By this view control is a passive factor, but the research reviewed above clearly goes counter to this idea. At roughly the same time Weiss (1971) argued that the proprioceptive feedback from the escape/coping response is paired with shock termination, and in essence, becomes a safety signal, thereby reducing the fear in the situation. Indeed, Minor et al. (1990) demonstrated that providing Entinostat nmr a safety signal mitigated the effects of IS, just as does control. However, the work reviewed above suggests that although safety signals are indeed effective,

the mechanism by which they blunt the impact of adverse events is different than the mechanism that mediates the impact of behavioral control. Instead, the current evidence suggests that the controlling escape response engages the corticostriatal act/outcome learning circuit, which then engages mPFC top–down inhibition of brainstem and limbic stress-responsive

structures. It should be highlighted that control was not stress-blunting if either the PL or the DMS was inactivated during the ES exposure thereby preventing the engagement of corticostriatal act/outcome circuit, even though the subjects turned the wheel Selleck LY294002 and escaped with the same latencies as did subjects from whom neither structure was inactivated. The escape response was learned and performed without deficit, presumably by engagement of the habit system, but the impact of the stressor was as if it was inescapable. Clearly, it is not just turning the wheel and terminating shock, or even learning of the response per se that is critical—it is engagement of the PL-DMS act/outcome circuit, which then leads to mPFC inhibition of the DRN, amygdala, etc. Activation of the PL-DMS machinery also leads to plasticity. ES increases the excitability of PL neurons, and after exposure to ES, later IS activates also this system, which it would not do without the prior ES experience. These changes

lead to behavioral and neurochemical immunization, and require the production of new proteins, NMDA activity, and ERK phosphorylation in the PL. Importantly, it is not just activation of the act/outcome system, but rather activation of the system in the presence of an adverse event that is required. It is as if the two become tied together in some fashion. It is as if the system, once having experienced control over a very potent event, is biased towards controllability being present in the future. If an adverse event can be mitigated in some fashion by active behavior, then it is likely best to do so. However, if an aversive event is uncontrollable, then passivity/withdrawal and the emotions (e.g., helplessness, fear) that mediate passivity may well be adaptive. This would allow the organism to conserve resources until active coping becomes possible.