Conditioned fear responses to a tone previously paired with a shock diminish if the tone is repeatedly presented without the shock, a process known as extinction. Since Pavlov it has been hypothesized that extinction does not erase conditioning, but forms a new memory. Destruction of the ventral medial prefrontal cortex, which consists of infralimbic and prelimbic cortices, blocks recall of fear extinction, indicating that medial prefrontal cortex might store long-term extinction memory. Here we show that infralimbic neurons recorded during fear conditioning and extinction fire to the tone only when rats are recalling extinction on the following day. Rats that froze the least showed the greatest increase in infralimbic tone responses. We also show that conditioned tones paired with brief electrical stimulation of infralimbic cortex elicit low freezing in rats that had not been extinguished. Thus, stimulation resembling extinction-induced infralimbic tone responses is able to simulate extinction memory. We suggest that consolidation of extinction learning potentiates infralimbic activity, which inhibits fear during subsequent encounters with fear stimuli.

Emotional learning is necessary for individuals to survive and prosper. Once acquired, however, emotional associations are not always expressed. Indeed, the regulation of emotional expression under varying environmental conditions is essential for mental health. The simplest form of emotional regulation is extinction, in which conditioned responding to a stimulus decreases when the reinforcer is omitted. Two decades of research on the neural mechanisms of fear conditioning have laid the groundwork for understanding extinction. In this review, we summarize recent work on the neural mechanisms of extinction learning. Like other forms of learning, extinction occurs in three phases: acquisition, consolidation, and retrieval, each of which depends on specific structures (amygdala, prefrontal cortex, hippocampus) and molecular mechanisms (receptors and signaling pathways). Pharmacological methods to facilitate consolidation and retrieval of extinction, for both aversive and appetitive conditioning, are setting the stage for novel treatments for anxiety disorders and addictions.

The psychology of extinction has been studied for decades. Approximately 10 years ago, however, there began a concerted effort to understand the neural circuits of extinction of fear conditioning, in both animals and humans. Progress during this period has been facilitated by an unusual degree of coordination between rodent and human researchers examining fear extinction. This successful research program could serve as a model for translational research in other areas of behavioral neuroscience. Here we review the major advances and highlight new approaches to understanding and exploiting fear extinction.

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The learning and remembering of fearful events depends on the integrity of the amygdala, but how are fear memories represented in the activity of amygdala neurons? Here, we review recent electrophysiological studies indicating that neurons in the lateral amygdala encode aversive memories during the acquisition and extinction of Pavlovian fear conditioning. Studies that combine unit recording with brain lesions and pharmacological inactivation provide evidence that the lateral amygdala is a crucial locus of fear memory. Extinction of fear memory reduces associative plasticity in the lateral amygdala and involves the hippocampus and prefrontal cortex. Understanding the signalling of aversive memory by amygdala neurons opens new avenues for research into the neural systems that support fear behaviour.

Current models of conditioned fear expression and extinction involve the basolateral amygdala (BLA), ventral medial prefrontal cortex (vmPFC), and the hippocampus (HPC). There is some disagreement with respect to the specific roles of these structures, perhaps due to subregional differences within each area. For example, growing evidence suggests that infralimbic (IL) and prelimbic (PL) subregions of vmPFC have opposite influences on fear expression. Moreover, it is the ventral HPC (vHPC), rather than the dorsal HPC, that projects to vmPFC and BLA. To help determine regional specificity, we used small doses of the GABAA agonist muscimol to selectively inactivate IL, PL, BLA, or vHPC in an auditory fear conditioning and extinction paradigm. Infusions were performed prior to extinction training, allowing us to assess the effects on both fear expression and subsequent extinction memory. Inactivation of IL had no effect on fear expression, but impaired the within-session acquisition of extinction as well as extinction memory. In contrast, inactivation of PL impaired fear expression, but had no effect on extinction memory. Inactivation of the BLA or vHPC impaired both fear expression and extinction memory. Post-extinction inactivations had no effect in any structure. We suggest a model in which amygdala-dependent fear expression is modulated by inputs from PL and vHPC, whereas extinction memory requires extinction-induced plasticity in IL, BLA and/or vHPC.

Conditioned fear responses to a tone paired with footshock extinguish when the tone is presented repeatedly in the absence of shock. Rather than erase the tone-shock association, extinction is thought to involve new learning accompanied by inhibition of conditioned responding. Despite much interest in extinction from a clinical perspective, little is known about the neural circuits that are involved. Although the prefrontal cortex has a well established role in the inhibition of inappropriate behaviors, previous reports have disagreed as to the role of the ventromedial prefrontal cortex (vmPFC) in extinction. We have reexamined the effects of electrolytic vmPFC lesions made before training on the acquisition, extinction, and recovery of conditioned fear responses in a 2 d experiment. On Day 1 vmPFC lesions had no effect on acquisition or extinction of conditioned freezing and suppression of bar pressing. On Day 2 sham rats recovered only 27% of their acquired freezing, whereas vmPFC-lesioned rats recovered 86%, which was indistinguishable from a control group that never received extinction. The high recovery in lesioned rats could not be attributed to decreased motivation or altered sensitivity to footshock. vmPFC lesions that spared the caudal infralimbic (IL) nucleus had no effect. Thus, the vmPFC (particularly the IL nucleus) is not necessary for expression of extinction, but it is necessary for the recall of extinction learning after a long delay. These data suggest a role of the vmPFC in consolidation of extinction learning or the recall of contexts in which extinction took place.Key words: extinction; infralimbic; prelimbic; fear conditioning; amygdala; inhibition Prefrontal cortex has long been implicated in inhibition of inappropriate responses. Lesions of medial prefrontal cortex (mPFC) cause perseverative responding in animals and humans and cause deficits in reversal tasks (for review, see Kolb, 1984;Fuster, 1997). Perseverative responding in prefrontal animals was extended to conditioned fear when it was shown that rats with mPFC lesions could acquire freezing responses to a tone paired with a footshock, but they required many more days to extinguish those responses when the tone was presented alone (Morgan et al., 1993). More recent data support the hypothesis that mPFC is involved in the inhibition of fear responses (Bremner et al., 1999;Herry et al., 1999;Morrow et al., 1999), and it has been suggested that deficits in extinction of conditioned fear may cause certain anxiety disorders (Charney and Deutch, 1996;Pitman, 1997).Many questions remain, however, concerning the role of the ventromedial prefrontal cortex (vmPFC) in extinction of fear. Following the original report by Morgan et al. (1993), Gewirtz et al. (1997 found no effect of vmPFC lesions on extinction of conditioned fear responses. To explain this discrepancy, Gewirtz et al. (1997) suggested that the prolonged extinction might have been attributable to increased acquisition in the lesioned animals, which was masked by asymptotic freezi...

Extinction is a form of inhibitory learning that suppresses a previously conditioned response. Both fear and drug seeking are conditioned responses that can lead to maladaptive behavior when expressed inappropriately, manifesting as anxiety disorders and addiction, respectively. Recent evidence indicates that the medial prefrontal cortex (mPFC) is critical for the extinction of both fear and drug-seeking behaviors. Moreover, a dorsal-ventral distinction is apparent within the mPFC, such that the prelimbic (PL-mPFC) cortex drives the expression of fear and drug seeking, whereas the infralimbic (IL-mPFC) cortex suppresses these behaviors after extinction. For conditioned fear, the dorsal-ventral dichotomy is accomplished via divergent projections to different subregions of the amygdala, whereas for drug seeking, it is accomplished via divergent projections to the subregions of the nucleus accumbens. Given that the mPFC represents a common node in the extinction circuit for these behaviors, treatments that target this region may help alleviate symptoms of both anxiety and addictive disorders by enhancing extinction memory.