Michael V. Baratta, Ph.D. - US grants

DESCRIPTION (provided by applicant): The degree of behavioral control that an organism has over a stressor is a crucial determinant of the behavioral and physiological impact of the stressor. Exposure to an uncontrollable stressor can result in numerous behavioral, neural, and immunological changes that do not occur if the identical stressor is controllable. These effects have been termed "learned helplessness effects" and include a number of features central to post-traumatic stress disorder and depression. Research has demonstrated that the neural mediation of these effects is due to the differential activation of the serotonergic (5-HT) dorsal raphe nucleus (DRN). 5-HT neurons within the DRN are activated to a greater degree following an uncontrollable stressor than to an identical, yet controllable stressor. This greater activation produces changes in 5-HT neurons that mediate the later consequences of uncontrollable stress. Yet, it is unclear which neural inputs to the DRN are critical for this differential activation. Recent evidence suggests that the medial prefrontal cortex (mPFC) is sensitive to the controllability of a stressor and differentially regulates the DRN depending on whether the stressor is controllable or not. The present proposal is designed to test a series of hypotheses related to the functional role of the mPFC in DRN regulation. The hypotheses explore a specific circuit in which a) different populations of mPFC cells are activated in response to the dimension of controllability; b) mPFC cells are able to either facilitate or inhibit DRN 5-HT activity; and c) the behavioral effects following pharmacological manipulation of different components of this circuitry.

? DESCRIPTION (provided by applicant): The experience of adverse 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. Human studies have suggested that coping factors are key, and that the actual or perceived ability to exert control over adverse events is an important coping process. The degree of behavioral control that an organism has over a stressor potently modulates the impact of the stressor, with uncontrollable stressors producing neurochemical and behavioral sequelae that do not occur if the stressor is controllable. Furthermore, an initial experience of controllable stress protects or immunizes against the typical negative outcomes of subsequent uncontrollable stress. The research to be conducted in this proposal will be directed at understanding the neural mechanisms that mediate the stress-buffering effects of coping/control. Prior work has identified a role for the medial prefrontal cortex (mPFC) as a structure that is sensitive to the dimension of control and here we will use genetic targeting strategies for monitoring and subsequently manipulating subcircuits embedded within the mPFC that are critical for immunization. Specific Aim I will determine if mPFC cells that are activated by an initial experience of control are also engaged during later adversity. Specific Aim II will determine if the mPFC is involved in mediating the effects of control because it participates in the corticostriatal action-outcome system, a circuit thought to be important for organisms to encode and use contingency information about the relationship between its actions and outcomes. The proposed research is the first of its kind, and will lay the groundwork for understanding how mPFC activity during coping behavior produces resilience to future challenge.

Project Summary/Abstract The degree of behavioral control that an organism (rodent to human) can exert over an adverse event is arguably the most potent variable yet discovered that modulates the behavioral and neurochemical impact of that event. When the organism does have an element of control, the behavioral and neurochemical sequelae of the adverse event are blunted or eliminated. Importantly, the experience of control not only blunts the impact of the stressor being controlled, but also blunts the impact of stressors experienced much later (at least one month), that is, control produces future resilience in the face of adversity. Recent research has extended the study of the impact of experiencing control to determining whether future fear processes might be altered. Indeed, the experience of control reduces future fear conditioning, facilitates future fear extinction and prevents the spontaneous recovery of fear. In addition, we have extended the study of controllability phenomena to females, and surprisingly, here control does not blunt the impact of stressors or alter later fear conditioning. The proposed research focuses on the roles of specific prefrontal cortex circuits in mediating the effects of control on fear processes, as well as a determination of exactly how critical prefrontal circuits may respond to stressors differently in males and females.