Early Life Stress and Depression: Molecular and Functional Imaging Approaches

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DESCRIPTION (provided by applicant): Epidemiological studies show that severe childhood adversity explains 32-44% of psychiatric disorders, and is associated with 4.6-fold risk for depression and 6.6-fold risk for substance abuse later in life. Emerging evidence indicates that 20-40% of adults with a history of childhood sexual abuse (CSA) report little to no symptomatology. In spite of these epidemiological data, the neurobiological underpinnings associated with adaptive (resilience) and maladaptive sequelae of CSA remain largely unknown. Preclinical research strongly suggests that early adversity leads to disruptions within mesolimbic and mesocortical dopaminergic pathways critically implicated in reward processing and stress reactivity. These data are consistent with theoretical arguments that a stable and well-functioning reward system and increased prefrontal cortex function might be markers of resilience. The overarching goal of the proposed research is to investigate mesocorticolimbic dopaminergic pathways within young adult females with a history of CSA between the ages of 5-9 years with ("CSA/MDD group") and without ("CSA/RES group") a current diagnosis of major depressive disorder (MDD). To disentangle CSA- vs. MDD-related effects, these groups will be compared to not only healthy controls but also MDD females without a history of CSA. Moreover, to minimize interpretative issues, participants with a past or current comorbidity of disorders known to affect dopamine and/or striatal pathways (attention deficit hyperactivity disorder, substance dependence/abuse, obsessive compulsive disorder) or disorders that might represent a pathway to depression (post traumatic stress disorder) will be excluded. Finally, to increase study generalizability and recruitment feasibility, co-occurrence of physical abuse with CSA will be allowed in light of prior findings that (1) physical abuse commonly occur with CSA; and (2) co-occurrence of CSA and physical abuse primarily increases the risk of developing MDD. We hypothesize that, relative to healthy control and CSA/RES groups, the CSA/MDD participants will be characterized by (1) reduced reward responsiveness and ventromedial prefrontal cortex activation but cortisol hypersecretion when exposed to an acute psychosocial stress manipulation, (2) reduced dopaminergic transmission, and (3) reduced dopamine transporter binding. These hypotheses will be tested using a novel integration of behavioral, endocrinological, and functional/molecular imaging approaches. Improving our understanding of neurobiological mechanisms associated with different CSA outcomes (specifically MDD and resilience) is of paramount importance in order to (1) identify individuals at risk for psychopathology and maladaptive behavior, (2) prevent revictimization, and (3) develop more targeted therapeutic interventions.