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. 2012 Jun;62(1):1-9.
doi: 10.1016/j.yhbeh.2012.04.004. Epub 2012 Apr 13.

Continuous estrone treatment impairs spatial memory and does not impact number of basal forebrain cholinergic neurons in the surgically menopausal middle-aged rat

Elizabeth B Engler-Chiurazzi  1 , Joshua S Talboom, B Blair Braden, Candy W S Tsang, Sarah Mennenga, Madeline Andrews, Laurence M Demers, Heather A Bimonte-Nelson
Affiliations

Continuous estrone treatment impairs spatial memory and does not impact number of basal forebrain cholinergic neurons in the surgically menopausal middle-aged rat

Elizabeth B Engler-Chiurazzi et al. Horm Behav. 2012 Jun.

Abstract

CEE (conjugated equine estrogens) is the most widely prescribed estrogen-only menopausal hormone therapy in the United States, and is comprised of over 50% estrone (E1) sulfate. Following CEE administration, E1 is the principal circulating estrogen. However, the cognitive and neurobiological effects of E1 in a middle-aged rodent model have not yet been evaluated. We assessed cognitive effects of continuous E1 treatment in middle-aged surgically menopausal rats using a maze battery. We also quantified number of choline acetyltransferase-immunoreactive (ChAT-IR) neurons in distinct basal forebrain regions known in earlier studies in to be impacted by the most potent naturally-circulating estrogen in rodents and women, 17β-estradiol (17β-E2), as well as CEE. On the spatial working memory delayed-match-to-sample water maze, the highest E1 dose impaired memory performance during acquisition and after delay challenge. E1 did not impact ChAT-IR neuron number in the medial septum (MS) or horizontal/vertical diagonal bands. In a comparison study, 17β-E2 increased MS ChAT-IR neuron number. Findings indicate that E1 negatively impacts spatial working memory and memory retention, and does not increase ChAT-IR neuron number in basal forebrain, as does 17β-E2. Thus, data from prior studies suggest that 17β-E2 and CEE can enhance cognition and increase number of ChAT-IR basal forebrain neurons, while here we show that E1 does not induce these effects. Findings from preclinical basic science studies can inform the design of specific combinations of estrogens that could be beneficial to the brain and cognition. Accumulating data suggest that E1 is not likely to be among these key beneficial estrogens.

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Figures

Figure 1
Figure 1
Study Timeline. A timeline summarizing the effects of Ovx surgery, pump insertion surgery for hormone administration, vaginal smears, and behavioral maze testing battery.
Figure 2
Figure 2
Delayed-Match-to-Sample Water Maze Performance. a) Mean (±SE) total errors during DMS testing. During the second three-day testing block, the highest dose of E1 impaired performance, with E1-High rats making more total errors than Vehicle rats (* p<0.05). b) Mean (±SE) total errors during DMS delay testing. Within subjects comparisons revealed that E1-High treated rats made more errors on the post-delay trial (trial two) of the combined delay measure, as compared to trial two of baseline (* p<0.05).
Figure 3
Figure 3
Markers of Peripheral Estrogenic Action. Mean (±SE) uterine weights (g). All doses of E1 increased uterine weights relative to Vehicle rats (* p<0.0001).
Figure 4
Figure 4
Basal Forebrain ChAT-IR Neuron Counts. a) Mean (±SE) ChAT-IR neurons in the MS. In a separate comparison study, a group treated with 17β-E2, and corresponding Vehicle group, was used. Treatment with 4.0 g/day 17β-E2, but no dose of E1, increased ChAT-IR neurons (* p<0.05). b) Mean (±SE) ChAT-IR neurons in the hDB/vDB. Neither 17β-E2 nor any dose of E1 impacted the number of ChAT-IR neurons compared to Vehicle rats in this region. Representative basal forebrain photomicrograph of the: c) Vehicle comparison group, d) 4.0 g/day 17β-E2 comparison group, e) Vehicle group, f) E1-Low group, g) E1-Med group, and h) of E1-High group.
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