown that glutamatergic synapses in the medial prefrontal cortex exhibit changes in the efficacy (depression or potentiation) following either a learning task or a train of electrical stimulation (high or low-frequency stimulation). High-frequency stimulation generally induces long-term potentiation (LTP), whereas low-frequency stimulation generally produces long-term depression (LTD) in behaving mice (Herry et al., 1999; Herry and Garcia, 2002). However, neither the direction of synaptic plasticity (LTP or LTD, as well as learning-induced potentiation or depression) was found to significantly alter the magnitude of freezing behavior (Herry et al., 1999; Herry and Garcia, 2002). For example, mice that received high-frequency stimulation before being re-exposed to the tone CS exhibited LTP that was still present during CS presentation, which, however, produced freezing levels similar to that expressed by the mice that did not receive tetanus (Fig. 3). Therefore, what the direction of the changes in plasticity of prefrontal neuronal activity signifies during the expression of traumatic memory remains unclear. However, because the prefrontal neurons play a key role in various cognitive functions, it is possible that the direction of changes in plasticity in this structure during CS-alone presentations may be related to processing of cognitive information such as the occurrence or the absence of danger (Herry et al., 1999). This may be mediated via its interactions with the amygdala.

Figure 2: Example of a cell, located (in A) in the dorsal part of the medial prefrontal cortex (dmPFC), showing (in B) decreased spontaneous spike number during re-exposure of a mouse to a tone CS, which was initially paired with footshock. Recordings were made 20 sec before the CS presentation (Pre-CS: 73 spikes) and during CS presentation (20 sec: 14 spikes).

Figure 2: Example of a cell, located (in A) in the dorsal part of the medial prefrontal cortex (dmPFC), showing (in B) decreased spontaneous spike number during re-exposure of a mouse to a tone CS, which was initially paired with footshock. Recordings were made 20 sec before the CS presentation (Pre-CS: 73 spikes) and during CS presentation (20 sec: 14 spikes).

Currently, we partially understand the role of the amygdala in the induction of changes in neuronal activity within the medial prefrontal cortex during the expression of traumatic memory. Neurons in the amygdala, which are involved in the expression of this type of memory, also seem to inhibit spontaneous activity in the medial prefrontal cortex in the presence of an aversive CS (Garcia et al., 1999). Our hypothesis is that, for certain subjects (humans and animals), following conditioning, CS-alone presentations rapidly trigger mechanisms, which still remain undetermined (and are in the heart of the debate on the relationship between fear responding and prefrontal neuronal plasticity), freeing prefrontal neurons from the traumatic CS-related activation of the amygdala. Moreover, this disconnection does not affect expression of traumatic memory, which remains under the control of neurons within the amygdala. However, the rapid return to baseline activity within the medial prefrontal cortex during fear responding may correspond to the processing of information such as that the CS is not followed by the US.

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