LONG TERM GOAL: To characterize the receptors and underlying mechanism of action of adrenalcortical steroids on hippocampal pyramidal cell activity. Adrenalcortical receptors in the hippocampus adjust corticosterone (CT) levels by regulating the hypothalamic-pituitary-adrenal axis (HPA). Homeostasis is maintained by basal activation of the hippocampal-HPA. In response to stress, CT secretion is increased. CT activation of receptors in the hippocampus leads to feedback inhibition of the HPA. Excessive CT secretion is neurotoxic to hippocampal pyramidal cells. The mechanism of the hippocampal regulation of the HPA is unknown. A step towards understanding this mechanism is to determine how CT alters pyramidal cell excitability. The hippocampal slice preparation in vitro will be used for intracellular recordings. CT concentrations will be controlled by adrenalectomy (ADX) and steroid replacement.
SPECIFIC AIM #1 : To determine the contribution of chronic CT receptor activation to pyramidal cell excitability. HYPOTHESES: Persistent Type 1 receptor activation, the non-stressed condition, will result in pyramidal cell depolarization and increased cell excitability as compared to cells from ADX rats. Chronic Type 1 and Type 2 receptor activation, the chronically stressed state, will decrease cell excitability to prolonged synaptic input by increasing the amplitude of an evoked slow hyperpolarization (sAHP).
SPECIFIC AIM #2 : To characterize the receptors mediating changes in hippocampal pyramidal cell physiology induced by acute CT administration. HYPOTHESES: Type 1 receptor activation will increase a cationic conductance and synaptic activation. Type 2 receptor activation will reduce prolonged synaptic excitability by increasing the sAHP amplitude. Activation of a plasma membrane receptor will hyperpolarize cells. The ionic mechanisms underlying these responses and genomic mediation will be determined SPECIFIC AIM #3: To determine the effect of chronic CT treatment on responses mediated by 5-hydroxytryptamine (5-HT) receptors. 5-HT exerts profound effects on pyramidal cells, and CT modulates 5-HT synthesis and receptor number. HYPOTHESES: CT will increase the sensitivity of the 5-HT(1A) hyperpolarization and decrease the sensitivity of the 5-HT receptor that decreases the amplitude of the sAHP. These results will provide important information on the control of pyramidal cell activity by CT and will help elucidate the mechanism of hippocampal regulation of the HPA.
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