Early Chronic Stress and Prefrontal Development

Stanford University, Stanford CA

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Abstract

DESCRIPTION (provided by applicant): Growth and development of prefrontal cortex extends across childhood into adulthood in humans and nonhuman primates. Based on indications that stressful conditions alter developing brain systems in rats, the proposed research investigates chronic early stress effects on subsequent prefrontal correlates of cognitive control, novelty-seeking behavior, dopamine neurochemistry, and sensitivity to cocaine in adolescent squirrel monkeys. Specific Aim 1: Test the hypothesis that early chronic stress increases perseverative tendencies and impairs cognitive control of behavior on tests previously shown to reflect prefrontal cortical dopamine related dysfunctions. Specific Aim 2: Test the hypothesis that early chronic stress enhances voluntary novelty seeking behavior in "stress-free" conditions that do not elicit increases in plasma levels of cortisol or adrenocorticotropic hormone. Specific Aim 3: Test the hypothesis that early chronic stress selectively impairs sensitivity to low but not high doses of cocaine as demonstrated by place preference conditioning. Specific Aim 4: Test the hypothesis that early chronic stress induces baseline hypocortisolism and attenuates baseline levels of cisternal cerebrospinal fluid dopamine and its metabolite HVA. Specific Aim 5: Determine the effects of early chronic stress on prefrontal growth and development assessed longitudinally in vivo by high resolution magnetic resonance imaging. Our hypotheses predict that stress-related group differences in behavioral, hormonal, and neurochemical measures in monkeys correspond with diminished peri-pubertal reductions in right ventromedial gray matter volumes, and diminished maturation of white matter integrity and connectivity as measured by diffusion anisotropy. The data collected to address these hypotheses are analyzed with respect to theories that consider psychostimulant drug-use, risk-taking, and novelty seeking as attempts to alleviate underarousal produced by neuroadaptations trigger in development by chronic stress.