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Estradiol exerts beneficial effects on neurodegenerative disorders associated with the decline of cognitive performance. The present study was designed to further investigate the effect of 17β-estradiol on learning and memory, and to evaluate its neuroprotective action on cholinergic cells of the nucleus basalis magnocellularis, a neural substrate of cognitive performance. Female rats were ovariectomized at an age of 6 months. Three weeks later they received injections of either a mid-physiological dose of 17β-estradiol or vehicle (oil), every other day for 2 weeks. The effect of estradiol on cognitive performance was tested in two associative learning paradigms. In the two-way active shock avoidance task estradiol-replaced animals learned significantly faster, while in the passive shock avoidance test no differences were observed between the experimental groups. Subsequent unilateral infusion of N-methyl-D-aspartate in the nucleus basalis magnocellularis resulted in a significant loss of cholinergic neurons concomitant with the loss of their fibers invading the somatosensory cortex. Estradiol treatment did not affect the total number of choline-acetyltransferase-immunoreactive neurons and their coexpression of the p75 low-affinity neurotrophin receptor either contralateral or ipsilateral to the lesion. In contrast, cholinergic fiber densities in estradiol-treated animals were greater both in the contralateral and ipsilateral somatosensory cortices as was detected by quantitative choline-acetyltransferase and vesicular acetylcholine transporter immunocytochemistry. However, estradiol treatment did not affect the lesion-induced relative percentage loss of cholinergic fibers. A significant decline of synaptophysin immunoreactivity paralleled the cholinergic damage in the somatosensory cortex of oil-treated animals, whereas an almost complete preservation of synaptic density was determined in estradiol-treated rats.Our results indicate that estradiol treatment enhances the cortical cholinergic innervation but has no rescuing effect on cholinergic nerve cells in the basal forebrain against excitotoxic damage. Nevertheless, estradiol may restore or maintain synaptic density in the cerebral cortex following cholinergic fiber loss. This estradiol effect may outweigh the lack of cellular protection on cholinergic cells at the functional level. [Copyright &y& Elsevier]