Live predator stress in adolescence results in distinct adult behavioral consequences and dorsal diencephalic brain activation patterns.

Exposure to traumatic events during childhood increases the risk of adult psychopathology, including anxiety, depression, alcohol use disorders and their co-morbidity. Early life trauma also results in increased symptom complexity, treatment resistance and poor treatment outcomes. The purpose of this study was to establish a novel rodent model of adolescent stress, based on an ethologically relevant life-threatening event, live predator exposure. Rats were exposed to a live predator for 10 min. at three different time points (postnatal day (PND)31, 46 and 61). Adult depression-, anxiety-like behaviors and ethanol consumption were characterized well past the last acute stress event (two weeks). Behavioral profiles across assessments were developed to characterize individual response to adolescent stress. CNS activation patterns in separate groups of subjects were characterized after the early (PND31) and last predator exposure (PND61). Subjects exposed to live-predator adolescent stress generally exhibited less exploratory behavior, less propensity to venture into open spaces, a decreased preference for sweet solutions and decreased ethanol consumption in a two-bottle preference test. Additional studies demonstrated blunted cortisol response and CNS activation patterns suggestive of habenula, rostromedial tegmental (RMTg), dorsal raphe and central amygdala involvement in mediating the adult consequences of adolescent stress. Thus, adolescent stress in the form of live-predator exposure results in significant adult behavioral and neurobiological disturbances. Childhood trauma, its impact on neurodevelopment and the subsequent development of mood disorders is a pervasive theme in mental illness. Improving animal models and our neurobiological understanding of the symptom domains impacted by trauma could significantly improve treatment strategies.

The rostromedial tegmental nucleus modulates the development of stress-induced helpless behavior.

A growing body of clinical and preclinical research suggests that structural and functional changes in the habenula, a component of the epithalamus, are associated with major depressive disorder. A major excitatory, efferent projection from the habenula targets the rostromedial tegmentum (RMTg), a mesopontine region that provides significant input to the ventral tegmentum and raphe nuclei. While the RMTg contributes to monoaminergic responses to aversive events, its role in stress-based animal models of depression has yet to be determined. In the present study, we test the hypothesis that the RMTg is a component of the circuitry mediating the development of a maladaptive behavior in which rats repeatedly exposed to inescapable footshock, fail to avoid or escape the same stressor when subsequently given the opportunity to do so. Excitotoxic lesions of the RMTg significantly diminished the frequency of these escape failures 24 h after exposure to inescapable footshock. Conversely, electrical stimulation of the Hb during the initial uncontrollable aversive event, a manipulation that enhances excitatory input to the RMTg, increased the number of trials in which subjects failed to escape an aversive stimulus when presented the option 24 h later. These complementary results provide evidence supporting a role for the RMTg in the expression of stress-induced helpless phenotype and are an important step in understanding the contribution made by this region to the development of depression-related maladaptive behaviors.