This is application is competing renewal to continue previously funded studies of hypothalamic-pituitary-adrenal (HPA) dysregulation in major depression using a model of hypercortisolism in monkeys. The studies proposed are based on the assumption that this animal model will provide insights into multiple aspects of depression that are difficult to study experimentally in humans. Preliminary data from this laboratory indicates that squirrel monkeys from groupings of paternal half-siblings demonstrate prolonged hypercortisolism after removal of mothers at 9-months of age. When re-evaluated 2-4 years later these monkeys subsequently exhibit impaired performance on tests of reversal learning and memory, and smaller hippocampi based on magnetic resonance imaging (MRI). These findings are similar to neuroimaging results reported in patients with recurrent depression, and they suggest that the smaller hippocampi detected in monkeys years after assessing separation induced hypercortisolism may reflect irreversible neuron loss. However, an alternative explanation may be that smaller hippocampi are a cause, and not a consequence of sustained secretion of cortisol and related impairments seen in major depression. To date studies of hippocampal atrophy in depression have relied on cross-sectional designs, and MRI based assessments of hippocampal atrophy have not been examined at the cellular level.
The aim of the research proposed is to map and quantify glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) mRNA expression in the brains of squirrel monkeys stratified by stress (social separation) and genotype (high-responsive vs. low-responsive). The focus will be on two brain regions: hippocampal subfields (CA1, CA2, CA3/4 and dentate) and hypothalamic subnuclei, particularly the paraventricular nucleus. These regions have previously been demonstrated to be critical in corticosteroid hormone mediated feedback regulation of the stress axis in rodent models. However, despite some apparent similarities between rodent and primate brain circuits, there is a paucity of data regarding CNS modulation of stress response in primates.
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