Active avoidance learning requires prefrontal suppression of amygdala-mediated defensive reactions.

Signaled active avoidance (AA) paradigms train subjects to prevent an aversive outcome by performing a learned behavior during the presentation of a conditioned cue. This complex form of conditioning involves pavlovian and instrumental components, which produce competing behavioral responses that must be reconciled for the subject to successfully avoid an aversive stimulus. In signaled AA paradigm for rat, we tested the hypothesis that the instrumental component of AA training recruits infralimbic prefrontal cortex (ilPFC) to inhibit central amygdala (CeA)-mediated Pavlovian reactions. Pretraining lesions of ilPFC increased conditioned freezing while causing a corresponding decrease in avoidance; lesions of CeA produced opposite effects, reducing freezing and facilitating avoidance behavior. Pharmacological inactivation experiments demonstrated that ilPFC is relevant to both acquisition and expression phases of AA learning. Inactivation experiments also revealed that AA produces an ilPFC-mediated diminution of pavlovian reactions that extends beyond the training context, even when the conditioned stimulus is presented in an environment that does not allow the avoidance response. Finally, injection of a protein synthesis inhibitor into either ilPFC or CeA impaired or facilitated AA, respectively, showing that avoidance training produces two opposing memory traces in these regions. These data support a model in which AA learning recruits ilPFC to inhibit CeA-mediated defense behaviors, leading to a robust suppression of freezing that generalizes across environments. Thus, ilPFC functions as an inhibitory interface, allowing instrumental control over an aversive outcome to attenuate the expression of freezing and other reactions to conditioned threat.