Major depressive disorder (MOD) is the fourth leading cause of disease burden worldwide, and the incidenceof MOD in women is twice that of men. Thus understanding its etiology will have important implications forattenuation of disease burden, particularly in women. In this translational SCOR integrating scientists frombasic and clinical fields in three Projects, we address the question of why women are at twice the risk forMOD than men. We hypothesize that sex differences in MOD are initiated during fetal development, duringhypothalamic-pituitary-adrenal (HPA) circuitry development and the sexual differentiation of the brain, and aperiod in which fetal risk factors for MOD have been identified. The overall SCOR will test hypothesesregarding the roles of adrenal and gonadal signaling pathways regulating brain-derived nerve growth factor(BDNF; associated with MOD) and its interactions with gamma aminobutyric acid (GABA)-ergic, glutamate(GLU)-tamatergic and nitric oxide (NO) mechanisms in development of key brain regions in stress responsecircuitry. In Project 1, specific aims are to test for contributions of genetic polymorphisms associated withthese pathways and maternal serum assessment of HPA abnormalities during mid-gestation tounderstanding sex differences in MOD. We identified 500 DSM-IV MOD cases and 500 normal controls froma birth cohort (followed from prenatal development to age 47) in which DMA has been stored and biosamplesindicating maternal-fetal HPA-placental stress at mid-gestation will be evaluated. We will test for specificgenetic polymorphisms associated with HPA circuitry development and MOD (cortiocotropin releasinghormone (CRH), BDNF, GABA, GLU, neuronal NO (nNOS), estrogen receptors (ER)a and p, and argininevasopressin (AVP)). Mid-gestational physiologic stress will be operationalized as: abnormal levels ofmaternal-fetal hormones during mid-gestation indicative of stress (CRH, dehydroepiandrosterone-sulfate(DHEA-S), human chorionic gonadotropin (hCG), and bioactive androgens); and high levels of pro-inflammatory cytokines (interleukine (IL)-1p, IL-6 & tumor necrosis factor (TNF)-a) during mid-gestation. Inaddition 40 recurrent MOD cases, equally divided by gender, and 40 individually-matched normal controlsfrom this birth cohort will be re-recruited for functional and structural brain imaging of stress responsecircuitry and neuroendocrine evaluations to test our hypotheses relating abnormal maternal-fetal HPAenvironment and genetic polymorphisms with sex differences in adult HPA axis dysfunction and functionalbrain activity deficits in stress response circuitry. We predict hormonal dysfunction will mediate sexdifferences in brain activity deficits in MOD, which will be associated with maternal-fetal HPA abnormalities.An understanding of the fetal mechanisms associated with sex differences in MOD will have etiologicimolications and imoortance for the development of sex-specific treatments and prevention of MOD.
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