The overall aim of this application is to systematically evaluate the hypothesis that early traumatic experience, in the form of childhood abuse, affects the development of the cerebral cortex and limbic system. This hypothesis endeavors to explain the psychiatric sequela of childhood traumatic experience using an integrative biopsychosocial model, that focuses on the possible biological consequences of adverse early social experience, and the subsequent psychological and behavioral ramifications of stress-induced corticolimbic abnormalities. A two pronged approach will be used, in which clinical studies exploring the association between early abuse and corticolimbic development, will be bolstered by preclinical studies in rodents focusing on the effects of early separation stress on the development of cortical connectivity, corticosteroid regulation, and monoaminergic innervation. In the clinical studies, two groups of unmedicated young adults (18 - 22 years of age) will be compared. The first group will consist of normal controls who have never been abused, or psychologically traumatized. They will be compared to a second group who have experienced forced sexual abuse accompanied by intense fear. Electrophysiological measures of coherence will be used, as a primary measure, to test whether early abuse is associated with an abnormal pattern of right vs left hemisphere interconnection, and attenuated frontal cortex development. The clinical sample will also be assessed using magnetic resonance imaging for abuse related alterations in hippocampal and corpus collosum volume. Dynamic Susceptibility Contrast MRI will be performed to calculate regional cerebral blood volume in the basal state, to test the hypothesis that abuse alters the normal pattern of laterality. Probe evoked potential studies will be used to assess shifts in cortical activity during recall of abuse. Neuropsychological tests will assess for left vs right hemisphere functional impairment. Measures of lymphocyte glucocorticoid receptors, and platelet alpha-2 receptors will provide covariate data on alterations in HPA axis and catecholamine function. In the preclinical component, repeated maternal isolation at cool temperature will be used as an intense life-threatening species relevant stressor, that elevates corticosteroid levels throughout development, and affects HPA axis regulation. The effects of acute and continuous stress on monoamine release in left and right hippocampus will be assessed using in vivo microdialysis in 10 day old rats. Measures will also be made of corticosteroid response. Enduring effects of chronic stress will be evaluated in measures of glucocorticoid receptors density in hippocampus and on lymphocytes, and alpha2 receptors density in locus coeruleus and platelets. Measures will be made of synaptic density in hippocampus, prefrontal cortex in striatum using synaptophysin immunocytochemistry, and the effects of early stress on the pattern of synaptic overproduction and elimination will be ascertained. Functional effects of early stress on hippocampus will be evaluated using radial arm maze. Effects of severe early stress on laterality of cortical and hippocampal function will be assessed under both basal and stressed states, using 2-deoxy-D-glucose as a measure of brain metabolism, and using measures of serotonin, dopamine and norepinephrine turnover. In tandem, the proposed clinical and preclinical investigations will provide urgently needed information on the effects of early trauma on the development of cortical and limbic system function, that may underlie the psychiatric sequelae observed in persons who were victims of early violence and trauma.
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