Active Avoidance Learning Requires Prefrontal Suppression of Amygdala-Mediated Defensive Reactions

In this study, Moscarello and LeDoux (2013) provide new insights into the role of infralimbic prefrontal cortex in resolving the conflict between Pavlovian conditioned freezing and instrumentally conditioned avoidance behavior in the process of signaled active avoidance learning. The authors conclude that these findings may have clinical implications for "therapies designed to facilitate adaptive coping strategies," and in a recent commentary, LeDoux (2013) suggests that "proactive avoidance" learned in this paradigm is distinct from the "pathological avoidance" that maintains anxiety disorders, and that future treatments may work by facilitating the transition from bad avoidance (freezing) to good avoidance (escape), perhaps by targeting the primate homolog of the neural substrates identified by Moscarello and LeDoux (2013). However, we contend that an important caveat is needed in considering the translational value of these findings for treating anxiety disorders in humans. Active avoidance can be beneficial when a human has an accurate representation of the contingency between the conditioned stimulus (CS) and the unconditioned stimulus (US). However, active avoidance can be quite harmful if one is wrong about a CS-US contingency, and anxiety disorders are virtually defined by this type of error. Individuals with panic disorder, for example, believe that symptoms of sudden autonomic arousal (CSs such as shortness of breath, rapid heart beat, or dizziness) signal catastrophic outcomes (USs such as a heart attack or psychotic break). These individuals do not freeze in response to CSs; instead, they are quite active in their avoidance, going out of their way to find means of escaping situations that elicit and sustain panic CSs. Such avoidance provides transient relief and perhaps a renewed sense of agency; however, it does not help to resolve panic disorder. Instead, it leads to agoraphobia: marked distress in situations that do not allow escape in the event of a panic attack. Indeed, all anxiety disorders are marked by efforts to prevent USs through active responding to CSs. Proactive avoidance is functionally equivalent to a host of other "safety behaviors" that maintain anxiety by preventing corrective learning about the CS-US contingency. To be precise, individuals with anxiety disorders mistake safety behaviors for negative occasion setters, that is, modulators that determine whether or not the CS will predict the US. In appearing to provide control over the US, safety behaviors may provide short-term benefits, but at the cost of maintaining the distortions that create pathological fear. In fact, the short-term relief provided by safety behaviors is itself problematic, as these behaviors become deeply entrenched due to their negative reinforcement and may become a serious impediment to exposure therapy. In conclusion, while the findings of Moscarello and LeDoux (2013) are intriguing with respect to animal models of normative fear learning, the mechanisms highlighted by this study may be more relevant to the maintenance of pathological fear, rather than its treatment, in humans.

Moscarello JM & LeDoux JE (2013) Active Avoidance Learning Requires Prefrontal Suppression of Amygdala-Mediated Defensive Reactions. J Neurosci 33: 3815-3823.

LeDoux J (2013) For the anxious, avoidance can have an upside. The New York Times (online only). Retrieved from http://opinionator.blogs.nytimes.com/2013/04/07/for-the-anxious-avoidance- can-have-an-upside/

Conflict of Interest:

None declared