Cerebral Cortex Of Female Mice Research Articles

Effects of chronic folate deficiency and sex differences on depression-like behavior in mice.

Although previous studies have reported that serum folate levels are negatively associated with depression in women but not men, it remains unclear whether folate deficiency can directly lead to depression and whether sex difference serves a role in this condition, since the potential mechanism remains elusive. Therefore, the present study aimed to investigate whether folate deficiency results in differences in parameters associated with depression between males and females. CD-1 mice received either a standard control diet or a folate-deficient diet from 10 to 38 weeks of age, following which behavioral assays, such as an open field test, sucrose preference test and forced swim test were performed throughout week 38. Serum and cerebral cortex samples were subsequently collected for assessment. Serum folate, homocysteine, estradiol (E2) and testosterone levels were measured using chemiluminescence, enzymatic cycling assay and electrochemiluminescence immunoassays. The cerebral cortex was used for western blot analysis, to detect the expression levels of estrogen receptor β (ERβ), PI3K/AKT pathway and caspase-3. The results revealed that compared with those in female mice that received standard control diet, female mice that received folate-deficient diet exhibited lower E2 concentrations, lower sucrose preferences (as determined through the sucrose preference test), longer durations of immobility (as determined in the forced swim test) and less time spent in the central areas of the open field test. Western blotting demonstrated that the expression levels of ERβ and the phosphorylation levels of PI3K and AKT were decreased, whilst the expression levels of cleaved caspase-3 were increased, in the cerebral cortex of female mice that received folate-deficient diet. However, no differences in E2 concentration, behavioral assay parameters or protein levels of ERβ, phosphorylated (p-)PI3K, p-AKT and cleaved caspase-3 could be observed in male mice regardless of whether they received standard control or folate-deficient diets. Collectively, these results revealed that folate deficiency only led to depression-like behavior in female mice. This may be associated with reduced E2 levels, which may inhibit the PI3K/AKT pathway and upregulate the expression of cleaved caspase-3 to promote neuronal apoptosis.

Paracoccidioides brasiliensis infection increases regulatory T cell counts in female C57BL/6 mice infected via two distinct routes.

Studies that show an overview of the peripheral immune response in a model of Paracoccidioides brasiliensis (Pb) infection in females are scarce in the literature. We sought to characterize the innate and adaptive immune responses in female C57BL/6 mice infected with Pb through two distinct routes of administration, intranasal and intravenous. In addition to the lung, P. brasiliensis yeast cells were observed in liver and brain tissues of females infected intravenously. To our knowledge, our study is the first to prove the presence of this pathogenic fungus in the cerebral cortex of female mice. During the initial stages of infection, augmented expression of both MHCII and CD86 was observed on the surface of CD11c+ pulmonary antigen-presenting cells (APCs) in intranasally and intravenously infected females. However, CD40 expression was downregulated in these cells. Concomitantly with increasing serum IL-10 levels, we noted that splenic dendritic cells (DCs) from both intravenously- and intranasally-infected female mice had acquired an immature phenotype. Further, increased T regulatory cell counts were observed in female mice infected via both routes, along with an increase in the infiltration of IL-10-producing CD8+ T cells into the lungs. Moreover, we noted that P. brasiliensis infection resulted in enhanced IL-10 production - by CD11c+ APCs in the lung tissue - and induction of Th17 polarization. Taken together, our results suggest that P. brasiliensis could modulates the immune response in female mice by influencing the balance between regulatory T cells (Tregs) and Th17 polarization.

Females are more susceptible than male mice to thermal hypernociceptive behavior induced by early-life bisphenol-A exposure: Effectiveness of diphenyl diselenide

Humans are ubiquitously exposed to bisphenol A (BPA), one of the most used synthetic monomers for manufacturing polycarbonate plastics. BPA exposure leads to abnormal nociceptive perception and neuroinflammation in rodents. This study investigated whether diphenyl diselenide (PhSe)2, a pleiotropic selenium-containing molecule, would be effective against the hypernociceptive behavior induced by the early-life BPA exposure to mice. Three-week-old male and female Swiss mice received intragastrically BPA (5 mg/kg) from 21st to 60th postnatal day. After, the mice received by the intragastric route (PhSe)2 (1 mg/kg) once a day for seven days. After the last day of treatment, the mice performed the hot plate and tail immersion tests. The cerebral cortex samples were used to determine the levels of proteins related to apoptosis and inflammation. The results demonstrated that females were more susceptible than male mice to thermal hypernociception induced by early-life exposure to BPA. (PhSe)2 was effective against the reduction in the latency to paw and tail withdrawal induced by BPA exposure in female mice. Furthermore, (PhSe)2 restored the impairment in the levels of inflammatory proteins (COX-2, IL-1β, and p-JNK/JNK) but not those of apoptosis in the cerebral cortex of female mice exposed to BPA. Collectively, these data showed that females were more susceptible to thermal hypernociceptive behavior induced by early-life exposure to BPA than male mice. The administration of (PhSe)2 reduced thermal hypernociceptive behavior, a sex independent effect, in BPA-exposed mice. (PhSe)2 modulated inflammatory protein levels in the cerebral cortex of female mice exposed to BPA.

Ovarian Hormone-Dependent Effects of Dietary Lipids on APP/PS1 Mouse Brain.

The formation of senile plaques through amyloid-β peptide (Aβ) aggregation is a hallmark of Alzheimer’s disease (AD). Irrespective of its actual role in the synaptic alterations and cognitive impairment associated with AD, different therapeutic approaches have been proposed to reduce plaque formation. In rodents, daily intake of omega-3 (n-3) long-chain polyunsaturated fatty acids (LC-PUFAs) is required for neural development, and there is experimental and epidemiological evidence that their inclusion in the diet has positive effects on several neurodegenerative diseases. Similarly, estradiol appears to reduce senile plaque formation in primary mouse cell cultures, human cortical neurons and mouse AD models, and it prevents Aβ toxicity in neural cell lines. We previously showed that differences in dietary n-6/n-3 LC-PUFAs ratios modify the lipid composition in the cerebral cortex of female mice and the levels of amyloid precursor protein (APP) in the brain. These effects depended in part on the presence of circulating estradiol. Here we explored whether this potentially synergistic action between diet and ovarian hormones may influence the progression of amyloidosis in an AD mouse model. Our results show that a diet with high n-3 LC-PUFA content, especially DHA (22:6n-3), reduces the hippocampal accumulation of Aβ1–40, but not amyloid Aβ1–42 in female APPswe/PS1 E9A mice, an effect that was counteracted by the loss of the ovaries and that depended on circulating estradiol. In addition, this interaction between dietary lipids and ovarian function also affects the composition of the brain lipidome as well as the expression of certain neuronal signaling and synaptic proteins. These findings provide new insights into how ovarian hormones and dietary composition affect the brain lipidome and amyloid burden. Furthermore, they strongly suggest that when designing dietary or pharmacological strategies to combat human neurodegenerative diseases, hormonal and metabolic status should be specifically taken into consideration as it may affect the therapeutic response.

The Synthetic Steroid Tibolone Decreases Reactive Gliosis and Neuronal Death in the Cerebral Cortex of Female Mice After a Stab Wound Injury.

Previous studies have shown that estradiol reduces reactive gliosis after a stab wound injury in the cerebral cortex. Since the therapeutic use of estradiol is limited by its peripheral hormonal effects, it is of interest to determine whether synthetic estrogenic compounds with tissue-specific actions regulate reactive gliosis. Tibolone is a synthetic steroid that is widely used for the treatment of climacteric symptoms and/or the prevention of osteoporosis. In this study, we have assessed the effect of tibolone on reactive gliosis in the cerebral cortex after a stab wound brain injury in ovariectomized adult female mice. By 7days after brain injury, tibolone reduced the number of glial fibrillary acidic protein (GFAP) immunoreactive astrocytes, the number of ionized calcium binding adaptor molecule 1 (Iba1) immunoreactive microglia, and the number of microglial cells with a reactive phenotype in comparison to vehicle-injected animals. These effects on gliosis were associated with a reduction in neuronal loss in the proximity to the wound, suggesting that tibolone exerts beneficial homeostatic actions in the cerebral cortex after an acute brain injury.

Effects of co-treatment of <i>Rauwolfia vomitoria</i> and <i>Gongronema latifolium</i> on neurobehaviour and the neurohistology of the cerebral cortex in mice

Rauwolfia vomitoria and Gongronema latifolium are medicinal plants with antioxidant, antidiabetic and analgesic properties among others. R. vomitoria is reported to possess adverse neural effects, which G. latifolium has shown the potential to address. This study therefore investigated the effects of co-treatment of R. vomitoria and G. latifolium on the neurobehaviour and histology of the cerebral cortex of female mice. Twenty female Wistar mice were divided into 4 groups (A, B, C and D). Group A designated as the control received 0.4 mL of 20 % Tween, while groups B, C and D received oral doses of 150 mg/kg of R. vomitoria (RV), 200 mg/kg of G. latifolium (GL) and a combination of 150 mg/kg of R. vomitoria and 200 mg/kg of G. latifolium (RV+GL), respectively for seven days. Light and dark field behaviour test was carried out on day 8 and the animals were immediately sacrificed. Their brains were excised and routinely processed by haematoxylin and eosin method. There was no difference in body and brain weights, and the behavioural parameters. Cellular cyto-architecture showed higher glial population with no apparent histopathology. The cellular population was higher (p<0.0001) in the RV and RV+GL groups, while the GL group was less (p<0.0001) populated all compared to the control.In conclusion, the reported treatment regimes, RV administered singly and in combination with GL may not affect some neurobehavioural activities, but may result in cellular increase in the cerebral cortex.KEY WORDS: Rauwolfia vomitoria; Gongronema latifolium; Cerebral cortex; Mice

Alterations in the Sp1 binding and Fmr-1 gene expression in the cortex of the brain during maturation and aging of mouse.

Fragile X mental retardation protein (FMRP) has been implicated in learning, memory and cognition, therefore, information on alterations in FMRP expression during maturation and aging may provide a clue towards understanding mechanisms of age-dependent cognitive changes in the brain. In the present paper, we have studied Fmr-1 gene expression and its correlation with interaction of a tans-acting factor Sp1with Fmr-1 promoter in the cerebral cortex of female mice at post natal period during maturation and aging. Our data reveal that level of Fmr-1 transcript in the cerebral cortex is significantly up regulated at day 7 after birth compared to day 0 (the day of birth) and is gradually down regulated from day 15 onward to old age. The pattern of Fmr-1 transcript levels corresponds with the level of FMRP, however, its level is significantly up regulated in old age compared to adult mice. Our EMSA data revealed the formation of a single complex as a result of binding of Sp1with Fmr-1 promoter sequence. Its intensity gradually decreased from the day 0 (day of birth) till day 15, remained unaltered in young, significantly decreased in adult and significantly increased in old age. Our data suggests that age-dependent alteration in the Fmr-1 gene expression is associated with Sp1 interaction with Fmr-1 promoter which in turn might be related with cognitive development during brain maturation and aging.

17β-Estradiol increases expression of the oxidative stress response and DNA repair protein apurinic endonuclease (Ape1) in the cerebral cortex of female mice following hypoxia

While it is well established that 17β-estradiol (E2) protects the rodent brain from ischemia-induced damage, it has been unclear how this neuroprotective effect is mediated. Interestingly, convincing evidence has also demonstrated that maintaining or increasing the expression of the oxidative stress response and DNA repair protein apurinic endonuclease 1 (Ape1) is instrumental in reducing ischemia-induced damage in the brain. Since E2 increases expression of the oxidative stress response proteins Cu/Zn superoxide dismutase and thioredoxin in the brain, we hypothesized that E2 may also increase Ape1 expression and that this E2-induced expression of Ape1 may help to mediate the neuroprotective effects of E2 in the brain. To test this hypothesis, we utilized three model systems including primary cortical neurons, brain slice cultures, and whole animals. Although estrogen receptor α and Ape1 were expressed in primary cortical neurons, E2 did not alter Ape1 expression in these cells. However, immunofluorescent staining and quantitative Western blot analysis demonstrated that estrogen receptor α and Ape1 were expressed in the nuclei of cortical neurons in brain slice cultures and that E2 increased Ape1 expression in the cerebral cortex of these cultures. Furthermore, Ape1 expression was increased and oxidative DNA damage was decreased in the cerebral cortices of ovariectomized female C57Bl/6J mice that had been treated with E2 and exposed to hypoxia. Taken together, our studies demonstrate that the neuronal microenvironment may be required for increased Ape1 expression and that E2 enhances expression of Ape1 and reduces oxidative DNA damage, which may in turn help to reduce ischemia-induced damage in the cerebral cortex and mediate the neuroprotective effects of E2.

Evidence for both neuronal cell autonomous and nonautonomous effects of methyl-CpG-binding protein 2 in the cerebral cortex of female mice with Mecp2 mutation

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the gene MECP2, encoding methyl-CpG-binding protein 2 (MeCP2). Few studies have explored dendritic morphology phenotypes in mouse models of RTT and none have determined whether these phenotypes in affected females are cell autonomous or nonautonomous. Using confocal microscopy analysis we have examined the structure of dendrites and spines in the motor cortex of wild-type (WT) and Mecp2-mutant mice expressing green fluorescent protein (GFP). In Mecp2 GFP female mice age 6–7 months we found significant decreases in the density of spines, width of dendrites, size of spine heads, while increases were found in the length of spine necks, dendritic irregularities, spineless spots, and long spines. We show for the first time that a lower density of spines and smaller spine head area are phenotypes that distinguish MeCP2+ from MeCP2− dendrites in female Mecp2 GFP mice. In Mecp2 GFP male mice at three weeks of age, we found reduced spine density, thinner apical oblique dendrites and increased dendritic irregularities and long spines. Significantly, the changes affected both MeCP2− and MeCP2+ neurons, pointing to the ability of MeCP2− to impact the structure of MeCP2+ neurons. Our findings are evidence that MeCP2 deficiency results in both cell autonomous and nonautonomous changes.