TO PUBLIC HEALTH: The experience of stressful events is an etiological factor in the development of numerous mental disorders, yet some individuals are resilient in the face of adversity. An understanding of factors that promote resilience is critical to the development of more effective therapies. An extensive literature suggests that coping processes are key, and that the perceived ability to exert control over negative circumstances is a key coping process. The research to be conducted is directed at understanding the neural mechanisms that produce the stress-buffering effects of control/coping. The degree of behavioral control that an organism has over a stressor modulates the behavioral and physiological impact of a stressor, with uncontrollable stressors producing sequelae that do not occur following physically identical controllable stressors. In addition, an initial experience with controllable stress blocks later uncontrollable stress from exerting its usual effects (""""""""behavioral immunization"""""""".) Prior research has focused on understanding the mechanisms by which uncontrollable stress produces its effects, but here the focus will be on understanding how it is that having control prevents stressors from producing negative outcomes. The basic hypothesis to be explored is that a) the presence of control activates medial prefrontal cortex (mPFC) inhibition of brainstem (dorsal raphe nucleus) and limbic (amygdala) structures that are activated by stressors and that play important roles in mediaitign the effects of stress., and b) the experience of controlling a stressor """"""""ties"""""""" mPFC activation to the stressor, or some aspect of the stress experience (e.g., fear), so that the later occurrence of stressors, even if they are uncontrollable, now activates the mPFC and thus inhibition of brainstem and limbic structures nortmally activated by uncontrolalble stress. This process is expected to provide protection and produce resilience. This overall rationale leads to 3 Specific Aims.
SPECIFIC AIM I : How does a prior experience with controllable stress (escapable shock, ES) block the subsequent behavioral impact of uncontrollable stress (inescapable shock, IS)? SPECIFIC AIM II: Are the protective effects of prior ES general, so that the impact of stressors other than tailshock is blunted? Are the protective effects of mPFC activation general, so that mPFC activation during defeat rather than IS will also be protective SPECIFIC AIM III: Do the resilience-producing effects of ES extend beyond behaviors & processes regulated by the DRN (e.g.. escape behavior) to processes regulated by other structures also innervated bv the PFC? ? ? ?
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