Ventral medial prefrontal cortex and emotional perseveration: the memory for prior extinction training

Abstract

Several years ago, we found that lesions of ventral medial prefrontal cortex (mPFCv) disrupted performance during the extinction component of a classical fear conditioning task without affecting acquisition performance. We called this emotional perseveration, hypothesizing that mPFCv may normally act to inhibit fear responses to a conditioned stimulus (CS) when the CS no longer signals danger. Subsequent studies have supported this hypothesis, showing that mPFCv is crucial for the memory of prior extinction training. The present study examined the effects of mPFCv lesions made after training. Such lesions resulted in reduced freezing to contextual stimuli and normal responding to the CS presented alone during a retention test. Rats were then subjected to extinction trials (CS without US) over multiple days. In contrast to pre-training lesions, post-training lesions had little effect on extinction rate. All rats were given additional training. Lesioned rats expressed greater fear reactions than controls, indicating that prior extinction was less effective in them. Lesioned rats also showed resistance to extinction during reextinction trials, confirming our earlier finding that lesions made before training weaken the effectiveness of extinction trials. These results suggest three conclusions. First, an intact mPFCv during acquisition may protect the animal from prolonged responding during extinction trials following brain insult. Second, changes in mPFCv may predispose subjects toward enhanced fear reactions that are difficult to extinguish when reexposed to fearful stimuli, due to a diminished capacity to benefit from the fear-reducing impact of prior extinction experience. Third, contextual cues processed by mPFCv may influence extinction performance.

Introduction

A prominent feature of prefrontal cortex (PFC) pathology is perseveration, the inability to inhibit behaviors that are no longer appropriate under present circumstances ([10], [23], [29], [30], [37], [51], [56]; see [31], [32]). While such perseverative behaviors have typically been observed in reversal learning tasks (see [21], [31]), several years ago we found evidence of perseveration in conditioned fear [40]. In a study examining the role of the ventral portion of medial PFC (mPFCv) in fear conditioning, lesioned rats exhibited emotional perseveration—an increased tendency to continue responding to a conditioned fear stimulus (a tone) in the absence of the unconditioned stimulus (US; foot shock) during extinction trials. We concluded that mPFCv plays an important role in regulating fear inhibition during the extinction process, when conditioned responses are weakened as a result of exposure to the conditioned stimulus (CS) alone.

Since that time, several studies have provided support for the idea that medial prefrontal cortex is involved in the extinction component of conditioned fear learning ([1], [24], [25], [38], [41], [50]; but see [22]). Morrow et al. [41] found that mPFCv lesions disrupt extinction performance, whether lesions were made prior to or following acquisition training. The work of Quirk and colleagues [38], [50] has been particularly informative in showing that mPFCv, the infralimbic cortex (IL) in particular, is important for the retention of extinction learning following a 24 h delay, but not during fear acquisition or the expression of extinction during massed extinction training. Their findings provide evidence for the prevailing idea that the extinction process involves formation of a new, inhibitory association that develops in competition with, but without erasure of, the excitatory association formed during acquisition [5], [33], [42], [45], [46], [50].

The current study had two objectives. The first was to examine the impact of post-acquisition lesions on the retention and extinction of fear responses. Previously, we found that pre-training lesions had no effect on the retention of acquisition but did affect extinction [40]. If mPFCv is only actively engaged during extinction retention [38], [50], then rats with post-acquisition lesions should show resistance to extinction just as they did when lesions were made prior to fear conditioning [40]. The second goal was to examine the effectiveness of extinction by determining the extent to which reacquisition of fear responses is affected by prior extinction. Bouton and King [8] have proposed that memories of acquisition and extinction are both available following extinction, and that responding to an extinguished CS may be affected by both. Using the reacquisition procedure, it was possible to examine whether lesioned and control rats were differentially affected by extinction. We hypothesized that lesioned animals would express more fear than controls during reacquisition, which would indicate that prior extinction trials were less effective in guiding their behavior.