Neural mechanisms of extinction learning and retrieval

Abstract

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.

Figures

Fig. 1

Extinction learning occurs in three phases. Acquisition is characterized by a decrease in conditioned responses to the presentation of a CS without the US. Consolidation is a time-dependent process during which a long-term extinction representation is formed. Retrieval of extinction occurs at a later time, when the CS is re-presented. Good extinction retrieval is characterized by low levels of conditioned responses (green bar), whereas poor extinction retrieval is characterized by high levels of conditioned responses (red bar). Poor retrieval of extinction is normally observed following renewal, reinstatement, spontaneous recovery, or in pathological conditions characterized by extinction failure.

Fig. 2

Consolidation of extinction involves NMDAr-mediated bursting in infralimbic (IL) cortex. A) Action potentials from a single IL neuron before and after systemic injection of CPP, a competitive antagonist the NMDA receptor. CPP did not change the firing rate, but reduced high-frequency bursting, as evidenced by short interspike intervals (20−30 ms). B) Rats were conditioned to freeze to a tone paired with a shock, and then extinguished (tone alone). The following day, two thirds of the rats showed good retrieval of extinction (extinction success), whereas one third were unable to retrieve extinction (extinction failure). Prior to extinction, these two groups showed equivalent bursting in IL (bar graph insets), but 30 minutes after extinction, there was significantly less bursting in the extinction failure group. Thus, post-training IL bursting predicts extinction success and is a physiological signature of extinction consolidation (modified from Burgos-Robles et al., 2007).

Fig. 3

Extinction learning and expression relies on a network of three structures. The amygdala stores both conditioning and extinction memories. CS information enters the amygdala, hippocampus, and infralimbic cortex. The infralimbic cortex integrates CS information with contextual information from the hippocampus in order to determine extinction retrieval. In the extinction context, the infralimbic cortex inhibits amygdala output to reduce fear. Outside the extinction context, amygdala output is uninhibited.