Extinction of learned fear in rodents: implications for exposure-based treatment of anxiety disorders such as post-traumatic stress

This article briefly reviews the science of learned fear and its implications for fear disorders, such as post-traumatic stress. It is by Fred Westbrook and Nathan Holmes from the School of Psychology at the University of New South Wales.
Published in Neuroscience
Extinction of learned fear in rodents: implications for exposure-based treatment of anxiety disorders such as post-traumatic stress

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Fear protects us against current threat. It is expressed in sympathetic nervous system activation that mobilizes the body for action and in defensive responses that minimize the current threat or avoid it entirely. Fear also protects us against future threat by creating an enduring memory whose subsequent retrieval by threat-related cues triggers the fear responses that prepares the body for the anticipated threat. Although fear is normally adaptive, disorders of this emotion, such as post-traumatic stress (PTSD), are common, chronic and debilitating conditions (1, Box 1). Medication (e.g., specific serotonin reuptake inhibitors, SSRIs) can alleviate the symptoms of PTSD, at least in the short-term (2). However, the front-line, long-term treatment for the disorder is cognitive-behavioural therapy (CBT). A component of CBT is exposure in which the patient, aided by the clinician, confronts, rather than avoids, the trauma memory and its associated reminder cues and behaviours. The aim of these confrontations is to reduce, even eliminate the emotional impact of the trauma memory, thereby undermining the ability of the associated cues/behaviours to elicit the fear/avoidance that undermine the quality of the patient’s life. This aim is frequently achieved, but CBT fails in many patients; and even when successful in the short-term relapse, is common (2).

Box 1
PTSD: Definition and prevalence

Some clues as to why CBT fails and, when successful, why relapse occurs, comes from the study of fear extinction in laboratory rodents. A standard protocol to produce fear or threat learning consists in exposing rats to pairings of an innocuous stimulus, such as a light, and an innate source of danger, such as a brief but intense burst of noise. One or a few such pairings produce an association between the light and danger that is stored in long-term memory. Subsequent presentation of the light, days, weeks, even months later, elicits autonomic (changes in heart rate and blood pressure) and defensive responses (immobility, analgesia) indicative of fear in people. The standard protocol to eliminate these fear responses is to present the light in the absence of the innate source of danger. The rats now learn that the light is safe and gradually inhibit their fear responses until, finally, they cease to exhibit any fear. Fear is said to be extinguished. However, these new safety memories are relatively specific to the physical or internal (e.g., a drug such as a benzodiazepine) context where the light was presented alone. The light presented in a different context or when the rats are drug-free again elicits fear responses. Extinguished fear responses can also be restored by exposing the rats to the original source of danger or to some other stressor, and by simply allowing time to lapse. These fear restoration phenomena - renewal by a context shift, reinstatement by a stressor and spontaneous recovery with the lapse of time - point to the factors likely to promote relapse after apparently successful treatment of PTSD (3).

Treatment may also fail because confronting the trauma memory will undermine the ability of some of the associated memories to elicit fear and distress but may not undermine all of these memories. As noted above, the standard protocol to produce fear learning consists in pairing an innocuous stimulus (the light) with the innate source of danger (the startle/fear eliciting brief burst of intense noise). Another protocol to produce learned fear consists in pairing an innocuous stimulus, not with an innate source of danger, but, rather, with a learned source of danger (Box 2). In this protocol, rats first learn to fear the light that signals the innate source of danger (the burst of noise) and are then exposed to pairings of say a tone and the fear-eliciting light. These tone-light pairings produce associations that are stored in long-term memory, such that subsequent presentations of the tone (days/weeks later) elicit fear responses. Pavlov (1927) termed this protocol second-order conditioning because the stimulus (the tone) was never paired with the innate source of danger [what he called an unconditioned stimulus (US)] but only with the stimulus (the first-order conditioned light) that had been paired with the US (4). Critically, reducing the emotional impact of the innate source of danger (e.g., by habituating the rats to the burst of intense noise across its repeated presentations) eliminates fear of the first-order conditioned light but leaves intact fear of the second-order conditioned tone (5). Moreover, rats that have learned to fear the first-order light and then learn to fear the tone across its pairings with the light continue to exhibit fear of the tone even after their fear of the light has been extinguished (5, 6). 

Box 2
Second-order fear conditioning protocol

These results suggest that the contents of fear memories differ. What could be called primary fear memories consist in an association between cues (e.g., the light) and the innate source of danger. The light effectively elicits fear in anticipation of that danger: hence, rendering that source of danger innocuous automatically eliminates fear of the light. In contrast, what could be called secondary fear memories (the tone) do not contain information about either the learned (the fear-eliciting light) or the original innate sources of danger. Rather, they consist in an association between the second-order stimulus (the light) and the emotional (fear) responses evoked by the conditioned sound: effectively, second-order conditioning converts an innocuous stimulus into one that simply elicits fear. Put another way, the rats recall being frightened but not the source of their fear. 

The implication of these results for disorders, such as PTSD, is that primary fear memories can be reduced by treatments aimed at confronting the sources of the fears; however, even after the impact of these memories has been reduced, secondary fear memories will continue to elicit fear/avoidance. Understanding how the mammalian brain encodes these two types of fear and how it forms the safety memories that control them will tell us about a fundamental adaptation to environmental sources of danger. It will also provide a principled basis for anticipating the types of fears that will be amenable to exposure-based therapies (primary fear memories), and importantly, the types of fears that may not (secondary fear memories).


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