The enhanced HPA axis drive seen in chronic unpredictable models is likely driven by uncontrollability and uncertainty regarding outcomes. Maier's work elegantly demonstrates that controllability over a stressor (shock) can protect against the development of helplessness behavior, social inhibition and behavioral withdrawal seen following inescapable stress (Maier and Watkins, 2010). Importantly, brain regions controlling development of helplessness overlap with those recruited during exposure to unpredictable stress (i.e., ventral divisions of the medial PFC) (Maier and Watkins, 2010). Thus, continued drive of the HPA axis may be mediated by engagement of the same (or parallel) circuits that control behavioral responses to unpredictability.
