Early Life Stress and Depression: Molecular and Functional Imaging Approaches

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Project Summary Epidemiological studies have shown 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. In spite of these epidemiological data, the neurobiological underpinnings associated with maladaptive sequelae of CSA remain largely unknown. Preclinical research strongly suggests that early adversity leads to (1) structural abnormalities in medial prefrontal cortex regions critically implicated in stress regulation; (2) increased oxidative stress; and (3) glutamatergic abnormalities. The current competing renewal was specifically designed to prospectively test the contributions of these abnormalities in individuals exposed to CSA. Together, these studies will test the hypotheses that abnormalities within “immuno-oxidative” mechanisms, including abnormal balance of redox regulation, oxidative stress and glutamate metabolites are linked to MDD and CSA pathophysiology. We expect that interactions among these abnormalities (1) lead to excitatory/inhibitory imbalance of local neuronal circuits and morphometrical abnormalities within key regions (mPFC); (2) are associated with key MDD phenotypes; and (3) prospectively predict future symptoms and functioning. These goals will be achieved by evaluating young adult females with a history of CSA between the ages of 12-16 years with a current (“MDD/CSA” group) or former (“rMDD/CSA” group) diagnosis of major depressive disorder. To disentangle CSA- vs. MDD-related effects, these groups will be compared to both healthy controls and MDD females without a history of CSA (“MDD” group). All subjects (N=160) will be tested at both 3T and 4T scanners using an integration of state-of-the-art 31P magnetic resonance spectroscopy (MRS) (to quantify redox ratio and brain bioenergetics in vivo), high field multinuclear MRS (to assess glutamate metabolites and glutathione), functional magnetic resonance imaging (to probe the neural correlates of anhedonic behavior and cognitive control deficits). To track disease course, all participants will be prospectively assessed at 6- and 12- month follow-up sessions. Based on our extensive set of preliminary findings, we hypothesize that, relative to both healthy controls and the MDD group, MDD/CSA individuals will show greater cortical thinning in the medial prefrontal cortex, lower redox ratio, lower glutamine/glutamate ratio, and higher inflammatory markers (Hypothesis 1). We further expect that these abnormalities will persist in euthymic rMDD/CSA subjects, particularly with increasing number of lifetime depressive episodes. Moreover, we expect that these abnormalities will be associated with increased anhedonic behavior and cognitive deficits (Hypotheses 2), and will predict anhedonic symptom, cognitive deficits and poorer general functioning at the follow-up assessments (Hypothesis 3). Improving our understanding of neurobiological mechanisms associated with different CSA outcomes 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.