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Cholesterol and Perhaps Estradiol Protect Against Corticosterone-Induced Hippocampal CA3 Dendritic Retraction in Gonadectomized Female and Male Rats

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Cholesterol and Perhaps Estradiol Protect Against Corticosterone-Induced Hippocampal CA3 Dendritic Retraction in Gonadectomized Female and Male Rats

J B Ortiz et al. Neuroscience.

Abstract

Chronic stress or glucocorticoid exposure simplifies hippocampal Cornu Ammonis region 3 (CA3) apical dendritic arbors in male rats. In contrast to males, chronic stress either reduces CA3 basal branching or exerts no observable morphological effects in gonadally intact female rats. Under conditions that females display stress-induced CA3 dendritic retraction, such as that following ovariectomy, chronic exposure to 17β-estradiol or cholesterol can negate these changes. Whether glucocorticoids produce CA3 dendritic retraction in ovariectomized females and whether neuroprotection from 17β-estradiol or cholesterol is sex-specific remains unknown. The current study examined the effects of chronic glucocorticoid exposure, in conjunction with 17β-estradiol or cholesterol administration, on hippocampal CA3 dendritic complexity. Adult male and female Sprague-Dawley rats were gonadectomized and implanted with 25% 17β-estradiol in cholesterol, 100% cholesterol, or blank Silastic capsules. Rats were then assigned to either a 21-day corticosterone (CORT) drink (400μg/ml CORT, 2.4% ethanol in tap water) or tap water (Tap, 2.4% ethanol in tap water) treatment. Brains were processed for Golgi staining, and hippocampal CA3 dendritic architecture was quantified. Results showed 21-day CORT administration reduced hippocampal CA3 apical dendritic branch points, CA3 apical dendritic length, body weight gain, and adrenal weights compared to male and female control counterparts. Furthermore, male and female rats implanted with Silastic capsules containing cholesterol or 25% 17β-estradiol in cholesterol were protected from CORT-induced CA3 apical dendritic branch reduction. No effects were observed in the CA3 basal dendritic arbors. The present results demonstrate that CORT produces hippocampal CA3 dendritic retraction in gonadectomized male and female rats and that cholesterol and 25% 17β-estradiol in cholesterol prevent this dendritic simplification.

Figures

Figure 1
Figure 1
Effects of chronic CORT exposure on CA3 dendritic complexity. Camera Lucida tracings of CA3 neurons are represented above corresponding Golgi-stained cells. CORT reduced CA3 apical dendritic branch points in both females and males, while cholesterol and 25% 17β-estradiol in cholesterol prevented these effects. Basal dendritic arbors were unaffected by drink treatment. Tap water treatment and blank Silastic implants (Tap-X), tap water treatment and cholesterol-filled implants (Tap-Chol), tap water treatment and 17β-estradiol-filled implants (Tap-E), CORT drink treatment and blank implants (CORT-X), CORT drink treatment and cholesterol-filled implants (CORT-Chol), CORT drink treatment and 17β-estradiol-filled implants (CORT-E). Scale bars = 100 µm.
Figure 2
Figure 2
Effects of chronic CORT exposure and cholesterol or 25% 17β-estradiol in cholesterol treatment on hippocampal CA3 dendritic branch points. A) Effects from females showing that CORT-treated rats with blank implants (CORT-X) exhibited diminished hippocampal CA3 dendritic complexity compared to all other groups, as marked by a reduction in apical branch points. Cholesterol and 25% 17β-estradiol in cholesterol Silastic implants prevented the simplification of CA3 apical dendritic branch points following CORT treatment. B) CA3 apical dendritic branch points in males showing that CORT drink induced a reduction in CA3 apical dendritic branch points and this CORT-induced effect was prevented by cholesterol and 25% 17β-estradiol in cholesterol Silastic implants. * p ≤ 0.05 compared to all other groups. Tap water treatment and blank Silastic implants (Tap-X), tap water treatment and cholesterol-filled implants (Tap-Chol), tap water treatment and 17β-estradiol-filled implants (Tap-E), CORT treatment and blank implants (CORT-X), CORT treatment and cholesterol-filled implants (CORT-Chol), CORT treatment and 17β-estradiol-filled implants (CORT-E).
Figure 3
Figure 3
Effects of prolonged exposure to CORT, cholesterol, and 17β-estradiol on body weight gain and adrenal weights. A) Although females gained significantly less weight than did males, as would be expected, CORT significantly reduced body weight gain in both sexes compared to tap water-treated rats, and weight was further attenuated by 17β-estradiol. B) Adrenal weights are represented as a ratio of adrenal weight per 100 grams of body weight. Rats that underwent chronic CORT exposure had significantly diminished adrenal weights regardless of sex. Rats implanted with 17β-estradiol capsules had significantly enlarged adrenals compared to their blank and cholesterol-implanted same-sex counterparts. Furthermore, females had significantly larger adrenal weights per 100 grams of body weight than compared to males. *** p< 0.001 Significant main effect of Sex. §§§ p<0.001 Significant main effect of CORT compared to tap water treatment. ‡‡‡ p<0.001 Significant main effect of 17β-estradiol Silastic implant. Tap water treatment and blank Silastic implants (Tap-X), tap water treatment and cholesterol-filled implants (Tap-Chol), tap water treatment and 17β-estradiol-filled implants (Tap-E), CORT drink treatment and blank implants (CORT-X), CORT drink treatment and cholesterol-filled implants (CORT-Chol), CORT drink treatment and 17β-estradiol-filled implants (CORT-E).
Figure 4
Figure 4
Effects of chronic CORT treatment and cholesterol and 17β-estradiol administration on 17β-estradiol serum levels. A) Female rats implanted with 17β-estradiol implants and given tap water (Tap-E) displayed significantly elevated 17β-estradiol serum levels compared to all other groups, except females treated with 17β-estradiol and CORT water (CORT-E). Females treated with 17β-estradiol and CORT water showed significantly higher 17β-estradiol serum levels than did CORT-treated females implanted with blank or cholesterol capsules. Males exposed to CORT and implanted with 17β-estradiol implants demonstrated significantly elevated serum levels of 17β-estradiol compared to males implanted with blank implants and given tap water (Tap-X), and females given CORT drink treatment and implanted with blank- and cholesterol-filled Silastic implants (CORT-X and CORT-Chol). B) Contents of implants significantly affected serum 17β-estradiol levels. Females implanted with 17β-estradiol-filled Silastic implants displayed higher serum levels of 17β-estradiol compared to female and male rats implanted with blank- and cholesterol-filled Silastic implants (X and Chol). Moreover, male rats implanted with 17β-estradiol showed significantly higher 17β-estradiol serum levels than did males with blank- and cholesterol-filled Silastic implants. ‡‡‡ p<0.001 compared to all other groups except females given CORT drink and implanted with 17β-estradiol implants. ++ p < 0.02 compare females to males. * p < 0.05 compared to females given CORT drink and blank (females CORT-X) or Cholesterol implants (females CORT-Chol) § p < 0.05 compared to males given tap water and blank Silastic implants (males Tap-X). † p < 0.01 compared to females and males implanted with blank- or cholesterol-filled Silastic implants and males implanted with 17β-estradiol Silastic implants. ¥ p < 0.05 compared to males implanted with blank Silastic implants. Tap water treatment and blank Silastic implants (Tap-X), tap water treatment and cholesterol-filled implants (Tap-Chol), tap water treatment and 17β-estradiol-filled implants (Tap-E), CORT drink treatment and blank implants (CORT-X), CORT drink treatment and cholesterol-filled implants (CORT-Chol), CORT drink treatment and 17β-estradiol-filled implants (CORT-E).

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