Dietary phytoestrogens enhance spatial memory and spine density in the hippocampus and prefrontal cortex of ovariectomized rats

doi:10.1016/j.brainres.2006.07.016

Brain Research

Volume 1126, Issue 1, 18 December 2006, Pages 183-187

https://doi.org/10.1016/j.brainres.2006.07.016 Get rights and content

Abstract

Long-term maintenance of ovariectomized rats (9 weeks) on chow containing high phytoestrogen levels (Purina LabDiet® 5001) as compared to chow with minimal phytoestrogens (Harlan 2016 Teklad) was associated with better performance of the spatial memory task, object placement, increased dendritic spine density in CA1 and prefrontal cortex pyramidal neurons, and higher uterine weights. Object recognition memory, anxiety on an elevated plus maze and body weight were unaffected by phytoestrogen levels in the diet.

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Acknowledgments

This research was supported by NIH grants SO6 GM60654, R25 GM60665, 2T34 GM007823 and G12-RR-TT03037.

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Estrogen replacement has been repeatedly shown to enhance memory and increase dendritic spine density in the hippocampus and prefrontal cortex of ovariectomized (OVX) female rats. Given the potential deleterious effects of chronic estrogen administration, the present study assessed cognitive function using recognition memory tasks and measured dendritic spine density in the CA1 region of the hippocampus and medial prefrontal cortex after subchronic androgen replacement to adult OVX female rats. All androgens enhanced recognition memory in OVX rats, but object placement (OP) and object recognition (OR) results differed. Only testosterone enhanced OR. Testosterone had no effect on OP while dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT) and androstenedione (AD) enhanced OP. Dendritic spine density was increased by both TP and DHEA in both brain areas (DHT and AD were not tested). Lastly, we used the aromatase inhibitor, letrozole, to discriminate between potential androgenic and estrogenic effects of androgens on behavior. Letrozole alone did not alter recognition memory in OVX rats and did not block the effects of either TP or DHEA on recognition memory suggesting that effects were mediated via androgenic mechanisms. The present results expand previous information on gonadal hormone actions and show that, in addition to estrogens, androgens also improve memory and increase spine density in brains of OVX female rats. While requiring further investigation, these observations provide a basis for therapeutic interventions in the treatment of menopausal, age or disease related memory loss.
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Across species, adolescence is a period of growing independence that is associated with the maturation of cognitive, social, and affective processing. Reorganization of neural circuits within the frontal cortex is believed to contribute to the emergence of adolescent changes in cognition and behavior. While puberty coincides with adolescence, relatively little is known about which aspects of frontal cortex maturation are driven by pubertal development and gonadal hormones. In this review, we highlight existing work that suggests puberty plays a role in the maturation of specific cell types in the medial prefrontal cortex (mPFC) of rodents, and highlight possible routes by which gonadal hormones influence frontal cortical circuit development.
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Citation Excerpt :
Stress causes peripheral release and central synthesis of estradiol (Liu et al., 2011) which might, for example, promote beneficial memories such as the location or details of an attack for animals or the locations of traffic jams or dangerous locales for people. Since phytoestrogens also enhance memory by acting through estrogen receptors, our ancestor hunter-gatherers, or grazing animals today, may have benefited from the presence of phytoestrogens in clover and soy plants because they would enhance place memory for these high protein containing plants by acting through estrogen receptors (Luine et al., 2006). Finally, because estradiol is synthesized de novo in the hippocampus and other brain areas (Kato et al., 2013), estrogens may contribute to normal memory formation (see Frick et al., 2015 for further discussion).
This review highlights fifty years of progress in research on estradiol's role in regulating behavior(s). It was initially thought that estradiol was only involved in regulating estrus/menstrual cycles and concomitant sexual behavior, but it is now clear that estradiol also influences the higher order neural function of cognition. We provide a brief overview of estradiol's regulation of memory and some mechanisms which underlie its effects. Given systemically or directly into the hippocampus, to ovariectomized female rodents, estradiol or specific agonists, enhance learning and/or memory in a variety of rodent cognitive tasks. Acute (within minutes) or chronic (days) treatments enhance cognitive functions. Under the same treatment conditions, dendritic spine density on pyramidal neurons in the CA1 area of the hippocampus and medial prefrontal cortex increase which suggests that these changes are an important component of estrogen's ability to impact memory processes. Noradrenergic, dopaminergic and serotoninergic activity are also altered in these areas following estrogen treatments. Memory enhancements and increased spine density by estrogens are not limited to females but are also present in castrate males. In the next fifty years, neuroscientists need to determine how currently described neural changes mediate improved memory, how interactions among areas important for memory promote memory and the potential significance of neurally derived estrogens in normal cognitive processing. Answering these questions may provide significant advances for treatment of dementias as well as age and neuro-degenerative disease related memory loss.
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Phytoestrogens are plant-derived compounds that can modulate estrogen activity in the brain and periphery. Laboratory rodent diets are typically high in soy-based phytoestrogens and therefore may influence neurophysiological and behavioural measures that are sensitive to estrogen signaling. Here we assessed such measures in rats (males and females) fed Australian made diets that varied in their soy levels. We found that a low-soy diet promoted greater weight, and lower levels of plasma estradiol, particularly in male rats. It also produced sex-specific effects on estrogen receptor gene expression in the brain, increasing ESR2 expression in the hippocampus and prefrontal cortex in female rats, and decreasing dopamine D1 receptor gene expression in the striatum of both male and female rats. We also found a dietary effect on short-term place recognition memory, but this was independent of soy levels in the diet. These results demonstrate that the choice of rodent laboratory diet can influence physiology, neurobiology and behavior, particularly on measures related to estrogen signaling.
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The concept that estradiol may act as a local neuromodulator in the brain, rapidly affecting connectivity and synaptic function, has been firmly established by research over the last 30 years. De novo synthesis of estradiol within the brain as well as signaling mechanisms mediating responses to the hormone have been demonstrated, along with morphological evidence indicating rapid changes in synaptic input following increases in local estradiol levels. These rapid synaptic effects may play important roles in both physiological and pathophysiological responses to changes in circulating hormone levels, as well as in neurodegenerative disease. How local effects of estradiol on synaptic plasticity are integrated into changes in the overall activity of neural networks in the brain, however, remains a subject that is only incompletely understood.
The interaction of dietary isoflavones and estradiol replacement on behavior and brain-derived neurotrophic factor in the ovariectomized rat
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Phytoestrogens are plant derived, non-steroidal compounds naturally found in rodent chows that potentially have endocrine-disrupting effects. Isoflavones, the most common phytoestrogens, have a similar structure and molecular weight to 17β-estradiol (E2) and have the ability to bind and activate both isoforms of the estrogen receptor (ER). Most isoflavones have a higher affinity for ERβ, which is involved in sexually dimorphic behavioral regulation. The goal of this study was to examine the interaction of isoflavones and E2 presence in the OVX rat on anxiety- and depressive- like behavior and the related BDNF pathophysiology. E2 administration resulted in anxiogenic behaviors when isoflavones were present in the diet (p < 0.05), but anxiolytic behaviors when isoflavones were not present (p < 0.05). E2 resulted in antidepressive-like behaviors in animals fed an isoflavone-rich diet (p < 0.05), with no effect when isoflavones were removed. Increased hippocampal BDNF expression was observed in animals fed an isoflavone-rich diet after E2 administration (p < 0.05). BDNF expression in the amygdala and hypothalamus was increased after E2 treatment in animals fed an isoflavone-rich diet. Overall, these results demonstrate that the presence of dietary isoflavones can differentially regulate the effect of E2 replacement on behavior and BDNF expression.

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Short CommunicationDietary phytoestrogens enhance spatial memory and spine density in the hippocampus and prefrontal cortex of ovariectomized rats

Abstract

Section snippets

Acknowledgments

Brain Res.

Lab. Invest.

Neurotoxicol. Teratol.

Brain Res. Bull.

Exp. Gerontol.

Brain Res.

Spatial memory, recognition memory, and the hippocampus

Neuroscience

Spontaneous object recognition and object location memory in rats: the effects of lesions in the cingulate cortices, the medial prefrontal cortex, the cingulum bundle and the fornix

Exp. Brain Res.

Spontaneous recognition of object configurations in rats: effects of fornix lesions

Brain Res.

Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood

J. Neurosci.

Oestrogen receptors mice: roles for oestrogen receptors α and β in reproductive tissues

Reproduction

Gonadal hormones are responsible for maintaining the integrity of spine synapses in the CA1 hippocampal subfield of female nonhuman primates

J. Comp. Neurol.

Short Communication
Dietary phytoestrogens enhance spatial memory and spine density in the hippocampus and prefrontal cortex of ovariectomized rats