Granule Cells in Aging Rats Are Sexually Dimorphic in Their Response to Estradiol

Miranda, Phillippa J.; Williams, Christina L.; Einstein, Gillian

doi:10.1523/jneurosci.19-09-03316.1999

Cited by 128 publications

(91 citation statements)

References 64 publications

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“…Long-term gonadal steroid deprivation in the aged males' dentate granule cells did not decrease dentate granule cell dendritic spines compared with short-term deprived young males. In contrast, gonadectomized aged males treated with short-term estradiol replacement had decreased spine density (Miranda et al 1999).…”

Section: The Menopausal Female Brain Memory Function and Estrogen-imentioning

confidence: 80%

Cellular and Molecular Mechanisms of Estrogen Regulation of Memory Function and Neuroprotection Against Alzheimer's Disease: Recent Insights and Remaining Challenges

Brinton¹

2001

Learn. Mem.

164

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This review focuses on recent advances in our knowledge of estrogen action in the brain. The greatest amount of attention was devoted to those studies that impact our understanding of estrogen regulation of memory function and prevention of degenerative diseases associated with memory systems, such as Alzheimer's disease. A review of recent advances in our understanding of estrogen receptors, both nuclear and membrane, is also presented. Finally, these data are considered in regard to their relevancy to the use of estrogen replacement therapy for cognitive health throughout menopause and the development of an estrogen replacement therapy designed for the unique requirements of the brain.The relationship between memory function and estrogen was first noted clinically as women entering menopause frequently voiced complaints of memory and concentration difficulties (Sherwin 1999). In fact, changes in cognitive functioning have long been associated with menopause (Neurgaren and Kraines 1965). The shift from observation of this phenomenon to scientific human study occurred in the mid-1980's when Sherwin and colleagues began a systematic analysis of the impact of estrogen loss and replacement on memory function (Sherwin 2000). Results of these analyses demonstrated that verbal memory declined with the loss of estrogen and was restored to premenopausal levels when estrogen replacement therapy was instituted immediately following menopause (Sherwin 1988). An earlier important discovery relevant to estrogen effects on memory function came from basic sciences studies in the mid and late 1970's by Luine and colleagues, who found that 17␤-estradiol increased choline acetyltransferase activity which led to increased acetylcholine levels (Luine 1985). Based on these findings, Fillit investigated the impact of estrogen replacement therapy on cognitive function in women with Alzheimer's disease (Fillit et al. 1986). The results of this small clinical trial proved to be pivotal and led to multiple international clinical and epidemiological studies which in turn led to an intense study of the impact of estrogen on the mechanisms of memory in both animals and humans (Brinton 1998). Presented here is a review of the more recent studies, with an emphasis on conceptually linking the many individual findings that have been generated in the past several years. In addition, an analysis of emerging data relevant to our understanding of estrogen regulation of memory function and prevention of Alzheimer's disease is presented. Estrogen-Induced Neurotrophism and Underlying MechanismsEstrogen-induced neurotrophic effects are now well documented in vitro and also in vivo preparations (Fig. 1) (ToranAllerand 1984(ToranAllerand , 2000 Brinton 1993;Murphy and Segal 1996;Brinton et al. 1997bWoolley, 1999). Investigations to determine the mechanism of estrogen-induced neurotrophism have pointed to a temporal cascade of estrogen-inducible effects that are mediated by separate but potentially interacting pathways. It also appears that blockade of ...

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Section: The Menopausal Female Brain Memory Function and Estrogen-imentioning

confidence: 80%

Cellular and Molecular Mechanisms of Estrogen Regulation of Memory Function and Neuroprotection Against Alzheimer's Disease: Recent Insights and Remaining Challenges

Brinton¹

2001

Learn. Mem.

164

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“…E 2 alters many aspects of hippocampal morphology, including synapse number, spine density, and astrocytic volume (50)(51)(52). In brain, astrocytes contain ER␤ (53,54).…”

Section: Discussionmentioning

confidence: 99%

Disruption of estrogen receptor β gene impairs spatial learning in female mice

Rissman

Heck

Leonard

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

225

136

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Here we provide the first evidence, to our knowledge, that estradiol (E 2) affects learning and memory via the newly discovered estrogen receptor ␤ (ER␤). In this study, ER␤ knockout (ER␤KO) and wild-type littermates were tested for spatial learning in the Morris water maze after ovariectomy, appropriate control treatment, or one of two physiological doses of E 2. Regardless of treatment, all wild-type females displayed significant learning. However, ER␤KOs given the low dose of E 2 were delayed in learning acquisition, and ER␤KOs administered the higher dose of E2 failed to learn the task. These data show that ER␤ is required for optimal spatial learning and may have implications for hormone replacement therapy in women.T he steroid hormone estradiol (E 2 ) either is required for or significantly modulates many behaviors, including cognitive behaviors (1-9). Learning tasks that involve reference memory tend to be impaired by E 2 (1,7,8). In contrast, low levels of E 2 may facilitate working memory (5, 9). In women, changes in ability on visuospatial tasks and memory recall over the menstrual cycle have been documented (10, 11). Also, beneficial effects of estrogen replacement on cognition have been noted in normally aging women (12, 13) and in women suffering from dementia associated with Alzheimer's disease (14,15).How estrogen acts on learning and memory is not clear. Estrogen binding has been reported throughout the rodent brain, including the hippocampus and cortex (16). Both characterized nuclear estrogen receptors (ER␣ and -␤) are present in extrahypothalamic regions (17,18). In addition, in vitro work suggests that estrogen acts in a nongenomic fashion in hippocampal tissues (19,20). Mice lacking functional ER␣ have severe deficits in several aspects of reproduction, including behavior (21-24). On the other hand, ER␤ knockout mice (ER␤KO) are subfertile, and sexual behavior is normal (25, 26). Thus, there has been speculation that ER␤ regulates estrogen's nonreproductive functions in the central nervous system (21, 27, 28).Here we describe our work on spatial learning in female ER␤KO mice. When treated with doses of E 2 that do not affect learning in wild-type (WT) littermates, ER␤KO mice had impaired ability to escape from the Morris water maze. Interactions between ER␣ and -␤ may contribute to the learning response; to test the hypothesis that lack of ER␤ influences the level of ER␣ protein, mouse brains were examined for ER␣ immunoreactivity (ER␣-ir), with emphasis on the hippocampus (HIPP). MethodsAnimals. Female mice (ages 5-7 mos) were of mixed 129͞J and C57BL͞6J background. Subjects were generated by crossing heterozygotic mating pairs carrying a single copy of the disrupted ER␤ gene (25). The resulting offspring were genotyped by PCR amplification of tail DNA. WT and ER␤ disrupted (ER␤KO) littermates were used in these studies. The ER␤ gene disruption was created by Neo insertion into exon 3 (25), thus the following three primers were used: one from intron 2 (5Ј-GGAGTAGAAACAAGCAATCCAGACATC-3Ј), a...

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“…However, many discrepancies between these two studies exist. For example, different strains of rat, different ages, and different post-ovariectomy times were used in these studies and all of these factors can profoundly influence the ability of estrogens to modulate neuroplasticity in the hippocampus (Miranda et al, 1999;Tanapat et al, 1999;Tanapat et al, 2005;Barha et al, 2009). Furthermore, although Premarin largely consists of estrone, it also contains other forms of estrogen including 17b-estradiol and 17a-estradiol.…”

Section: Estrone Impaired Contextual Fear Conditioningmentioning

confidence: 99%

Low Doses of 17α-Estradiol and 17β-Estradiol Facilitate, Whereas Higher Doses of Estrone and 17α- and 17β-Estradiol Impair, Contextual Fear Conditioning in Adult Female Rats

Barha

Dalton

Galea

2009

Neuropsychopharmacol

108

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Estrogens are known to exert significant structural and functional effects in the hippocampus of adult rodents. In particular, 17b-estradiol can improve, impair, or have no effect on hippocampus-dependent learning and memory depending on dose and time of administration. The effects of other forms of estrogen, such as estrone and 17a-estradiol, on hippocampus-dependent learning have not been as thoroughly investigated. Therefore, the purpose of this study was to investigate the effects of 17b-estradiol, estrone, and 17a-estradiol at three different doses on two different tasks: hippocampus-dependent contextual fear conditioning and hippocampusindependent cued fear conditioning. Adult ovariectomized female rats were injected with one of the estrogens at one of the three doses 30 mins before conditioning to assess the rapid effects of these estrogens on acquisition. Twenty-four hours later memory for the context was examined and 1 h later memory for the cue (tone) was assessed. Levels of synaptophysin were examined in the dorsal hippocampus of rats to identify a potential synaptic correlate of hormonal effects on contextual fear conditioning. Low 17b-estradiol and 17a-estradiol enhanced, whereas high 17b-estradiol and 17a-estradiol impaired, contextual fear conditioning. Only the middle dose of estrone severely impaired contextual fear conditioning. Estrogens did not alter performance in the hippocampus-independent cued task. Synaptophysin expression was increased by estrone (at a middle and high dose) and 17b-estradiol (at a middle dose) in the CA3 region of the hippocampus and was not correlated with cognition. The results of this study indicate that estradiol can positively or negatively influence hippocampus-dependent learning and memory, whereas estrone impairs hippocampus-dependent learning and memory in a dose-dependent manner. These results have important therapeutic implications, as estrone, a main component of a widely used hormone replacement therapy, was shown to have either a negative effect or no effect on learning and memory. It may be possible to use 17a-estradiol and lower doses of estrogens as potential alternatives in hormone replacement therapies.

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Granule Cells in Aging Rats Are Sexually Dimorphic in Their Response to Estradiol

Cited by 128 publications

References 64 publications

Cellular and Molecular Mechanisms of Estrogen Regulation of Memory Function and Neuroprotection Against Alzheimer's Disease: Recent Insights and Remaining Challenges

Cellular and Molecular Mechanisms of Estrogen Regulation of Memory Function and Neuroprotection Against Alzheimer's Disease: Recent Insights and Remaining Challenges

Disruption of estrogen receptor β gene impairs spatial learning in female mice

Low Doses of 17α-Estradiol and 17β-Estradiol Facilitate, Whereas Higher Doses of Estrone and 17α- and 17β-Estradiol Impair, Contextual Fear Conditioning in Adult Female Rats

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