This project studies the regulation of CRH gene expression by glucocorticoids (GCs) in neonatal rats. It will test the hypothesis that the negative effect of GCs on CRH gene expression (present in adult rats) is not operative in neonates. CRH, an ENDOGENOUS convulsant, is more potent and rapid-acting in neonates, when the peptide's gene expression is low, compared to adults. The project tests the hypothesis that the low CRH gene expression in the neonate contributes to the enhanced convulsant potency of CRH in this age. A specific GC-receptor antagonist (RU-38486) will be implanted adjacent to the paraventricular nucleus of neonatal rats starting on the third postnatal day. CRH-mRNA abundance in implanted rats will be compared to littermate controls using semi-quantitative in situ hybridization (ISH), and the earliest age at which GC-blockade increases CRH gene expression will be determined. The abundance of GC-receptor gene expression, and the effects of Ru-38486 will be examined (using ISH). The effects of experimentally increasing CRH gene expression, via RU- 38486 implantation, on the convulsant responses of neonatal rats to CRH will be determined. Electrographic recording using bipolar electrodes from cortex, amygdala and hippocampus will allow precise definition and localization of the neuroanatomic origin of CRH- induced seizures. These studies will yield important information relevant to human neonatal epilepsy: A better understanding of CRH gene expression and the epileptic properties of this ENDOGENOUS CONVULSANT in the neonate will help elucidate mechanisms of age-specific neonatal seizures, some of which respond to modulation of the CRH-GC feedback loop. In addition, it will provide insight into intrinsically important issues of neuropeptide regulation in the neonatal brain.
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