Life-long environmental enrichment differentially affects the mnemonic response to estrogen in young, middle-aged, and aged female mice

The present study was designed to examine whether life-long exposure to standard or enriched housing affects the ability of estrogen to improve spatial and object memory throughout the lifespan. Three-week-old female mice were maintained in standard or enriched housing up to and through ovariectomy and behavioral testing at 5, 17, or 22 months of age. Spatial memory was tested in the Morris water maze and object memory was tested using an object recognition task. Immediately after training each day, mice were injected intraperitoneally with vehicle or 0.2 mg/kg 17beta-estradiol. Among young females, object recognition was enhanced by estradiol alone, an effect that was reduced by enrichment. In contrast, spatial water maze performance was impaired by estradiol alone, but improved by the combination of both estradiol and enrichment. At middle-age, object recognition was enhanced by estradiol or enrichment alone, and the combination of both treatments. Spatial memory in the water maze was also improved by both treatments at middle-age, but the beneficial effects of estradiol were limited to standard-housed females. Finally, whereas enrichment in aged females significantly enhanced performance in both tasks, estradiol had no effect at this age in either task. In total, the data indicate that life-long enrichment can significantly alter the extent to which estradiol affects memory in mice throughout the lifespan. Importantly, the interaction between these treatments is highly dependent on age and type of memory tested.     

Systemic and local administration of estradiol into the prefrontal cortex or hippocampus differentially alters working memory

The influence of estradiol on learning and memory is dependent on a number of factors. The effects of physiological levels of estradiol on the acquisition of a spatial working memory task mediated by the prefrontal cortex (PFC) and the hippocampus were examined in Experiment 1. Ovariectomized Long-Evans rats received daily injections of estradiol or vehicle were tested on the win-shift version of the radial arm maze. A high dose of estradiol benzoate (5 microg) enhanced acquisition of the task, whereas a low dose of estradiol (0.3 microg) increased the number of errors committed over 17 days of testing. Experiment 2 was conducted to examine site-specific influences of estradiol on spatial working memory in well-trained rats. Saline and estradiol cyclodextrin (0.1 and 0.9 microg) were infused into the prelimbic region of the PFC or dorsal hippocampus 40 min prior to testing on the win-shift task. Infusions of estradiol into both brain areas attenuated saline-infusion disruptions in working memory. Specifically, the higher dose of estradiol facilitated working memory when infused into the PFC, whereas the lower dose of estradiol facilitated performance when infused into the dorsal hippocampus. Moreover, working memory was significantly impaired 24 h after infusions of estradiol into the dorsal hippocampus but not the PFC. These data provide further evidence for the notion that estradiol can dose-dependently alter memory processes and suggest that facilitation or disruptions of working memory by estradiol are site- and time-specific.     

Short-term estrogen treatment in ovariectomized rats augments hippocampal acetylcholine release during place learning

Estrogen modulates learning and memory in ovariectomized and naturally cycling female rats, especially in tasks using spatial learning and navigation. Estrogen also modulates cholinergic function in various forebrain structures. Past studies have shown positive correlations between hippocampal ACh output and performance on hippocampus-dependent tasks. The present study examined whether estradiol replacement would potentiate hippocampal ACh release during place learning. In vivo microdialysis and HPLC were used to measure extracellular ACh levels in the hippocampus of ovariectomized female rats that had received s.c. injections of 17beta-estradiol (10 microg) or sesame oil (vehicle treatment) 48 and 24h prior to training on a place task. Estrogen did not alter baseline levels of extracellular ACh in the hippocampus. During training, hippocampal ACh increased in ovariectomized rats regardless of estrogen status. However, while estradiol did not enhance learning in this experiment, estradiol significantly potentiated the increase in hippocampal ACh release seen during place training. This represents the first demonstration of on-line assessment of ACh output in hippocampus during learning in female rats and suggests that estrogen-dependent modulation of ACh release during training might control activation of different neural systems used during learning.     

Estrogen modulates place learning through estrogen receptors in the hippocampus

Moderate elevations in circulating estradiol enhance learning in tasks that tap place learning strategies such as those requiring the use of extramaze cues. Use of place learning strategies is particularly impaired by damage to the hippocampus, a structure shown to be sensitive to estrogen treatments. We have shown that direct estrogen infusions into the dorsal hippocampus, and not the dorsolateral striatum, enhance place learning, suggesting that the hippocampus may be an important modulatory site for the effects of estrogen on place learning. The current experiment tested whether the hippocampus is indeed a critical site of estrogen modulation through classical estrogen receptors. Young adult female Sprague-Dawley rats were ovariectomized for 21 days and given systemic injections (0.1 ml) of sesame oil (OIL) or 10 microg of 17beta-estradiol-benzoate (E2), 48 and 24 h before being trained on a place task. Twenty-four hours prior to the first systemic injection, separate groups of rats received bilateral hippocampal implants of either the antiestrogen ICI 182,780 (ICI) or cholesterol vehicle. Implants were maintained until and throughout training. Intrahippocampal ICI reversed the enhancement in place learning seen with systemic E2 treatment. Unexpectedly, intrahippocampal ICI in OIL-treated rats also enhanced place learning. These data suggest that ICI may have some mixed agonist and antagonist effects in the hippocampus and that estrogen enhances place learning through activation of estrogen receptors located in the hippocampus.     

Endogenous estradiol is associated with verbal memory in nondemented older men

This study examined the relationship between endogenous hormones and cognitive function in nondemented, ethnically-diverse community-dwelling older men enrolled in the Einstein Aging Study (EAS). All eligible participants (185 men, mean age=81 years) received neuropsychological assessment (Free and Cued Selective Reminding Test (FCSRT), Logical Memory (LM), Trail Making Test B (TMTB), block design (BD)) and provided blood samples for hormonal assays (total estradiol, total testosterone, calculated free testosterone index). Linear regression analysis adjusted for age, education, body mass index, and cardiovascular comorbidities indicated that men with high levels of total estradiol demonstrated better FCSRT verbal memory performance (β=0.17, p<0.02) compared to men with lower levels of total estradiol. The results remained unchanged when the model was further adjusted for ethnicity. We did not detect an association between testosterone and cognitive performance. These findings indicate that high levels of total estradiol in older men are associated with better performance on a cue-based, controlled learning test of verbal memory that is a sensitive predictor of dementia.     

Baby babbling at five months linked to sex hormone levels in early infancy

Gender-dependent differentiation of the brain at morphological, neurochemical and functional levels of organization have been shown to be primarily controlled by sex differences in gonadal hormone concentrations during pre- and early postnatal development. Indeed, previous studies have reported that pre- and perinatal hormonal environments influence brain development and, consequently, affect sex specific long-term language outcomes.Herein, we investigated whether postnatal surges of estrogen (estradiol) and androgen (testosterone) may predict properties of pre-speech babbling at five months. This study is the first attempt to investigate a possible correlation between sex hormones and infants’ articulatory skills during the typical postnatal period of extended hormonal activity known as ‘mini-puberty.’ A hierarchical, multiple regression approach revealed a significant, robust positive relationship between 4-week concentrations of estradiol and individual articulatory skills. In contrast, testosterone concentrations at five months negatively correlated with articulatory skills at the same age in both boys and girls. Our findings reinforce the assumption of the importance of sex hormones for auditory–vocal development towards language in human infants.