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      Memory and exploratory behavior impairment in ovariectomized Wistar rats

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          Abstract

          Background

          Estrogen deficiency is linked to changes in several physiological processes, but the extent to which it associates with cognitive changes in menopause context is controversial.

          Rationale

          We evaluated the impact of ovariectomy on memory processes and normal exploratory behavior in Wistar rats.

          Methods

          Young adult rats (4–6 months) were either ovariectomized (OVX group) (N = 10), sham operated (N = 10), or untouched (naïve controls) (N = 8). Afterwards, they were monitored for 12 weeks during which their cognitive functions were evaluated at first week (S1), second (S2), every 3 weeks (S5, S8) and then at week 12 (S12) using: (i) object recognition test to evaluate the short-term and long-term non-spatial memory; (ii) the object placement test to assess the spatial memory; and (iii) normal exploratory behavior components like locomotor and vertical activities in an open field arena.

          Results

          Marked changes in ovariectomized rats were observed in long-term non-spatial memory (~ 40% change vs. naïve and sham, P < 0.001) and spatial memory (~ 30% change, P < 0.05) from S2. Instead, from S5 the exploratory behavior was affected, with decreases in line crossing and rearing episode numbers (~ 40% change, P < 0.01), and in the time spent in the center of open field arena (~ 60% change, P < 0.01).

          Conclusions

          Our findings support the involvement of sex hormones in cognitive functions in female rats and suggest that controversy on the importance of cognitive affections in menopause context may emerge from differences between short-term and long-term memory processes.

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          Most cited references33

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          Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017alpha and P450 aromatase localized in neurons.

          In adult mammalian brain, occurrence of the synthesis of estradiol from endogenous cholesterol has been doubted because of the inability to detect dehydroepiandrosterone synthase, P45017alpha. In adult male rat hippocampal formation, significant localization was demonstrated for both cytochromes P45017alpha and P450 aromatase, in pyramidal neurons in the CA1-CA3 regions, as well as in the granule cells in the dentate gyrus, by means of immunohistochemical staining of slices. Only a weak immunoreaction of these P450s was observed in astrocytes and oligodendrocytes. ImmunoGold electron microscopy revealed that P45017alpha and P450 aromatase were localized in pre- and postsynaptic compartments as well as in the endoplasmic reticulum in principal neurons. The expression of these cytochromes was further verified by using Western blot analysis and RT-PCR. Stimulation of hippocampal neurons with N-methyl-d-aspartate induced a significant net production of estradiol. Analysis of radioactive metabolites demonstrated the conversion from [(3)H]pregnenolone to [(3)H]estradiol through dehydroepiandrosterone and testosterone. This activity was abolished by the application of specific inhibitors of cytochrome P450s. Interestingly, estradiol was not significantly converted to other steroid metabolites. Taken together with our previous finding of a P450scc-containing neuronal system for pregnenolone synthesis, these results imply that 17beta-estradiol is synthesized by P45017alpha and P450 aromatase localized in hippocampal neurons from endogenous cholesterol. This synthesis may be regulated by a glutamate-mediated synaptic communication that evokes Ca(2+) signals.
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            Estradiol and cognitive function: past, present and future.

            A historical perspective on estradiol's enhancement of cognitive function is presented, and research, primarily in animals, but also in humans, is reviewed. Data regarding the mechanisms underlying the enhancements are discussed. Newer studies showing rapid effects of estradiol on consolidation of memory through membrane interactions and activation of inter-cellular signaling pathways are reviewed as well as studies focused on traditional genomic mechanisms. Recent demonstrations of intra-neuronal estradiol synthesis and possible actions as a neurosteroid to promote memory are discussed. This information is applied to the critical issue of the current lack of effective hormonal (or other) treatments for cognitive decline associated with menopause and aging. Finally, the critical period hypothesis for estradiol effects is discussed along with novel strategies for hormone/drug development. Overall, the historical record documents that estradiol positively impacts some aspects of cognitive function, but effective therapeutic interventions using this hormone have yet to be realized.
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              Minireview: translational animal models of human menopause: challenges and emerging opportunities.

              Increasing importance is placed on the translational validity of animal models of human menopause to discern risk vs. benefit for prediction of outcomes after therapeutic interventions and to develop new therapeutic strategies to promote health. Basic discovery research conducted over many decades has built an extensive body of knowledge regarding reproductive senescence across mammalian species upon which to advance animal models of human menopause. Modifications to existing animal models could rapidly address translational gaps relevant to clinical issues in human menopausal health, which include the impact of 1) chronic ovarian hormone deprivation and hormone therapy, 2) clinically relevant hormone therapy regimens (cyclic vs. continuous combined), 3) clinically relevant hormone therapy formulations, and 4) windows of opportunity and optimal duration of interventions. Modifications in existing animal models to more accurately represent human menopause and clinical interventions could rapidly provide preclinical translational data to predict outcomes regarding unresolved clinical issues relevant to women's menopausal health. Development of the next generation of animal models of human menopause could leverage advances in identifying genotypic variations in estrogen and progesterone receptors to develop personalized menopausal care and to predict outcomes of interventions for protection against or vulnerability to disease. Key to the success of these models is the close coupling between the translational target and the range of predictive validity. Preclinical translational animal models of human menopause need to keep pace with changes in clinical practice. With focus on predictive validity and strategic use of advances in genetic and epigenetic science, new animal models of human menopause have the opportunity to set new directions for menopausal clinical care for women worldwide.
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                Author and article information

                Contributors
                +237 678585770 , sefirin.djiogue@gmail.com
                Armando_djiyou@yahoo.fr
                paul.seke@gmail.com
                ketchawanda@gmail.com
                rudig25@gmail.com
                dnjamen@gmail.com
                Journal
                Behav Brain Funct
                Behav Brain Funct
                Behavioral and Brain Functions : BBF
                BioMed Central (London )
                1744-9081
                16 July 2018
                16 July 2018
                2018
                : 14
                : 14
                Affiliations
                [1 ]ISNI 0000 0001 2173 8504, GRID grid.412661.6, Laboratory of Animal Physiology, Department of Animal Biology and Physiology, Faculty of Science, , University of Yaounde I, ; P.O. Box 812, Yaoundé, Cameroon
                [2 ]ISNI 0000 0001 2173 8504, GRID grid.412661.6, Department of Psychology, Faculty of Arts, Letters and Social Science, , University of Yaounde I, ; P.O. Box 7011, Yaoundé, Cameroon
                [3 ]GRID grid.440604.2, Center for Sustainable Health and Development, , University of Ngaoundere, ; P.O. Box 454, Ngaoundere, Cameroon
                Author information
                http://orcid.org/0000-0002-3525-7047
                Article
                146
                10.1186/s12993-018-0146-7
                6047120
                30012162
                f8fb78d4-9ef4-491c-97cd-570db12351cb
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 23 April 2018
                : 10 July 2018
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Neurology
                ovariectomy,memory,object recognition,spatial memory,ovarian hormones,wistar rats
                Neurology
                ovariectomy, memory, object recognition, spatial memory, ovarian hormones, wistar rats

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