Continuously delivered ovarian steroids do not alter dendritic spine density or morphology in macaque dorsolateral prefrontal cortical neurons

Abstract

Aged ovariectomized female monkeys, a model for menopause in humans, show declines in spine density in the dlPFC and diminished performance in cognitive tasks requiring this brain region. Previous studies in our laboratory have shown that long-term cyclic treatment with 17β-estradiol (E) produces an increase in spine density and in the proportion of thinner spines in layer III pyramidal neurons in the dorsolateral prefrontal cortex (dlPFC) of both young and aged ovariectomized rhesus monkeys. Here we used 3D reconstruction of Lucifer yellow-loaded neurons to investigate whether clinically relevant schedules of hormone therapy would produce similar changes in prefrontal cortical neuronal morphology as long-term cyclic E treatment in young female monkeys. We found that continuously delivered E, with or without a cyclic progesterone treatment, did not alter spine density or morphology in the dlPFC of young adult OVX rhesus monkeys. We also found that the increased density of thinner spines evident in the dlPFC 24 hours after E administration in the context of long-term cyclic E therapy is no longer detectable 20 days after E treatment. When compared with the results of our previously published investigations, our results suggest that cyclic fluctuations in serum E levels may cause corresponding fluctuations in the density of thin spines in the dlPFC. By contrast, continuous administration of E does not support sustained increases in thin spine density. Physiological fluctuations in E concentration may be necessary to maintain the morphological sensitivity of the dlPFC to E.

Age and Long-Term Hormone Treatment Effects on the Ultrastructural Morphology of the Median Eminence of Female Rhesus Macaques

“…To mimic luteal phase P 4 levels, the YEP and AEP groups received micronized progesterone (100 mg; Catalent Pharm Solutions) in their daily fruit treat for 10 consecutive days once per month. Serum concentrations and assay characteristics of E 2 were previously reported for this cohort of young [42] and aged monkeys [43]. For the young YV, YE, and YEP groups at perfusion, serum E 2 concentrations (mean ± SEM, pg/ml) were 2.0 ± 2.2, 109 ± 15, and 118 ± 13, respectively.…”

Estrogen Effects on Cognitive and Synaptic Health Over the Lifecourse

“…Consistent with these findings, these same treatments also failed to restore dendritic spine synapses on area 46 neurons that had been observed with cyclic unopposed estrogen treatment (159) (FIGURE 6). Young ovariectomized monkeys also showed parallel results; continuous estrogen with or without progesterone resulted in area 46 spine density and morphology that were indistinguishable from those receiving vehicle alone (249). Homeostatic mechanisms likely take effect with chronic estrogen administration, during which its levels remain high, leading to desensitization of mechanisms involved in spinogenesis.…”

Estrogen enhances hippocampal gray-matter volume in young and older postmenopausal women: a prospective dose-response study

“…The current results provide evidence that similar sensitivity may be seen in older postmenopausal women, as a significant portion of the 2 mg E2 group were over the age of 60 and there was no a significant effect of age on changes in gray matter volume. In the non-human primate studies, the morphological effects of estrogen were only seen in cyclic (as opposed to continuous) administration (Young et al, 2013). In contrast, this study utilized continuous administration.…”