Neural mechanisms of extinction learning and retrieval

Quirk, G.J. & Mueller, D. (2008). Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology, 33, 56-72.

Early in the study of classical conditioning, Pavlov observed spontaneous recovery of responding to an extinguished conditioned stimulus. This witnessed 'uncovering phenomena', brought on by a change in context or stimulus presentation, led to the belief that extinction is not erasure of a previous fear memory but rather the learning of an additional inhibitory memory. This paper reviews what has been learned about extinction learning ever since. Like other types of learning, extinction occurs in three phases: acquisition, consolidation, and retrieval. Acquisition seems to depend on the basolateral amygdala (BLA) and the ventrolateral periaqueductal gray (vlPAG) structures. Consolidation seems to be most dependent on the BLA, where the learning of new memories (requiring protein synthesis) appears to take place. It also seems to rely on the involvement of the prefrontal cortex and the hippocampus. Retrieval requires expression of an inhibitory memory, and as such, during retrieval we see activation of inhibitory networks in the amygdala, cortical control of amygdala inhibition by the IL mPFC, and contextual regulation provided by the hippocampus and mPFC. Thus, like classical conditioning, extinction seems to be distributed across a network of structures, rather than centered in any one particular area.

The paper also raises many fascinating special issues. One challenges the Pavlovian idea that extinction is purely an additional inhibitory memory: recent evidence seems to indicate that extinction leads to reversal of conditioning-induced phosphorylation of CREB, indicating some erasure of the original BLA fear memory!

It also discusses anxiety disorders and PTSD which may be caused by a failure to retrieve an extinction memory generated in extinction-based treatment. Subjects with PTSD show reduced volume and activity in the vmPFC and hippocampus areas, along with increased activity in the amygdala, suggesting inhibitory control and contextual modulation of extinction may be compromised. It also mentions that chronic stress can impede extinction-based therapies, decreasing dendritic branching and spine count in the vmPFC and hippocampus, and increasing dendritic branching and spine count in the BLA, thereby enhancing conditioning effects and impairing extinction. Recently, deficits in fear extinction observed in these human disorders have been combated with pharmacological agents, facilitating extinction of the fear memory with the help of D-cycloserine and impairing fear memory reconsolidation with the B-adrenergic receptor blocker propranolol.