RMTg circuitry mediates psychiatric consequences of early life-threatening trauma

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Project Summary Childhood trauma occurs at an unacceptably high rate. In the most recent National Survey of Children's Health, almost half of the children experienced at least one or more types of serious childhood trauma- nearly 35 million children. Childhood trauma has dramatic and costly effects in adulthood. Childhood trauma increases the risk of developing major depressive disorder (MDD), generalized anxiety, panic reaction, obsessive compulsive disorder (OCD), somatoform disorders, substance abuse and psychotic disorders. Childhood trauma significantly alters treatment trajectories and outcome for the worse. It is our contention that the ratio of basic research effort to clinical impact is too low. The purpose of this application is accelerate the development of a novel trauma model we believe delivers robust and relevant outcomes and to explore a novel hypothesis concerning the etiology of increased mental illness liability. We will pursue our studies in two research aims. Aim 1 is designed to further develop a novel live-predator model (snake) with the proposition that a highly salient, ethologically-relevant trauma will engage the nervous system in a manner relevant to studies of psychiatric disorders. We will systematically manipulate timing and number of adolescent trauma exposures and conduct large-scale mining in adulthood for physiological, behavioral and neurobiological profiles indicative of behavioral constructs that cross diagnostic boundaries (e.g. hyper arousal, anhedonia, depression and anxiety). Neural activation patterns will be assessed in key RMTg-centric circuitry via cFos activation patterns. A wealth of within subjects behavioral and neurobiological data will be subject to multidimensional scaling and categorical analysis to identify patterns of circuitry involvement associated with specific abnormal behavioral profiles. Aim 2 will test the novel hypothesis that adolescent exposure to ethologically-relevant trauma results in enduring behavioral and neurobiological disruptions that require rostral medial tegmentum (RMTg) function. The combination of roles hypothesized to involve the RMTg (threat, fear, avoidance and negative affect) place it in an ideal situation to mediate disruptive consequences of early trauma and some of the core symptoms found to cross diagnostic domains. We will systematically inhibit (RMTg-directed muscimol) or potentiate (RMTg-directed AMPA) RMTg function during trauma exposure to test our hypothesis. A similar analysis as described in Aim 1 will determine if RMTg inhibition or potentiation dampens or worsens, respectively, behavioral and neurobiological outcomes. Childhood trauma and the subsequent development of mood disorders is emerging as a pervasive theme in mental illness. Preclinical research is uniquely qualified to systematically investigate the consequences of early-life trauma. Improving animal models and our neurobiological understanding of the symptom domains impacted by trauma could significantly improve treatment strategies to help alleviate the individual and societal burden.