It has been known for many years that the ability to exert behavioral control over an adverse event blunts the behavioral and neurochemical impact of the event. More recently, it has become clear that the experience of behavioral control over adverse events also produces enduring changes that reduce the effects of subsequent negative events, even if they are uncontrollable and quite different from the original event controlled. This review focuses on the mechanism by which control both limits the impact of the stressor being experienced and produces enduring, trans-situational “immunization”. The evidence will suggest that control is detected by a corticostriatal circuit involving the ventral medial prefrontal cortex (mPFC) and the posterior dorsomedial striatum (DMS). Once control is detected, other mPFC neurons that project to stress-responsive brainstem (dorsal raphe nucleus, DRN) and limbic (amygdala) structures exert top–down inhibitory control over the activation of these structures that is produced by the adverse event. These structures, such as the DRN and amygdala, in turn regulate the proximate mediators of the behavioral and physiological responses produced by adverse events, and so control blunts these responses. Importantly, the joint occurrence of control and adverse events seems to produce enduring plastic changes in the top–down inhibitory mPFC system such that this system is now activated by later adverse events even if they are uncontrollable, thereby reducing the impact of these events. Other issues are discussed that include a) whether other processes such as safety signals and exercise, that lead to resistance/resilience, also use the mPFC circuitry or do so in other ways; b) whether control has similar effects and neural mediation in humans, and c) the relationship of this work to clinical phenomena.
