Effects of estrogen on basal forebrain cholinergic neurons vary as a function of dose and duration of treatment

Studies suggest that estrogen replacement can influence learning and memory processes via effects on cholinergic neurons located in specific regions of the basal forebrain. In the present study, immunocytochemical techniques were used to examine the effects of estrogen on basal forebrain cholinergic neurons as a function of the dose and duration of estrogen treatment. Ovariectomized rats received 2, 10, 25, or 100 microg estradiol every other day for a period of 1, 2, or 4 weeks. Sections through the basal forebrain were then processed for the detection of choline acetyltransferase (ChAT) or the low-affinity nerve growth factor receptor (p75NGFR), and the number of immunoreactive cells in the medial septum (MS), the horizontal limb of the diagonal band of Broca (HDB) and the nucleus basalis magnocellularis (NBM) were counted. The effects of dose and duration of estrogen treatment were evaluated by analysis of variance and individual group means were compared with ovariectomized controls using a two-tailed Dunnets test. Administration of 2, 10, or 25 microg estradiol for 1 week produced a dose-related increase in the number of ChAT-like immunoreactive (IR) cells detected in the MS. Likewise treatment with 10 microg estradiol for 1 week, or with 2 microg estradiol for 2 weeks resulted in a significant increase in the number of ChAT-IR cells detected in the NBM. These effects were not observed following treatment with higher doses of estradiol. Nor were they maintained following repeated administration of estradiol for longer periods of time. In contrast, repeated administration of estradiol for 2 or 4 weeks resulted in significant decreases in the number of p75NGFR-IR cells detected in the MS, with the greatest effects observed following treatment with the higher doses of estradiol for longer periods of time. These findings demonstrate that (1) estrogen replacement produces regionally selective effects on basal forebrain cholinergic neurons which vary as a function of both the dose and duration of estrogen treatment, and (2) estrogen has both short-term and longer-term effects on basal forebrain cholinergic neurons, each of which may contribute to the effects of estrogen on learning and memory process and the development of age- and disease-related cognitive decline.