Hippocampal Estrogen Research Articles

The Effect of Statin Treatment on Synaptogenesis in the Hippocampus.

Deranged lipid homeostasis has been implicated in neurodegenerative diseases. Cholesterol reducing compounds such as statins have received special attention for the possibility that they may be able to ameliorate or prevent cognitive loss associated with neurodegeneration. However, there is much dissension concerning the actual effect of statins on cognitive function. The aim of this study is to investigate the effects of pitavastatin on hippocampal synaptogenesis because the hippocampus is crucial for memory formation. We also evaluated the effects of pitavastatin on local hippocampal estrogen synthesized in the hippocampus itself and its effect on Brain-Derived Neurotrophic Factor (BDNF). Using a hippocampal cell line, H19-7, we found that hippocampal neurons exposed to pitavastatin demonstrate a significant reduction in the synaptic marker postsynaptic density protein 95 (psd-95). The pitavastatin treated neurons also exhibited decreased production of local estrogen and their expression of BDNF mRNA was decreased. These results suggest that statins reduce the ability of hippocampal neurons to form synapses by restricting the production of local estrogen. Because neural connections in the hippocampus are crucial for memory formation, our findings implicate statins as medications that may compromise cognitive function.

Reiterated male-to-female violence disrupts hippocampal estrogen receptor β expression, prompting anxiety-like behavior

Intimate partner violence (IPV) is a significant public health concern whose neurological/behavioral sequelae remain to be mechanistically explained. Using a mouse model recapitulating an IPV scenario, we evaluated the female brain neuroendocrine alterations produced by a reiterated male-to-female violent interaction (RMFVI). RMFVI prompted anxiety-like behavior in female mice whose hippocampus displayed a marked neuronal loss and hampered neurogenesis, namely reduced BrdU-DCX-positive nuclei and diminished dendritic arborization in the dentate gyrus (DG): effects paralleled by a substantial downregulation of the estrogen receptor β (ERβ). After RMFVI, the DG harbored reduced brain-derived neurotrophic factor (BDNF) pools and tyrosine kinase receptor B (TrkB) phosphorylation. Accordingly, ERβ knockout (KO) mice had heightened anxiety and curtailed BDNF levels at baseline while dying prematurely during the RMFVI procedure. Strikingly, injecting an ERβ antagonist or agonist into the wild-type (WT) female hippocampus enhanced or reduced anxiety, respectively. Thus, reiterated male-to-female violence jeopardizes hippocampal homeostasis, perturbing the ERβ/BDNF axis and ultimately instigating anxiety and chronic stress.

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.

APOE4 homozygote females are resistant to the beneficial effects of 17β-estradiol on memory and CA1 dendritic spine density in the EFAD mouse model of Alzheimer's disease

Female APOE4 carriers are at greatest risk of Alzheimer's disease (AD). The potent estrogen 17β-estradiol (E2) may mediate AD risk, as the onset of memory decline coincides with the menopausal transition. Whether APOE genotype mediates E2’s effects on memory and neuronal morphology is poorly understood. We used the APOE+/+/5xFAD+/- (EFAD) mouse model to examine how APOE3 homozygote (E3FAD), APOE3/4 heterozygote (E3/4FAD), and APOE4 homozygote (E4FAD) genotypes modulate effects of E2 on object and spatial memory consolidation, dendritic spine density, and dorsal hippocampal estrogen receptor expression in 6-month-old ovariectomized EFAD mice. Dorsal hippocampal E2 infusion enhanced memory consolidation and increased CA1 apical spine density in E3FAD and E3/4FAD, but not E4FAD, mice. CA1 basal mushroom spines were also increased by E2 in E3FADs. E4FAD mice exhibited reduced CA1 and mPFC basal spine density, and increased dorsal hippocampal ERα protein, independent of E2. Overall, E2 benefitted hippocampal memory and structural plasticity in females bearing one or no APOE4 allele, whereas two APOE4 alleles impeded the memory-enhancing and spinogenic effects of E2.

Hippocampal Estrogen Signaling Mediates Sex Differences in Retroactive Interference.

Despite being a crucial physiological function of the brain, the mechanisms underlying forgetting are still poorly understood. Estrogens play a critical role in different brain functions, including memory. However, the effects of sex hormones on forgetting vulnerabilitymediated by retroactive interference (RI), a phenomenon in which newly acquired information interferes with the retrieval of already stored information, are still poorly understood. The aim of our study was to characterize the sex differences in interference-mediated forgetting and identify the underlying molecular mechanisms. We found that adult male C57bl/6 mice showed a higher susceptibility to RI-dependent memory loss than females. The preference index (PI) in the NOR paradigm was 52.7 ± 5.9% in males and 62.3 ± 13.0% in females. The resistance to RI in female mice was mediated by estrogen signaling involving estrogen receptor α activation in the dorsal hippocampus. Accordingly, following RI, females showed higher phosphorylation levels (+30%) of extracellular signal-regulated kinase1/2 (ERK1/2) in the hippocampus. Pharmacological inhibition of ERK1/2 made female mice prone to RI. The PI was 70.6 ± 11.0% in vehicle-injected mice and 47.4 ± 10.8% following PD98059 administration. Collectively, our data suggest that hippocampal estrogen α receptor-ERK1/2 signaling is critically involved in a pattern separation mechanism that inhibits object-related RI in female mice.

Endogenous hippocampal estrogen is involved in stress-induced depression-like behaviors and spine plasticity in male rats

The estrogen (17β-estradiol, E2) level in the hippocampus is higher and more stable in male rats than female rats. Both stress and estrogen affect spine plasticity, and many studies have demonstrated that peripheral estrogen treatment can prevent stress-induced spine loss in both males and females. Some in vitro studies have indicated that neural estrogen (nE2) participates in the modulation of spine plasticity in cultured neurons. However, whether nE2 regulates spine density in vivo in males is not clear, and the specific role of nE2 in stress-induced depression-like behaviors of male rats remains unknown. We delivered letrozole (a selective aromatase inhibitor that blocks the conversion of testosterone to estradiol) and estrogen into the hippocampus of rats and found that letrozole treatment induced the same depression-like behaviors in control rats as observed in chronic unpredictable mild stress (CUMS) rats. Estrogen treatment reversed/or alleviated depression-like behaviors induced by CUMS or letrozole infusion and elevated Kalirin-7 expression in hippocampus. Estrogen treatment also rescued letrozole-induced spine loss. Expression of GluN1 and PSD-95 also changed with Kalirin-7 and spine density. All these proteins were decreased in CUMS rats and letrozole infusion rats but increased in rats treated with estrogen. In conclusion, nE2 in the hippocampus plays an important role in CUMS-induced depression-like behaviors in male rats and Kalirin-7 is involved in this process. GluN1 and PSD-95 possibly mediate the regulation of Kalirin-7 by nE2, which ultimately leads to changes in spine density and depression-like behaviors.

Coumestrol alleviates oxidative stress, apoptosis and cognitive impairments through hippocampal estrogen receptor-beta in male mouse model of chronic restraint stress

Background: Coumestrol is well-known as a natural estrogen receptor-beta modulator. Since the role of estrogen receptors in controlling stressful situations has already been reported and their cognitive functions in hippocampus seem to be independent of sexual tasks, the aim of this study was to investigate the improving effects of this phytoestrogen on negative consequences of exposing male mice to chronic restraint stress. Methods: This study was divided into two separate but consecutive phases. In the first phase, the possible effects of Coumestrol (30, 60, 120 µg.kg-1.day-1, i.p.) and its vehicle (sesame oil) on restraint stress-induced cognitive impairments, oxidative stress and apoptosis were evaluated. During the second phase, a selective estrogen receptor-beta antagonist was used to investigate the possible involvement of beta-type estrogen receptors in these processes. Morris water maze and novel object recognition tests were performed to evaluate memory while elevated plus maze test was used to measure the level of anxiety. Spectroscopy and western blotting methods were also employed to evaluate oxidative and apoptotic status in hippocampal tissue. Furthermore, serum level of corticosterone was measured for each group. Results: Behavioral tests indicated memory enhancing and anxiolytic effects of coumestrol. Biochemical evaluations also proved its antioxidant and anti-apoptotic potential. On the other hand, the mentioned behavioral and biochemical improvements were reversed in the group treated with estrogen receptor-beta antagonist. Conclusion: Coumestrol may ameliorate negative consequences of exposure to chronic stress such as oxidative stress, apoptosis and cognitive impairments, via the modulation of beta-type estrogen receptors in hippocampus.

Perinatal low-dose bisphenol AF exposure impairs synaptic plasticity and cognitive function of adult offspring in a sex-dependent manner

Bisphenol AF (BPAF), a kind of the ideal substitutes of Bisphenol A (BPA), has frequently been detected in environmental media and biological samples. Numerous studies have focused on the reproductive toxicity, cardiotoxicity and endocrine disrupting toxicity of BPAF. However, little evidence is available on neurodevelopmental toxicity of BPAF. Here, our study is to evaluate the effect of perinatal BPAF exposure (0, 0.34, 3.4 and 34 mg/kg body weight/day, correspond to Ctrl, low-, medium- and high-dose groups) on the cognitive function of adult mouse offspring. This study firstly found that perinatal BPAF exposure caused cognitive impairments of mouse offspring, in which male offspring was more sensitive than female offspring in low- and medium-dose BPAF groups. Furthermore, the dendritic arborization and complexity of hippocampal CA1 and DG neurons in male offspring were impaired in all BPAF groups, and these effects were only found in high-dose BPAF group for female offspring. The damage of BPAF to dendritic spines, and the structural basis of learning and memory, was found in male offspring but not in females. Correspondingly, perinatal BPAF exposure significantly downregulated the expressions of hippocampal PSD-95 and Synapsin-1 proteins, and male offspring was more vulnerable than female offspring. Meanwhile, we explored the alteration of hippocampal estrogen receptors (ERs) to explain the sex specific impairment of cognitive function in low- and medium-dose BPAF groups. The results showed that perinatal BPAF exposure significantly decreased the expression of ERα in male offspring in a dose-dependent manner, but not in female offspring. In addition, we found that perinatal BPAF exposure can disordered the balance of oxidation and antioxidation in hippocampus of male offspring. In summary, perinatal low-dose bisphenol AF exposure impairs synaptic plasticity and cognitive function of adult offspring in a sex-dependent manner. The present results provide a pierce of potential mechanism of BPAF-caused neurodevelopmental toxicity.

Inhibition of brain 17β-estradiol synthesis by letrozole induces cognitive decline in male and female rats

BackgroundHippocampal aromatase is responsible for local synthesis of 17β-estradiol (E2) that has much higher concentrations than serum levels in males and females. Letrozole, an aromatase inhibitor, passes through the brain barriers, distributes to the brain, and affects local E2 synthesis. Here, the effects of intra-cerebroventricular (ICV) letrozole administration in the presence and absence of gonads were examined on the cognitive abilities of male and female rats. MethodAnimals received intra-ICV injection of letrozole or vehicle for 14 consecutive days. Spatial working memory, novel object recognition memory, and anxiety-related behavior, were evaluated using Y-maze, object recognition test, and elevated plus maze, respectively. The E2 levels in the serum and hippocampal tissue were measured by the ELISA technique. RT-PCR was performed to assess the hippocampal estrogen receptors (ER) expression. Moreover, letrozole effect on neuronal activity of CA1 pyramidal neurons was studied by in vivo single-unit recording. ResultsLetrozole (0.2, 0.4, and 0.8 µg) significantly decreased the hippocampal E2 levels compared to the vehicle group. Letrozole caused cognitive impairments in a dose-dependent manner in male and female rats in the presence or absence of gonads. Dose-response analysis revealed that the minimum effective dose of letrozole on the behavioral measures was 0.4 μg. Letrozole also caused an up-regulation of ERα and ERβ and a down-regulation of GPR30 gene expression. The firing rate of pyramidal neurons was reduced by letrozole in gonadal-intact animals. ConclusionThe detrimental effects of letrozole treatment on cognitive abilities in the presence and absence of gonads indicate that local E2 synthesis in the hippocampus is a crucial factor in normal cognitive performance. The suppressive effect of letrozole on hippocampal neuronal firing might alter synaptic plasticity that is critical for memory formation. These data potentially suggest that memory deficits following letrozole administration should be monitored.

Impairment of learning and memory induced by perinatal exposure to BPA is associated with ERα-mediated alterations of synaptic plasticity and PKC/ERK/CREB signaling pathway in offspring rats

The effect of bisphenol A (BPA) on learning and memory has attracted much attention recently, but its underlying mechanism remains unclear. We aimed to investigate whether the impairment of learning and memory induced by perinatal exposure to BPA was associated with the hippocampal estrogen receptor α (ERα)-mediated synaptic plasticity and PKC/ERK/CREB signaling pathway in different sex offspring rats. Pregnant Sprague–Dawley rats were treated with BPA (1 and 10 μg/mL) through drinking water from gestational day (GD) 6 to postnatal day (PND) 21. After weaning, offspring drank BPA-free water until PND 56. Morris water maze, placement and object recognition, and step-down passive avoidance task were performed. The serum estradiol (E2) levels, histopathology of hippocampus, and the expression of learning and memory related proteins were measured. The results showed that spatial and recognition memory were impaired in BPA-exposed female and male offspring, but the impaired passive avoidance memory presented only in males, not in females. The serum E2 levels were increased in BPA-exposed females and males. BPA altered the morphology and quantity of hippocampal neurons. The levels of ERα, NMDA receptor subunit 2B (NR2B), p-NR2B, AMPA receptor 1 (GluA1), p-GluA1, PSD-95, synapsin I, PKC, p-ERK and p-CREB protein expression were decreased in BPA exposed females and males, and there were interactions of sex × BPA exposure in ERα, p-NR2B and p-ERK levels. These findings suggested that perinatal exposure to BPA has sex-specific effects on learning and memory, which is associated with ERα-mediated impairment of synaptic plasticity and down-regulation of PKC/ERK/CREB signaling pathway.

Neonatal Dexamethasone Treatment Suppresses Hippocampal Estrogen Receptor α Expression in Adolescent Female Rats

Previous studies showed that neonatal dexamethasone treatment (NDT) transiently impaired hippocampal function in male rats. Hippocampal estrogen receptors (ERs) participate in avoidance learning. As previous studies focused on males only, this study was aimed to investigate the NDT effects on the hippocampal function of female rats. Newborn Wistar female rats were subjected to a tapering dose of dexamethasone (0.5mg, 0.3mg, and 0.1mg/kg, subcutaneously) from postnatal days 1 to 3 and were subjected to experiments at the age of 6weeks (adolescence). Brain slice extracellular recording and the inhibitory avoidance (IA) test were used to evaluate the NDT effects on hippocampal function. The results showed that NDT completely blocked the hippocampal long-term potentiation (LTP) formation and IA learning of adolescents. The expression of hippocampal estrogen receptor alpha (ERα) was attenuated in NDT subjects. Reduced histone acetylation of the ERα gene was found, possibly explaining the reduced hippocampal ERα expression in NDT female rats. Suprafusion of estradiol (E2) partially restored the hippocampal LTP formation in adolescent NDT female rats. Coadministration of the histone deacetylase inhibitor trichostatin-A restored the hippocampal ERα expression, hippocampal LTP formation, and IA learning in adolescent NDT female rats. Collectively, these results suggested that NDT has an epigenetic modulation effect on the expression of hippocampal ERα, which is responsible for its adverse effect on hippocampal function.

Both oophorectomy and obesity impaired solely hippocampal-dependent memory via increased hippocampal dysfunction.

Our previous study demonstrated that obesity aggravated peripheral insulin resistance and brain dysfunction in the ovariectomized condition. Conversely, the effect of obesity followed by oophorectomy on brain oxidative stress, brain apoptosis, synaptic function and cognitive function, particularly in hippocampal-dependent and hippocampal-independent memory, has not been investigated. Our hypothesis was that oophorectomy aggravated metabolic impairment, brain dysfunction and cognitive impairment in obese rats. Thirty-two female rats were fed with either a normal diet (ND, n = 16) or a high-fat diet (HFD, n = 16) for a total of 20 weeks. At week 13, rats in each group were subdivided into sham and ovariectomized subgroups (n = 8/subgroup). At week 20, all rats were tested for hippocampal-dependent and hippocampal-independent memory by using Morris water maze test (MWM) and Novel objective recognition (NOR) tests, respectively. We found that the obese-insulin resistant condition occurred in sham-HFD-fed rats (HFS), ovariectomized-ND-fed rats (NDO), and ovariectomized-HFD-fed rats (HFO). Increased hippocampal oxidative stress level, increased hippocampal apoptosis, increased hippocampal synaptic dysfunction, decreased hippocampal estrogen level and impaired hippocampal-dependent memory were observed in HFS, NDO, and HFO rats. However, the hippocampal-independent memory, cortical estrogen levels, cortical ROS production, and cortical apoptosis showed no significant difference between groups. These findings suggested that oophorectomy and obesity exclusively impaired hippocampal-dependent memory, possibly via increased hippocampal dysfunction. Nonetheless, oophorectomy did not aggravate these deleterious effects under conditions of obesity.

Dangguijakyak-san ameliorates memory deficits in ovariectomized mice by upregulating hippocampal estrogen synthesis

BackgroundDangguijakyak-san (DJS) is an herbal formulation that has been clinically applicable for treating postmenopausal symptoms and neurological disorders. It is reported that hippocampal estrogen attenuates memory impairment via neuroprotection and synaptogenesis. However, the effect of DJS on hippocampal estrogen synthesis remains unknown. In this study, we explored the effect of DJS and its neuroprotective mechanism against memory impairment in ovariectomized (OVX) mice, with respect to hippocampal estrogen stimulation.MethodsCell cultures were prepared from the hippocampi of 18-day-old embryos from timed pregnant Sprague–Dawley rats. The hippocampi were dissected, collected, dissociated, and plated in 60-mm dishes. The cells were treated with DJS for 48 h and the supernatant was collected to determine estrogen levels. Female ICR mice (8-weeks-old) were housed for 1 week and ovariectomy was performed to remove the influence of ovary-synthesized estrogens. Following a 2-week post-surgical recovery period, the mice were administrated with DJS (50 and 100 mg/kg/day, p.o.) or 17β-estradiol (200 μg/kg/day, i.p.) once daily for 21 days. Hippocampal and serum estrogen levels were determined using enzyme-linked immunosorbent assay kit. Memory behavioral tests, western blot, and immunohistochemical analyses were performed to evaluate the neuroprotective effects of DJS in this model.ResultsDJS treatment promoted estrogen synthesis in primary hippocampal cells and the hippocampus of OVX mice, resulting in the amelioration of OVX-induced memory impairment. Hippocampal estrogen stimulated by DJS treatment contributed to the activation of cAMP response element-binding protein and synaptic protein in OVX mice.ConclusionDJS may attenuate memory deficits in postmenopausal women via hippocampal estrogen synthesis.

Estrogen-dependent modifications to hippocampal plasticity in paternal California mice (Peromyscus californicus)

In many biparental species, mothers and fathers experience similar modifications to circulating hormones. With these modifications come alterations in neural structure and function suggesting that neuroendocrine mechanisms may underlie postpartum plasticity in both males and females. In the biparental California mouse (Peromyscus californicus), adult neurogenesis is maintained and anxiety-like behavior is attenuated in fathers during the mid-postpartum period. Given a causal relationship between estrogen and regulation of both adult neurogenesis and anxiety, we aimed to elucidate the role of estrogen-dependent mechanisms in paternal experience-related modifications to hippocampal neuroplasticity in California mice. In Experiment 1, hippocampal estrogen receptor beta (ERβ) mRNA expression, along with circulating estradiol concentrations, were determined throughout the postpartum period. An upregulation in ERβ expression was observed in postnatal day 16 males compared to virgins. Additionally, a rise in circulating estradiol concentrations was detected on postnatal day 2 compared to virgins; levels began to decline toward virgin levels on postnatal day 16 and postnatal day 30. In Experiment 2, we determined the role of estrogen-dependent mechanisms in adult neurogenesis and anxiety-like behavior by treating virgin and paternal males with saline or the selective estrogen receptor modulator, tamoxifen (TMX), during the time of axon extension (i.e., one week after bromodeoxyuridine injection). While TMX failed to alter elevated plus maze performance, TMX treatment inhibited survival of adult born neurons but only in paternal mice. These findings highlight the potential for estrogen-dependent pathways to mediate hippocampal adult neurogenesis in paternal mice.

Effect of short-term DHEA supplementation on serum and hippocampal estrogen concentrations in perimenopausal female rhesus macaques

The hippocampus of rhesus macaques expresses genes that encode key enzymes involved in the intracrine conversion of dehydroepiandrosterone (DHEA) to estradiol. Therefore, it is plausible that supplementary DHEA may enhance hippocampal estradiol concentrations and help to compensate for the marked postmenopausal attenuation of circulating estrogen levels. To test this hypothesis, we used LC-MS/MS to measure estradiol and estrone concentrations in the serum and hippocampus of young and old perimenopausal female rhesus macaques, as well as old perimenopausal females that received daily DHEA (5 mg) oral supplementation for 1 week. Despite lower concentrations of these estrogens in the serum of the older animals, their concentrations in the hippocampus did not show any obvious differences due to age or to DHEA supplementation. The results suggest that de novo estrogen synthesis in the brain may compensate for the perimenopausal loss of estrogens in the circulation even without supplemental DHEA.

The hippocampal transcriptomic signature of stress resilience in mice with microglial fractalkine receptor (CX3CR1) deficiency

Clinical studies suggest that key genetic factors involved in stress resilience are related to the innate immune system. In the brain, this system includes microglia cells, which play a major role in stress responsiveness. Consistently, mice with deletion of the CX3CR1 gene (CX3CR1−/− mice), which in the brain is expressed exclusively by microglia, exhibit resilience to chronic stress. Here, we compared the emotional, cognitive, neurogenic and microglial responses to chronic unpredictable stress (CUS) between CX3CR1−/− and wild type (WT) mice. This was followed by hippocampal whole transcriptome (RNA-seq) analysis. We found that following CUS exposure, WT mice displayed reduced sucrose preference, impaired novel object recognition memory, and reduced neurogenesis, whereas CX3CR1−/− mice were completely resistant to these effects of CUS. CX3CR1−/− mice were also resilient to the memory-suppressive effect of a short period of unpredictable stress. Microglial somas were larger in CX3CR1−/− than in WT, but in both genotypes CUS induced a similar decline in hippocampal microglial density and processes length. RNA sequencing and pathway analysis revealed basal strain differences, particularly reduced expression of interferon (IFN)-regulated and MHC class I gene transcripts in CX3CR1−/− mice. Furthermore, while CUS exposure similarly altered neuronal gene transcripts (e.g. Arc, Npas4) in both strains, transcripts downstream of hippocampal estrogen receptor signaling (particularly Igf2 and Igfbp2) were altered only in CX3CR1−/− mice. These findings indicate that emotional and cognitive stress resilience involves CX3CR1-dependent basal and stress-induced alterations in hippocampal transcription, implicating inhibition of CX3CR1 signaling as a novel approach for promoting stress resilience.

Chelidonic acid evokes antidepressant-like effect through the up-regulation of BDNF in forced swimming test.

Depression is usually accompanied by neuro-inflammatory reactions. Chelidonic acid, in particular, has shown anti-inflammatory effects. The objective of this study was to evaluate the anti-depressant effects of chelidonic acid and to discuss the potential mechanisms of a forced swimming test. Chelidonic acid was administered orally once a day for 14 days. On the 14th day, chelidonic acid resulted in a significant decrease in immobility time during the forced swimming test without alteration of locomotor activity, in an open field test. Chelidonic acid also increased the number of nissl bodies in the hippocampus. Brain-derived neurotrophic factor expression and extracellular signal-regulated protein kinase phosphorylation in the hippocampus were up-regulated by the administration of chelidonic acid. Chelidonic acid administration significantly increased the mRNA expression of hippocampal estrogen receptor-β. The levels of hippocampal interleukin (IL)-1β, IL-6, and tumor necrosis factor-α were effectively attenuated by the administration of chelidonic acid. In addition, chelidonic acid significantly increased the levels of 5-hydroxytryptamine (serotonin), dopamine, and norepinephrine compared with those levels for the mice that were administered distilled water in the hippocampus. These results suggest that chelidonic acid might serve as a new therapeutic strategy for the regulation of depression associated with inflammation.

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.

Acute inhibition of neurosteroid estrogen synthesis suppresses status epilepticus in an animal model.

Status epilepticus (SE) is a common neurological emergency for which new treatments are needed. In vitro studies suggest a novel approach to controlling seizures in SE: acute inhibition of estrogen synthesis in the brain. Here, we show in rats that systemic administration of an aromatase (estrogen synthase) inhibitor after seizure onset strongly suppresses both electrographic and behavioral seizures induced by kainic acid (KA). We found that KA-induced SE stimulates synthesis of estradiol (E2) in the hippocampus, a brain region commonly involved in seizures and where E2 is known to acutely promote neural activity. Hippocampal E2 levels were higher in rats experiencing more severe seizures. Consistent with a seizure-promoting effect of hippocampal estrogen synthesis, intra-hippocampal aromatase inhibition also suppressed seizures. These results reveal neurosteroid estrogen synthesis as a previously unknown factor in the escalation of seizures and suggest that acute administration of aromatase inhibitors may be an effective treatment for SE.

Exercise improves hippocampal estrogen and spatial memory of ovariectomized rats.

The present study aimed at examining the effects of regular exercise on hippocampal estrogen and estrogen receptor β (ERβ) levels, as well as the spatial memory of ovariectomized rats. A decrease of estrogen levels leads to dysfunctions of hippocampus, including spatial learning and memory. Studies have shown that physical exercise improved spatial memory of ovariectomized rats and was associated with an increased extragonadal aromatization. This in turn affects the expression of estrogen receptors. Ovariectomized Sprague Dawley rats were randomly assigned into the two groups, i.e. exercise and control groups. Rats of the exercise group were trained to run on a treadmill. The exercise was performed five times per week for 12 weeks. The spatial memory of rats was measured using the Morris water maze. The hippocampal estrogen and ERβ levels of rats were determined using ELISA. The spatial memory retention of the exercise group was significantly better than that of the control group. The hippocampal estrogen level of the exercise group was significantly higher than that of the control group. Regular exercise increases hippocampal estrogen levels and improves spatial memory retention of ovariectomized rats (Tab. 1, Fig. 4, Ref. 53).