Cardiometabolic health, menopausal estrogen therapy and the brain: How effects of estrogens diverge in healthy and unhealthy preclinical models of aging.

Research in preclinical models indicates that estrogens are neuroprotective and positively impact cognitive aging. However, clinical data are equivocal as to the benefits of menopausal estrogen therapy to the brain and cognition. Pre-existing cardiometabolic disease may modulate mechanisms by which estrogens act, potentially reducing or reversing protections they provide against cognitive decline. In the current review we propose mechanisms by which cardiometabolic disease may alter estrogen effects, including both alterations in actions directly on brain memory systems and actions on cardiometabolic systems, which in turn impact brain memory systems. Consideration of mechanisms by which estrogen administration can exert differential effects dependent upon health phenotype is consistent with the move towards precision or personalized medicine, which aims to determine which treatment interventions will work for which individuals. Understanding effects of estrogens in both healthy and unhealthy models of aging is critical to optimizing the translational link between preclinical and clinical research.

History of Previous Midlife Estradiol Treatment Permanently Alters Interactions of Brain Insulin-like Growth Factor-1 Signaling and Hippocampal Estrogen Synthesis to Enhance Cognitive Aging in a Rat Model of Menopause.

Across species, including humans, elevated levels of brain estrogen receptor (ER) α are associated with enhanced cognitive aging, even in the absence of circulating estrogens. In rodents, short-term estrogen treatment, such as that commonly used in the menopausal transition, results in long-term increases in ERα levels in the hippocampus, leading to enhanced memory long after termination of estrogen treatment. However, mechanisms by which increased levels of brain ERα enhances cognitive aging remain unclear. Here we demonstrate in aging female rats that insulin-like growth factor-1 (IGF-1), which can activate ER via ligand-independent mechanisms, requires concomitant synthesis of brain-derived neuroestrogens to phosphorylate ERα via MAPK signaling, ultimately resulting in enhanced memory. In a rat model of menopause involving long-term ovarian hormone deprivation, hippocampal neuroestrogen activity decreases, altering IGF-1 activity and resulting in impaired memory. However, this process is reversed by short-term estradiol treatment. Forty days of estradiol exposure following ovariectomy results in maintenance of neuroestrogen levels that persist beyond the period of hormone treatment, allowing for continued interactions between IGF-1 and neuroestrogen signaling, elevated levels of hippocampal ERα, and ultimately enhanced memory. Collectively, results demonstrate that short-term estradiol use following loss of ovarian function has long-lasting effects on hippocampal function and memory by dynamically regulating cellular mechanisms that promote activity of ERα in the absence of circulating estrogens. Translational impacts of these findings suggest lasting cognitive benefits of short-term estrogen use near menopause and highlight the importance of hippocampal ERα, independent from the role of circulating estrogens, in regulating memory in aging females.SIGNIFICANCE STATEMENT Declines in ovarian hormones following menopause coincide with increased risk of cognitive decline. Because of potential health risks, current recommendations are that menopausal estrogen therapy be limited to a few years. Long-term consequences for the brain and memory of this short-term midlife estrogen therapy are unclear. Here, in a rodent model of menopause, we determined mechanisms by which short-term midlife estrogen exposure can enhance hippocampal function and memory with cognitive benefits and molecular changes enduring long after termination of estrogen exposure. Our model indicates long-lasting benefits of maintaining hippocampal estrogen receptor function in the absence of ongoing estrogen exposure and suggests potential strategies for combating age-related cognitive decline.

Previous estradiol treatment during midlife maintains transcriptional regulation of memory-related proteins by ERα in the hippocampus in a rat model of menopause.

Previous midlife estradiol treatment, like continuous treatment, improves memory and results in lasting increases in hippocampal levels of estrogen receptor (ER) α and ER-dependent transcription in ovariectomized rodents. We hypothesized that previous and continuous midlife estradiol act to specifically increase levels of nuclear ERα, resulting in transcriptional regulation of proteins that mediate estrogen effects on memory. Ovariectomized middle-aged rats received estradiol or vehicle capsule implants. After 40 days, rats initially receiving vehicle received another vehicle capsule (ovariectomized controls). Rats initially receiving estradiol received either another estradiol (continuous estradiol) or a vehicle (previous estradiol) capsule. One month later, hippocampi were dissected and processed. Continuous and previous estradiol increased levels of nuclear, but not membrane or cytosolic ERα and had no effect on Esr1. Continuous and previous estradiol impacted gene expression and/or protein levels of mediators of estrogenic action on memory including ChAT, BDNF, and PSD-95. Findings demonstrate a long-lasting role for hippocampal ERα as a transcriptional regulator of memory following termination of previous estradiol treatment in a rat model of menopause.

Medroxyprogesterone opposes estradiol-induced renal damage in midlife ovariectomized Long Evans rats.

OBJECTIVE: Our laboratory previously published that long-term administration of estradiol (E2) was detrimental to the kidneys of midlife ovariectomized Long Evans rats, contrasting clinical studies in showing that menopausal hormone therapy is associated with decreased albuminuria. However, it is unknown whether this renal benefit was due to estrogen and/or the combination with progestogen. Therefore, the objective of the current study was to determine the impact of medroxyprogesterone (MPA) on E2-mediated renal damage using a rodent model. METHODS: Female Long Evans retired breeders underwent ovariectomy at 11 months of age and were treated for 40 days with subcutaneous E2, E2+MPA or vehicle at doses mimicking that of menopausal hormone therapy (N = 5-7 per group). Systolic blood pressure was measured along with indices of renal damage and function to investigate the impact of MPA on E2-mediated renal outcomes. Renal estrogen receptor alpha and G protein-coupled estrogen receptor transcript copy numbers were measured in all treatment groups through droplet digital PCR. RESULTS: Middle-aged female Long Evans rats displayed spontaneous hypertension with similar systolic blood pressures and heart weights between groups. Even though blood pressure was comparable, E2 reduced glomerular filtration rate and increased proteinuria indicating pressure-independent renal damage. Coadministration with MPA prevented E2-induced glomerular filtration rate impairment and proteinuria by promoting renal hypertrophy and preventing renal interstitial fibrosis. Both E2 and E2+MPA reduced renal estrogen receptor alpha (ERα) and increased renal G protein-coupled estrogen receptor mRNA, but neither ERα nor ERß protein was different between groups. CONCLUSION: MPA was protective against E2-induced renal damage and dysfunction in middle-aged female Long Evans rats. Assessing the impact of hormone therapy on renal outcomes may be an important clinical factor when considering treatment options for postmenopausal women.

Sex differences in impulsivity in adult rats are mediated by organizational actions of neonatal gonadal hormones and not by hormones acting at puberty or in adulthood.

Males as compared to females display increased impulsivity and inefficient inhibitory control and are more frequently diagnosed with disorders characterized by impulsivity. We previously demonstrated male rats make more impulsive action responses (i.e. premature responding) than females on the 5-choice serial reaction time task (5-CSRTT). Furthermore, pre-pubertal male rats make more impulsive choice responses (i.e. choosing an immediate small reward over a delayed larger reward) than females on a delayed-based reward T-maze task. The goal of the current work was to determine if gonadal hormones impact sex differences in impulsivity in adult rats. In an initial experiment, male and female rats underwent sham surgeries or were gonadectomized either pre-pubertally or during adulthood and tested on the 5-CSRTT in adulthood. Males displayed more impulsive action responses than females regardless of hormone status. In a second experiment, females received testosterone or vehicle injections on postnatal days 1 and 2. Males received vehicle injections. All rats were gonadectomized prior to puberty and tested on the 5-CSRTT in adulthood. Females treated neonatally with testosterone and control males made more impulsive action responses than control females. In another set of experiments, manipulation of gonadal hormones led to no differences in performance on the delayed-based reward T-maze task in males and females. Results indicate that no sex difference is apparent in impulsive choice on a delayed-base reward task in adult rats. They also reveal that adult sex differences on a task of impulsive action is mediated by organizational effects of gonadal hormones acting during the neonatal period and not impacted by hormones acting during puberty or adulthood.

Neuroestrogen-Dependent Transcriptional Activity in the Brains of ERE-Luciferase Reporter Mice following Short- and Long-Term Ovariectomy.

Previous work has demonstrated that estrogen receptors are transcriptionally active in the absence of ovarian estrogens. The current work aims to determine whether brain-derived estrogens influence estrogen receptor-dependent transcription after short- or long-term loss of ovarian function. Experiments were conducted using estrogen response element (ERE)-Luciferase reporter mice, which express the gene for luciferase driven by consensus ERE, allowing for the quantification of ERE-dependent transcription. Brain regions examined were hippocampus, cortex, and hypothalamus. In Experiment 1, short-term (10 d) ovariectomy had no impact on ERE-dependent transcription across brain regions compared with sham surgery. In Experiment 2, chronic intracerebroventricular administration of the aromatase inhibitor letrozole significantly decreased transcriptional activity in 10-d-old ovariectomized mice across brain regions, indicating that the sustained transcription in short-term ovariectomized mice is mediated at least in part via actions of neuroestrogens. Additionally, intracerebroventricular administration of estrogen receptor antagonist ICI-182,780 blocked transcription in 10-d-old ovariectomized mice across brain regions, providing evidence that sustained transcription in ovariectomized mice is estrogen receptor dependent. In Experiment 3, long-term (70 d) ovariectomy significantly decreased ERE-dependent transcription across brain regions, though some residual activity remained. In Experiment 4, chronic intracerebroventricular letrozole administration had no impact on transcription in 70 d ovariectomized mice across brain regions, indicating that the residual ERE-dependent transcription in long-term ovariectomized mice is not mediated by neuroestrogens. Overall, the results indicate that ERE-dependent transcription in the brain continues after ovariectomy and that the actions of neuroestrogens contribute to the maintenance of ERE-dependent transcription in the brain following short-term, but not long-term, loss of ovarian function.

Nuclear estrogen receptor activation by insulin-like growth factor-1 in Neuro-2A neuroblastoma cells requires endogenous estrogen synthesis and is mediated by mutually repressive MAPK and PI3K cascades.

Non-canonical mechanisms of estrogen receptor activation may continue to support women's cognitive health long after cessation of ovarian function. These mechanisms of estrogen receptor activation may include ligand-dependent actions via locally synthesized neuroestrogens and ligand-independent actions via growth factor-dependent activation of intracellular kinase cascades. We tested the hypothesis that ligand-dependent and ligand-independent mechanisms interact to activate nuclear estrogen receptors in the Neuro-2A neuroblastoma cell line in the absence of exogenous estrogens. Transcriptional output of estrogen receptors was measured following treatment with insulin-like growth factor-1 (IGF-1) in the presence of specific inhibitors for mitogen-activated protein kinase (MAPK), phosphoinositde-3 kinase (PI3K), and neuroestrogen synthesis. Results indicate that IGF-1-dependent activation of nuclear estrogen receptors is mediated by MAPK, is opposed PI3K, and requires concomitant endogenous neuroestrogen synthesis. We conclude that both cellular signaling context and endogenous ligand availability are important modulators of ligand-independent nuclear estrogen receptor activation.

Pubertal hormones mediate sex differences in levels of myelin basic protein in the orbitofrontal cortex of adult rats.

Previous work from our lab revealed that adult female rats have increased levels of myelin basic protein (MBP), a marker for myelination, in the orbitofrontal cortex (OFC) as compared to adult males. The goal of the present study was to determine the role of gonadal hormones, acting either in adulthood or at puberty, in the development of an adult sex difference in OFC levels of MBP. In an initial experiment, we replicated our previous results demonstrating that gonadally intact female rats have increased levels of MBP in the OFC as compared to males. In a second experiment, gonadectomy in adulthood did not alter MBP levels in rats of either sex. In a third experiment, gonadectomy immediately prior to pubertal onset resulted in significant reduction of levels of MBP in adult females but not males. This reduction eliminated the sex difference in adult MBP levels in the OFC. These results reveal puberty to be an organizational time point for a sex difference in the OFC of adult rats in levels of a marker of myelination. This neuroanatomical difference may contribute to observed sex differences in OFC-associated behaviors including in inhibitory control.

Lasting impact on memory of midlife exposure to exogenous and endogenous estrogens.

We previously demonstrated that 40 days of prior midlife estradiol treatment results in enhanced spatial memory in aging ovariectomized rats long after termination of the estradiol treatment. Our current goal was to determine whether this benefit is due to lasting impacts on memory specifically of previous exogenous estradiol treatment or simply due to delaying cognitive deficits that occur following loss of ovarian hormones. Middle-aged rats were ovariectomized or underwent sham surgery. Ovariectomized rats received estradiol (Previous Estradiol) or vehicle (Previous Vehicle) implants. Rats undergoing sham surgery (Previous Intact) received vehicle implants. Forty days later, Previous Intact rats were ovariectomized, the other 2 groups underwent sham surgeries, and all implants were removed. Thus, no ovarian or exogenously administered hormones were present during behavior testing. Rats underwent 24 days of acquisition training on an 8-arm radial maze. Following acquisition and again 2 months later, rats were tested on delay trials, during which animals had to remember the location of food rewards across time delays inserted between fourth and fifth arm choices. During acquisition, rats that had previous extended exposure to exogenous estradiol (Previous Estradiol) and endogenous ovarian hormones (Previous Intact) significantly outperformed rats that did not experience extended hormone exposure (Previous Vehicle). However, during delays trials the Previous Estradiol group significantly outperformed both the Previous Vehicle and Previous Intact groups. Results demonstrate that whereas extended exposure to endogenous ovarian hormones may provide short-term cognitive benefits, midlife estradiol treatment following ovariectomy provides additional benefits that persist for months following termination of treatment. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Long- but not short-term estradiol treatment induces renal damage in midlife ovariectomized Long-Evans rats.

Clinical recommendations limit menopausal hormone therapy to a few years, yet the impact of a shorter treatment duration on cardiovascular health is unknown. We hypothesized that both short- and long-term estradiol (E2) treatment exerts positive and lasting effects on blood pressure, vascular reactivity, and renal health. This study was designed to mimic midlife menopause, followed by E2 treatment, that either followed or exceeded the current clinical recommendations. Female Long-Evans retired breeders were ovariectomized (OVX) at 11 mo of age and randomized into three groups: 80-day (80d) vehicle (Veh>Veh), 40-day (40d) E2 + 40d vehicle (E2>Veh), and 80d E2 (E2>E2). In comparison to Veh>Veh, both the E2>Veh and E2>E2 groups had lower systolic blood pressure and enhanced mesenteric relaxation in response to estrogen receptor-α stimulation. Despite the reduced blood pressure, E2>E2 induced renal and cardiac hypertrophy, reduced glomerular filtration, and increased proteinuria. Interestingly, kidneys from E2>Veh rats had significantly fewer tubular casts than both of the other groups. In conclusion, long-term E2 lowered blood pressure but exerted detrimental effects on kidney health in midlife OVX Long-Evans rats, whereas short-term E2 lowered blood pressure and reduced renal damage. These findings highlight that the duration of hormone therapy may be an important factor for renal health in aging postmenopausal women.

Circulating Estradiol Regulates Brain-Derived Estradiol via Actions at GnRH Receptors to Impact Memory in Ovariectomized Rats.

Systemic estradiol treatment enhances hippocampus-dependent memory in ovariectomized rats. Although these enhancements are traditionally thought to be due to circulating estradiol, recent data suggest these changes are brought on by hippocampus-derived estradiol, the synthesis of which depends on gonadotropin-releasing hormone (GnRH) activity. The goal of the current work is to test the hypothesis that peripheral estradiol affects hippocampus-dependent memory through brain-derived estradiol regulated via hippocampal GnRH receptor activity. In the first experiment, intracerebroventricular infusion of letrozole, which prevents the synthesis of estradiol, blocked the ability of peripheral estradiol administration in ovariectomized rats to enhance hippocampus-dependent memory in a radial-maze task. In the second experiment, hippocampal infusion of antide, a long-lasting GnRH receptor antagonist, blocked the ability of peripheral estradiol administration in ovariectomized rats to enhance hippocampus-dependent memory. In the third experiment, hippocampal infusion of GnRH enhanced hippocampus-dependent memory, the effects of which were blocked by letrozole infusion. Results indicate that peripheral estradiol-induced enhancement of cognition is mediated by brain-derived estradiol via hippocampal GnRH receptor activity.

Evidence for Ligand-Independent Activation of Hippocampal Estrogen Receptor-α by IGF-1 in Hippocampus of Ovariectomized Rats.

In the absence of ovarian estrogens, increased levels of estrogen receptor (ER)α in the hippocampus are associated with improvements in cognition. In vitro evidence indicates that under conditions of low estrogen, growth factors, including Insulin-Like Growth Factor 1 (IGF-1), can activate ERα and regulate ERα-mediated transcription through mechanisms that likely involve modification of phosphorylation sites on the receptor. The goal of the current work was to investigate a role for IGF-1 in ligand-independent activation of ERα in the hippocampus of female rats. Ovariectomized rats received a single intracerebroventricular infusion of IGF-1 and hippocampi were collected 1 or 24 hours later. After 1 h, IGF-1 increased hippocampal levels of phosphorylated ERα at serine 118 (S118) as revealed by Western blotting. Coimmunoprecipitation revealed that at 1 hour after infusion, IGF-1 increased association between ERα and steroid receptor coactivator 1, a histone acetyltransferase that increases transcriptional activity of phosphorylated ERα. IGF-1 infusion increased levels of the ERα-regulated proteins ERα, choline acetyltransferase, and brain-derived neurotrophic factor in the hippocampus 24 hours after infusion. Results indicate that IGF-1 activates ERα in ligand-independent manner in the hippocampus via phosphorylation at S118 resulting in increased association of ERα with steroid receptor coactivator 1 and elevation of ER-regulated proteins. To our knowledge, these data are the first in vivo evidence of ligand-independent actions of ERα and provide a mechanism by which ERα can impact memory in the absence of ovarian estrogens.

Choline acetyltransferase in the hippocampus is associated with learning strategy preference in adult male rats.

One principle of the multiple memory systems hypothesis posits that the hippocampus-based and striatum-based memory systems compete for control over learning. Consistent with this notion, previous research indicates that the cholinergic system of the hippocampus plays a role in modulating the preference for a hippocampus-based place learning strategy over a striatum-based stimulus--response learning strategy. Interestingly, in the hippocampus, greater activity and higher protein levels of choline acetyltransferase (ChAT), the enzyme that synthesizes acetylcholine, are associated with better performance on hippocampus-based learning and memory tasks. With this in mind, the primary aim of the current study was to determine if higher levels of ChAT and the high-affinity choline uptake transporter (CHT) in the hippocampus were associated with a preference for a hippocampus-based place learning strategy on a task that also could be solved by relying on a striatum-based stimulus--response learning strategy. Results confirmed that levels of ChAT in the dorsal region of the hippocampus were associated with a preference for a place learning strategy on a water maze task that could also be solved by adopting a stimulus-response learning strategy. Consistent with previous studies, the current results support the hypothesis that the cholinergic system of the hippocampus plays a role in balancing competition between memory systems that modulate learning strategy preference.

Long-term consequences of estrogens administered in midlife on female cognitive aging.

This article is part of a Special Issue "Estradiol and cognition". Many of the biochemical, structural, and functional changes that occur as the female brain ages are influenced by changes in levels of estrogens. Administration of estrogens begun during a critical window near menopause is hypothesized to prevent or delay age-associated cognitive decline. However, due to potential health risks women often limit use of estrogen therapy to a few years to treat menopausal symptoms. The long-term consequences for the brain of short-term use of estrogens are unknown. Interestingly, there are preliminary data to suggest that short-term use of estrogens during the menopausal transition may afford long-term cognitive benefits to women as they age. Thus, there is the intriguing possibility that short-term estrogen therapy may provide lasting benefits to the brain and cognition. The focus of the current review is an examination of the long-term impact for cognition of midlife use of estrogens. We review data from our lab and others indicating that the ability of midlife estrogens to impact estrogen receptors in the hippocampus may contribute to its ability to exert lasting impacts on cognition in aging females.

Comparison of the validity of the use of the spontaneously hypertensive rat as a model of attention deficit hyperactivity disorder in males and females.

The spontaneously hypertensive rat (SHR) is a commonly used and well-studied rodent model of attention deficit hyperactivity disorder (ADHD). Sex differences in the cognitive symptoms of ADHD are reported. However, the female SHR rat is much less studied than its male counterpart. The goal of the current study was to assess the validity of the SHR rodent model of ADHD by examining attentional performance, inhibitory control, and hyperactivity in both male and female SHR rats. Adult SHR and control Wistar-Kyoto rats were trained on the 5-choice serial reaction time task, a self-paced test of attention and inhibitory control. This task requires animals to identify the location of a brief light stimulus among five possible locations under several challenging conditions. Analyses of percent correct revealed that attentional performance in SHR females was not significantly different from control females, whereas attentional performance in SHR males was significantly different from control males. Analyses of the number of premature responses revealed that SHR rats made more inhibitory control errors than did control rats and that this decrease in inhibitory control was present in both SHR males and females. Analyses of activity in the open field revealed that SHR rats were more hyperactive than were control rats and that this increased hyperactivity was present in both SHR males and females. The current findings have implications for the study of sex differences in ADHD and for the use of SHR rats as a model of ADHD in females.

Antagonism of brain insulin-like growth factor-1 receptors blocks estradiol effects on memory and levels of hippocampal synaptic proteins in ovariectomized rats.

RATIONALE: Treatment with estradiol, the primary estrogen produced by the ovaries, enhances hippocampus-dependent spatial memory and increases levels of hippocampal synaptic proteins in ovariectomized rats. Increasing evidence indicates that the ability of estradiol to impact the brain and behavior is dependent upon its interaction with insulin-like growth factor-1 (IGF-1). OBJECTIVE: The goal of the current experiment was to test the hypothesis that the ability of estradiol to impact hippocampus-dependent memory and levels of hippocampal synaptic proteins is dependent on its interaction with IGF-1. METHODS: Adult rats were ovariectomized and implanted with estradiol or control capsules and trained on a radial-maze spatial memory task. After training, rats were implanted with intracerebroventricular cannulae attached to osmotic minipumps (flow rate 0.15 µl/h). Half of each hormone treatment group received continuous delivery of JB1 (300 µg/ml), an IGF-1 receptor antagonist, and half received delivery of aCSF vehicle. Rats were tested on trials in the radial-arm maze during which delays were imposed between the fourth and fifth arm choices. Hippocampal levels of synaptic proteins were measured by western blotting. RESULTS: Estradiol treatment resulted in significantly enhanced memory. JB1 blocked that enhancement. Estradiol treatment resulted in significantly increased hippocampal levels of postsynaptic density protein 95 (PSD-95), spinophilin, and synaptophysin. JB1 blocked the estradiol-induced increase of PSD-95 and spinophilin and attenuated the increase of synaptophysin. CONCLUSIONS: Results support a role for IGF-1 receptor activity in estradiol-induced enhancement of spatial memory that may be dependent on changes in synapse structure in the hippocampus brought upon by estradiol/IGF-1 interactions.

Mechanisms by which neonatal testosterone exposure mediates sex differences in impulsivity in prepubertal rats.

Neonatal testosterone, either acting directly or through its conversion to estradiol, can exert organizational effects on the brain and behavior. The goal of the current study was to examine sex differences and determine the role of neonatal testosterone on prefrontal cortex-dependent impulsive choice behavior in prepubertal rats. Male and female prepubertal rats were tested on the delay-based impulsive choice task. Impulsive choice was defined as choosing an immediate small food reward over a delayed large reward. In a first experiment to examine sex differences, males made significantly more impulsive choices than did females. In a second experiment to examine the organizational effects of testosterone, females treated with neonatal testosterone made significantly more impulsive choices than did control females and their performance was indistinguishable from that of control males. In a third experiment to determine if the effect of testosterone on performance is due to the actions of androgens or estrogens through its conversion to estradiol, males treated neonatally with the aromatase inhibitor formestane, which blocks the conversion of testosterone to estradiol, females treated neonatally with the non-aromatizable androgen dihydrotestosterone, and females treated neonatally with estradiol made significantly more impulsive choices than did control females and their performance was indistinguishable from that of control males. Results indicate that male pubertal rats display increased impulsive choice behavior as compared to females, that this sex difference results from organizing actions of testosterone during the neonatal period, and that this effect can result from both androgenic and estrogenic actions.

Estrogens, estrogen receptors, and female cognitive aging: the impact of timing.

Estrogens have been shown to be protective agents against neurodegeneration and associated cognitive decline in aging females. However, clinical data have been equivocal as to the benefits to the brain and cognition of estrogen therapy in postmenopausal women. One factor that is proposed to be critical in determining the efficacy of hormone therapy is the timing of its initiation. The critical period or window of opportunity hypothesis proposes that following long-term ovarian hormone deprivation, the brain and cognition become insensitive to exogenously administered estrogens. In contrast, if estrogens are administered during a critical period near the time of cessation of ovarian function, they will exert beneficial effects. The focus of the current review is the examination of evidence from rodent models investigating the critical period hypothesis. A growing body of experimental data indicates that beneficial effects of 17ß-estradiol (estradiol) on cognition and on cholinergic function and hippocampal plasticity, both of which have been linked to the ability of estradiol to exert beneficial effects on cognition, are attenuated if estradiol is administered following a period of long-term ovarian hormone deprivation. Further, emerging data implicate loss of estrogen receptor alpha (ERα) in the brain resulting from long-term hormone deprivation as a basis for the existence of the critical period. A unifying model is proposed by which the presence or absence of estrogens during a critical period following the cessation of ovarian function permanently alters the system resulting in decreased or increased risk, respectively, of neurodegeneration and cognitive decline.

Short-term estradiol administration in aging ovariectomized rats provides lasting benefits for memory and the hippocampus: a role for insulin-like growth factor-I.

We previously demonstrated that aged ovariectomized rats that had received prior estradiol treatment in middle age exhibited enhanced spatial memory and increased levels of estrogen receptor (ER)-α in the hippocampus long after estradiol treatment was terminated. The implication for cognition of increased levels of ERα resulting from prior estradiol exposure is unknown. In the absence of estrogens, growth factors, including IGF-I, can induce ERα-mediated transcription through ligand-independent mechanisms. Our current goal was to determine whether IGF-I mediates the ability of short-term exposure to estradiol to exert long-term effects on cognition and the hippocampus of aging females. Ovariectomized middle-aged rats were implanted with estradiol or cholesterol vehicle capsules. After 40 days, all capsules were removed and drug treatments were initiated. Half of each hormone treatment group received chronic intracerebroventricular delivery of the IGF-I receptor antagonist JB1, and the other half received artificial cerebrospinal fluid vehicle. Rats were tested on a spatial memory radial-arm maze task and hippocampi were immunostained for proteins of interest by Western blotting. As expected, previous treatment with estradiol enhanced spatial memory and increased levels of ERα in the hippocampus. JB1 reversed these effects. Previous treatment with estradiol resulted in lasting increases in levels of IGF-I receptors and phosphorylation of ERK/MAPK, a downstream signaling molecule of both ERα and IGF-I receptors, and increased levels of the ERα-regulated protein, choline acetyltransferase. JB1 blocked effects on ERK/MAPK and choline acetyltransferase. Results indicate that activation of IGF-I receptors is necessary for prior estradiol exposure to exert lasting impact on the hippocampus and memory.