Hetereogeneity of dose and time effects of estrogen on neuron-specific neuronal protein and phosphorylated cyclic AMP response element-binding protein in the hippocampus of ovariectomized rats.

Previous studies have shown changes in the cyclic AMP response element-binding protein (CREB) signaling pathway in CA1 and CA3 regions of the rostral hippocampus with 10 μg estrogen treatment for 14 days. It appears that estrogen's action on CREB phosphorylation in brain structures depends on other estrogen doses and lengths of treatment. We therefore examined the effects of moderate regimens [2.5 μg estradiol benzoate (EB) for 4 or 14 days] on mean numbers of neuron-specific neuronal protein (NeuN)-positive cells and phosphorylated CREB (pCREB)-positive cells and subregion volume defined by NeuN and pCREB immunolabeling and compared those results with results from the high regimen (10 μg EB for 14 days) in CA1, CA2, and CA3 regions and dorsal (DDG) and ventral (VDG) dentate gyrus and hilus of the hippocampus of ovariectomized rats by stereology. For whole hippocampus, all regimens increased mean neuronal (NeuN) numbers and pCREB-positive cell and volume compared with sesame oil (SO) in CA1, CA2, and CA3 regions, DDG and VDG, and hilus. In rostral hippocampus, however, some hippocampal subregions were not responsive to the high regimen, and the moderate regimens appear to be more effective for increasing mean number of NeuN-positive neurons and pCREB-positive cells and subregion volume. Heterogeneity in responsiveness to estrogen was mainly seen within rostral, but not whole, hippocampal subregions. Our results indicate that responsiveness of cells expressing NeuN and pCREB to different EB regimens may vary depending on the specific region of the hippocampus.