The long term goal is to reveal the acute and chronic effect(s) of normal and pathological levels of adrenalcortical steroids on hippocampal cell activity. The adrenalcortical steroids have protective actions to maintain homeostasis, yet high chronic levels produce neurotoxic effects. Aldosterone and corticosterone (CT, rat) or cortisol (human) are the primary adrenalcortical steroids. Plasma hormone levels are controlled by the hypothalamic-pituitary-adrenal (HPA) axis. Feedback regulation of the HPA axis is through interaction with CT receptors in the brain; the hippocampus is a primary target. Activation of hippocampal CT receptors adjusts the gain of the HPA axis. Basal activation maintains homeostasis, acute activation increases activity to regain homeostasis. Prolonged excessive CT secretion leads to pathological states such as depression and enhances neurotoxic vulnerability of hippocampal pyramidal cells. Hypothesis 1: The different CT receptor subtypes. i.e.. the mineralocorticoid (MR) and glucocorticoid (GR) receptors, differentially regulate the functioning of hippocampal pyramidal cells under conditions of no stress. acute stress and chronic stress. This regulation occurs through independent mechanisms. i.e., by altering pyramidal cell properties and/or by altering receptor-mediated actions. Previous research has defined CT actions on CA1 pyramidal cells, which provide the final output of the hippocampus. Input from CA3 cells directly influences CA1 activity; CT may alter CA1. output by affecting CA3 pyramidal cell activity. The distribution of MR and GR receptors is different between CA1, and CA3 subfields. CT selectively alters CA3 pyramidal cell morphology leading to cell death. Hypothesis 2: The effects of CT on CA1, and CA3 pyramidal cell activity are different. Defining the actions of CT on CA1, and CA3 cells may provide important information towards differentiating the protective versus destructive actions of CT. To test these hypotheses the following Specific Aims are proposed. CT levels will be controlled by adrenalectomy (ADX) and replacement steroid treatment. SP1: To determine the chronic effects of normal and pathophysiologicaI levels of CT on CA3 hippocampal cell properties. We have previously shown that CT alters CAL. hippocampal pyramidal cell properties. In this application the modulatory actions of CT on CA3 cell properties will be determined and compared to our previous results. SP2: To determine the mechanism of action of the chronic effects of normal and pathophysiological levels of CT on 5-HT neurotransmitter-mediated actions in CA1 and CA3. We have previously shown that CT has different effects on the different 5-HT receptor-mediated responses in CA1. CT effects on 5-HT responses in area CA3 will be measured. Electrophysiology, receptor autoradiography, immunocytochemistry, and Western blot techniques will be used to determine if the modulatory actions of CT are at the receptor, receptor-effector coupling and/or effector level. SP3. To determine if the acute effects of high CT concentrations, that mimic an acute stress response, are dependent upon normal daily activation of MR and GR receptors. The hypothesis that basal activation of MR and circadian activation of GR is required to maintain specific protein products necessary for feedback inhibition will be tested. The effects of acute CT administration on pyramidal cell properties and neurotransmitter mediated responses recorded in areas CA1, and CA3 of Sham, ADX and chronically treated rats with pathophysiological levels of CT will be measured.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurological Sciences Subcommittee 1 (NLS)
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Edwards, Emmeline
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Children's Hospital of Philadelphia
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