Children with Fetal Alcohol Spectrum Disorder (FASD) have problems ranging from the severe manifestations of Fetal Alcohol Syndrome (FAS), to milder neurobehavioral deficits. Regardless of symptom severity, however, all children tend to exhibit similar cognitive, neuropsychological and neurobehavioral problems. Moreover, secondary problems in a number of life domains are common, including a high incidence of depression and anxiety disorders. Hypothalamic-pituitary-adrenal (HPA) dysregulation is a common finding in major depression. Furthermore, there is a strong relationship between depression in adulthood and adverse early life events. Consistent with these findings, brain areas implicated in depression overlap with areas that mediate the stress response, with the HPA axis a key player in both. Both clinical and preclinical data demonstrate that prenatal alcohol exposure (PAE) reprograms the fetal HPA axis such that HPA tone is increased throughout life. PAE offspring are typically hyperresponsive to stressors, and show both increased HPA drive and deficits in feedback regulation. Furthermore, interactions between the HPA axis and both the gonadal and serotonergic systems are altered by PAE. This pattern of dysregulation parallels in many ways what is observed in depression. The present proposal will utilize our well-established animal model of PAE to examine the links among PAE, stress system abnormalities, the gonadal and serotonergic systems and depression. In the context of the stress-diathesis model, we will test the hypothesis that fetal programming of HPA activity by PAE can permanently sensitize neuroadaptive mechanisms that mediate responses to stress, resulting in hyperreactivity to subsequent, even mild, stressful life events. Ultimately, repeated stress exposure results in a maladaptive cascade of events and increased vulnerability to depression and anxiety. Indeed, our Preliminary Studies demonstrate sex-dependent increases in depressive symptomatology in PAE animals following exposure to unpredictable mild stress in adulthood. The proposed studies will extend these finding in important and novel directions. Our Specific Aims are to investigate: 1) the role of the maternal glucocorticoid milieu in programming fetal HPA activity and mediating increased vulnerability to adverse effects of stress on offspring HPA, brain and behavioural outcomes; 2) the role of HPA dysregulation in adult PAE males and females in mediating increased vulnerability to adverse effects of stress on HPA, brain and behavioural outcomes; 3) the impact of factors (sex and developmental age) that confer further vulnerability to the adverse effects of stress on HPA, brain and behavioural outcomes; and 4) whether antidepressant treatment can reverse or alleviate the adverse effects of stress on HPA, brain and behavioural outcomes. The proposed studies will begin to elucidate mechanisms mediating the link between PAE and increased vulnerability to depression and anxiety disorders in children with FASD.