Childhood trauma is one of the single greatest environmental factors known to increase risk for a broad range of adult psychiatric illnesses. The consequences of childhood trauma not only affect the risk for mental illness, but significantly alter symptom complexity and predict treatment resistance within a diagnostic category. It could be argued that sleep disturbance is the single greatest drive (others being eating, drinking, sex) known to increase risk for adult psychiatric illness. Sleep abnormalities co-occur with virtually all psychiatric illnesses and, like adolescent trauma, significantly worsens the trajectory, severity and complexity of the illness. Each component of sleep architecture contributes to cognitive, emotional and somatic health. For example, rapid-eye movement sleep (REM), plays a key role in processing affective, emotional information and is thought to be critically involved in ‘depotentiating’ the emotional charge of a stress event and ameliorating its autonomic arousal burden. A recent report strongly suggests that activation of the rostromedial tegmental nucleus (RMTg) can dramatically decrease REM sleep via its main output to the ventral tegmental area (VTA). This finding is intriguing since our lab recently implicated RMTg activation in mediating the maladaptive adult consequences of adolescent stress. RMTg activation and subsequent REM deficits during adolescence could have dramatic impact since sleep and circadian processes help drive and guide neuronal development. We will utilize adolescent exposure to an ethologically-relevant stress (live predator) to test the following hypotheses: 1) Adolescent exposure to ethologically-relevant stress results in enduring changes in component- specific sleep architecture that are associated with maladaptive behavior in adulthood, and 2) Adolescent stress- induced changes in RMTg function underly the changes in sleep architecture associated with maladaptive behavioral profiles in adulthood. The goal of AIM 1 is to determine if individual sleep profiles following adolescent stress are predictive of adult behavior in a panel of tests designed to assess depression and anxiety. We will characterize sleep architecture in adolescence and adulthood and then characterize behavior profiles in adulthood. We expect individual differences in sleep architecture following adolescent stress to be predictive of normal, maladaptive and stress-resilient adult behavioral profiles. The goal of AIM 2 is to test the functional role of the RMTg-VTA circuit in mediating disturbed sleep architecture and/or changes in adolescent stress-induced maladaptive behavior in adulthood. An intersectional chemogenetic (DREADD) approach will be used to specifically inhibit the RMTg-VTA circuit in order to test causal associations. Adolescent childhood trauma- induced sleep disturbance may be a primary factor in the trajectory towards adult mental illness. Investigating the specific alterations in sleep architecture and underlying neurobiology will help facilitate therapeutic discovery efforts.

Childhood trauma dramatically increases the risk for adult mental illness. We propose that sleep disturbance is a key mediator of the path from adolescent trauma to adult psychiatric illness. The experiments outlined in this proposal test the association between adolescent stress-induced sleep disturbance and adult maladaptive behavior in adulthood and test the functional role that a ventral midbrain region, the rostromedial tegmentum, plays in this pathway.