Hippocampal Protein Levels Research Articles

The effects of neurosteroid allopregnanolone on synaptic dysfunction in the hippocampus in experimental parkinsonism rats: An electrophysiological and molecular study

The dopaminergic system is a powerful candidate targeted for changes of synaptic plasticity in the hippocampus. Higher incidence of Parkinson's disease (PD) in men than women indicates the influence of sex hormones on the PD development. Previous studies have shown that neurodegenerative diseases such as PD are related to the decline of Allopregnanolon (Allo), a metabolite of progesterone; it is also well known that learning and memory are influenced by oscillations in steroidal hormones. Although abnormalities in hippocampal plasticity have been observed in the toxic models of PD, effects of Allo on hippocampal LTP and hippocampal synaptic protein levels, which play an important role in maintaining the integrity of neural connections, have never been analyzed thus far. Experimental groups subjected to the long-term potentiation (LTP) were studied in the CA1 area of the hippocampus. In addition, the levels of hippocampal postsynaptic density protein 95 (PSD-95), neurexin-1 (Nrxn1) and neuroligin (Nlgn) as synaptic molecular components were determined by immunoblotting. Although dopamine denervation did not alter basal synaptic transmission and pair-pulse facilitation of field excitatory postsynaptic potentials (fEPSPs), the induction and maintenance of LTP were impaired in the CA1 region. In addition, the levels of PSD-95, Nrxn1 and Nlgn were significantly decreased in the hippocampus of 6-OHDA-treated animals. Such abnormalities in synaptic electrophysiological aspects and protein levels were abolished by the treatment with Allo. These findings showed that partial dopamine depletion led to unusual synaptic plasticity in the CA1 as well as the decrease in synaptic proteins in the hippocampus. Our results demonstrated that Allo ameliorated these deficits and preserved pre- and post-synaptic proteins. Therefore, Allo may be an effective factor in maintaining synaptic integrity in the mesolimbic pathway.

Lack of occlusal support did not impact amyloid β deposition in APP knock-in mice.

The lack of occlusal support is an epidemiological risk factor linked to Alzheimer's disease. This study sought to assess the relationship between amyloid β (Aβ) deposition and the lack of occlusal support in amyloid precursor protein (APP) knock-in mice. Sixteen experimental animals were divided into two groups. The upper molars were extracted in the extraction group (group E), and a sham operation was performed in the control group (group C). The Morris water maze test was performed 4 months after the tooth extraction. Aβ immunohistochemical staining and Nissl staining of the hippocampus were performed. Hippocampal plasma corticosterone and Aβ protein levels were measured. In the maze task, the escape latency was significantly longer in group E than in group C. In the probe trials, the time elapsed in the target quadrant was significantly shorter in group E than in group C. The number of hippocampal neurons decreased in group E. There was no significant difference in the plasma corticosterone levels between the two groups, indicating that there was no effect of chronic stress on the behavioral results. Hippocampal Aβ40 and Aβ42 protein levels and Aβ deposition areas by immunohistochemical staining were not significantly different between the two groups. Aβ deposition was not increased in the hippocampus of molarless APP knock-in mice. As such, it appears that cognitive impairment due to a lack of occlusal support was not related to Aβ deposition.

The detrimental effects of APOE4 on risk for Alzheimer's disease may result from altered dendritic spine density, synaptic proteins, and estrogen receptor alpha

Women carriers of APOE4, the greatest genetic risk factor for late-onset Alzheimer's disease (AD), are at highest risk of developing AD, yet factors underlying interactions between APOE4 and sex are not well characterized. Here, we examined how sex and APOE3 or APOE4 genotypes modulate object and spatial memory, dendritic spine density and branching, and protein expression in 6-month-old male and female E3FAD and E4FAD mice (APOE+/+/5xFAD+/−). APOE4 negatively impacted object recognition and spatial memory, with male E3FADs exhibiting the best memory across 2 object-based tasks. In both sexes, APOE4 reduced basal dendritic spine density in the medial prefrontal cortex and dorsal hippocampus. APOE4 reduced dorsal hippocampal levels of PDS-95, synaptophysin, and phospho-CREB, yet increased levels of ERα. E4FAD females exhibited strikingly increased GFAP levels, in addition to the lowest levels of PSD-95 and pCREB. Overall, our results suggest that APOE4 negatively impacts object memory, dendritic spine density, and levels of hippocampal synaptic proteins and ERα. However, the general lack of sex differences or sex by genotype interactions suggests that the sex-specific effects of APOE4 on AD risk may be related to factors unexplored in the present study.

Chronic Administration of Thymoquinone Enhances Adult Hippocampal Neurogenesis and Improves Memory in Rats Via Regulating the BDNF Signaling Pathway.

Thymoquinone is a pharmacologically active component of Nigella sativa Linn. seeds. Despite the diverse neuropharmacological attributes of TQ, limited reports related to adult neurogenesis and memory research are available. In this study, we investigated the effects of TQ on the proliferation and neural differentiation of cultured neural stem/progenitor cells (NSCs/NPCs). We also investigated the effect of TQ chronic administration on neurogenesis and memory in adult rats. Under proliferation conditions, TQ (0.05-0.3μM) significantly increased NSCs/NPCs viability, neurosphere diameter, and cell count. TQ treatment under differentiation conditions increased the proportion of cells positive for Tuj1 (a neuronal marker). Furthermore, chronic oral administration of TQ (25mg/kg/day for 12weeks) to adult rats increased the number of bromodeoxyuridine (BrdU)-immunopositive cells double-stained with a mature neuronal marker, neuronal nuclei (NeuN), and a proliferation marker, doublecortin (Dcx), in the dentate gyrus of the hippocampus. TQ-administered rats showed a profound beneficial effect on avoidance-related learning ability, associated with an increase in the hippocampal mRNA and protein levels of brain-derived neurotrophic factor (BDNF), as measured by both real-time PCR and ELISA. Western blot analysis revealed that TQ stimulates the phosphorylation of cAMP-response element-binding protein (CREB), the upstream signaling molecule in the BDNF pathway. Furthermore, chronic administration of TQ decreased lipid peroxide and reactive oxygen species levels in the hippocampus. Taken together, our results suggest that TQ plays a role in memory improvement in adult rats and that the CREB/BDNF signaling pathways are involved in mediating the actions of TQ in hippocampal neurogenesis.

Effect of Continuous and Interval Training on Amyloid β 42 (Aβ42) and Malondialdehyde (MDA) Levels in Hippocampus of Elderly Rats

Introduction: Amyloid plaques in the brain increase with age. Thus, the present study aimed to evaluate the effect of continuous and interval training on Amyloid β 42 (Aβ42) and Malondialdehyde (MDA) levels in hippocampus of elderly rats. Methods: The present study was experimental one with two experimental groups and one control group. Thirty old male Wistar rats (18 weeks-old) divided into 3 groups, including interval training, continuous training, and control. Continuous training was performed for 8 weeks with 65 to 70% VO2max and interval training was performed for 8 weeks with 5-8 repetitions of 2 minutes of working with 80-100% VO2max and 2 minutes active rest with 50% of VO2max for 8 weeks. Hippocampal samples were extracted 48 hours after the last training session to measure protein levels of Aβ42 and MDA. One-way ANOVA and Tukey post hoc test was used for data analysis. Results: Hippocampus Aβ42 levels in continuous training groups were significantly lower than the control group (P=0.001). In addition, Aβ42 levels in hippocampus of interval training groups were significantly lower than the control group (P=0.001). However, no significant differences were found in Aβ42 levels between continuous and interval training groups (p=0.502). MDA levels in continuous training groups were significantly lower than the control group (P=0.016). In addition, MDA levels in interval training groups were significantly lower than the control group (P=0.046) But no significant differences were found in hippocampal MDA protein levels between continuous and interval training groups (p=866). Conclusion: Continuous and interval training through decreasing oxidative stress, decrease Aβ42 levels in the hippocampus of the elderly rat, thus probably continuous and interval training can prevent neurodegenerative disease caused by aging through modulating oxidative stress and Aβ42.

The Role of Zinc Status on Spatial Memory, Hippocampal Synaptic Plasticity, and Insulin Signaling in icv-STZ-Induced Sporadic Alzheimer's-Like Disease in Rats.

Alzheimer's disease (AD), especially its sporadic form (sAD), is of multifactorial nature. Brain insulin resistance and disrupted zinc homeostasis are two key aspects of AD that remain to be elucidated. Here, we investigated the effects of dietary zinc deficiency and supplementation on memory, hippocampal synaptic plasticity, and insulin signaling in intracerebroventricular streptozotocin (icv-STZ)-induced sAD in rats. The memory performance was evaluated by Morris water maze. The expression of hippocampal protein and mRNA levels of targets related to synaptic plasticity and insulin pathway was assessed by Western blot and real-time quantitative PCR. We found memory deficits in icv-STZ rats, which were fully recovered by zinc supplementation. Western blot analysis revealed that icv-STZ treatment significantly reduced hippocampal PSD95 and p-GSK3β, and zinc supplementation restored the normal protein levels. mRNA levels of BDNF, PSD95, SIRT1, GLUT4, insulin receptor, and ZnT3 were found to be reduced by icv-STZ and reestablished by zinc supplementation. Our data suggest that zinc supplementation improves cognitive deficits and rescues the decline in key molecular targets of synaptic plasticity and insulin signaling in hippocampus caused by icv-STZ induced sAD in rats.

Coping with Exercise Induced Spatial Memory Improvement in Morphine Dependent Rats by Inhibiting Brain Derived Neurotrophic Factor (BDNF)

Background: Addiction as a chronic disorder that requires long treatment. One way to treating this chronic disease is exercise. Chronic exposure to opiates impairs spatial learning and memory. Given the well-known beneficial effects of voluntary exercise on cognitive functions, we investigated whether voluntary exercise would ameliorate the cognitive deficits that are induced by morphine dependence. If an effect of exercise was observed, we aimed to investigate the possible role of hippocampal brain-derived neurotropic factor (BDNF) in the exercise-induced enhancement of learning and memory in morphine-dependent rats. Methods: The rats were injected with bi-daily doses (10 mg/kg, at 12 hr. intervals) of morphine over a period of 10 days of voluntary exercise. Following these injections, a water maze task was performed twice a day for 5 consecutive days, followed by a probe trial 2 days later. A specific BDNF inhibitor (TrkB-IgG chimera) was used to block the hippocampal BDNF action during the 10 days of voluntary exercise. Results: The voluntary exercise diminished the severity of the rats’ dependency on morphine. A blockade of the BDNF action blunted the exercise-induced improvement of spatial memory, hippocampal neuron counting and BDNF protein levels in the dependent rats. Our results indicate that voluntary exercise could be increase the expression of LTP by lowering the induction threshold for LTP in the DG of morphine-dependent rats. Conclusion: Thus, voluntary exercise might be considered as a potential method to ameliorate some of the deleterious behavioral consequences of the abuse of morphine and other opiates.

Involvement of TRPV4 in changes in rapidly inactivating potassium channels in the early stage of pilocarpine-induced status epilepticus in mice.

The rapidly inactivating potassium current (IA ) is important in controlling neuronal action potentials. Altered IA function and K+ channel expression have been found in epilepsy, and activation of the transient receptor potential vanilloid 4 (TRPV4) channel is involved in epilepsy pathogenesis. This study examined whether TRPV4 affects Kv4.2 and K+ channel interacting protein (KCHIP) expression and IA changes following pilocarpine-induced status epilepticus (PISE) in mice. Herein, hippocampal protein levels of Kv4.2 and KCHIP2 increased 3 h-3 d and decreased 7-30 d; that of KCHIP1 increased 3-24 h and decreased 3-30 d post-PISE. The TRPV4 antagonist HC-067047 attenuated the increased protein levels of Kv4.2 and KCHIP2 but not that of KCHIP1 post-PISE. The TRPV4 agonist GSK1016790A increased hippocampal protein levels of Kv4.2 and KCHIP2 but had no effect on KCHIP1 expression. HC-067047 attenuated the increased IA in hippocampal pyramidal neurons 24 h and 3 d post-PISE. GSK1016790A increased IA in hippocampal pyramidal neurons, shifting the voltage-dependent inactivation curve toward depolarization. The GSK1016790A-induced increase of IA was blocked by protein kinase A and calcium/calmodulin-dependent kinase II antagonists but was unaffected by protein kinase C antagonists. We conclude that TRPV4 activation may be responsible for the increases of Kv4.2 and KCHIP2 expression in hippocampi and IA in hippocampal pyramidal neurons in PISE mice, which are likely compensatory measures for hyperexcitability at the early stage of epilepsy.

Ghrelin improves cognition via activation of the cAMP- CREB signalling pathway in depressed male C57BL/6J mice

Background Depression leads to a cognitive decline and decreases in ghrelin are observed in depression. Ghrelin affects the level of Brain-derived nerve growth factor (BDNF) through the cAMP-CREB signalling pathway, and lower BDNF levels lead to cognitive decline. Therefore, it is reasonable to assume that in depression, lower ghrelin causes a decrease in BDNF levels and cognitive decline though the cAMP- CREB signalling pathway. Methods A total of 120 C57BL/6J male mice were randomly divided into six groups of 20 mice: non-depression groups (sham group, ghrelin group, and ghrelin + (D-lys3)-GHRP-6 group) and depression groups (depression group, depression + ghrelin group and depression + ghrelin + (D-lys3)-GHRP group). A depression mouse model was established by injecting normal saline, ghrelin or ghrelin + (D-lys3) -GHRP-6 into the lateral ventricle of each group. Cognition, hippocampal long-term potentiation (LTP), ghrelin mRNA and protein level, BDNF level and CREB level in the hippocampus were detected. Results In the depression mouse model groups, all comparison indexes (cognition and hippocampal levels of LTP, ghrelin mRNA and proteins, and BDNF and CREB) had significant negative changes. In the mice with depression, ghrelin or ghrelin + (D-lys3)-GHRP-6 was injected, and all the comparison indicators showed significant positive changes. Supplementation of ghrelin+(D-lys3))-GHRP-6 resulted in more significant positive changes in all comparison indexes than those of ghrelin alone. Conclusions In the depression model, lower ghrelin causes hippocampal BDNF to decrease and results in cognitive decline via the cAMP-CREB signalling pathway.

Antidepressant mechanism of catalpol: Involvement of the PI3K/Akt/Nrf2/HO-1 signaling pathway in rat hippocampus

Catalpol is a major compound in Rehmanniae Radix with outstanding medicinal and nutritional values. Our previous studies have demonstrated catalpol's antidepressant effect, but its mechanisms remain unclear. This study aimed to explore the antidepressant mechanisms of catalpol via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1 (HO-1) pathway. Results demonstrated that chronic unpredictable mild stress (CUMS) for 5 consecutive weeks caused significant decreases in the sucrose preference and the horizontal and vertical scores of open-field test, as well as a significant increase in the swimming-immobility time of rats; catalpol administration significantly reversed the abnormality of these indicators. Further real-time fluorescent quantitative polymerase chain reaction and Western blotting results together showed that CUMS significantly downregulated the expression levels of hippocampal genes and proteins, including PI3K, Akt, Nrf2, HO-1, tropomyosin-related kinase B (TrkB), and brain-derived neurotrophic factor; catalpol administration significantly reversed the abnormal expression of these genes and proteins. CUMS also caused a significant decrease in the hippocampal superoxide dismutase, catalase, glutathione peroxidase, glutathione-s transferase, and reduced glutathione levels, as well as a significant increase in thiobarbituric acid reactive substances level in rats; catalpol administration significantly reversed the abnormality of these indicators. Taken together, this study confirmed for the first time that the antidepressant effect of catalpol on CUMS-induced depression involved the upregulation of the PI3K/Akt/Nrf2/HO-1 signaling pathway, thereby improving the hippocampal neurotrophic, neuroprotective, and antioxidant levels. The PI3K/Akt/Nrf2/HO-1 pathway-related molecules may serve as potential new biomarkers and candidate molecular targets for catalpol's antidepressant effects.

Vitamin D Regulatory Effect on Restraint Stress-Induced Changes in Serum Corticosterone and Hippocampus BDNF Levels in the Male Rats

Background: Chronic stress exerts negative effects on cognitive functions through inducing changes in the hippocampus. Brain-derived neurotrophic factor (BDNF) is an essential factor in cognitive functions, which is considerably reduced under chronic stress. 1,25(OH)2 vitamin D plays neuroprotective roles partially by regulating the expression of various neurotrophic factors. Objectives: Since few studies have studied the impact of vitamin D on BDNF levels, we conducted this brief experiment to understand the role of vitamin D in maintaining hippocampal BDNF protein levels by using restraining as a model of chronic stress in rats. Methods: Rats underwent restraint stress 3 h/day for 28 days, during which they received vitamin D (5, 10 μg/kg) or its vehicle (IP, twice weekly). After the stress period, serum corticosterone (CORT) and hippocampus BDNF protein levels were measured. Results: Restraint stress increased serum CORT (P < 0.001) and reduced BDNF protein levels (P < 0.001) as compared to the non-stress group. Vitamin D markedly maintained BDNF levels close to normal (P < 0.001), but did not change CORT levels significantly. Conclusions: This study demonstrated that 3h/day of chronic restraint stress for 28 days boosted serum CORT and declined hippocampal BDNF levels, similar to stronger restraint stress models. Vitamin D maintained BDNF level close to normal in the hippocampus, but it did not affect CORT level significantly.

The effect of electronic cigarettes exposure on learning and memory functions: behavioral and molecular analysis

Objective: Electronic cigarettes (ECIGs) are battery-powered devices that emit vaporized solutions for the user to inhale. ECIGs are marketed as a less harmful alternative to combustible cigarettes. The current study examined the effects of ECIG aerosol exposure on learning and memory, expression of brain derived neurotrophic factor (BDNF), and the activity of antioxidant enzymes in the hippocampus. Methods: Male Wistar rats were exposed to ECIG aerosol, by a whole-body exposure system, 1 h/day for 1 week, 4 weeks, and 12 weeks. Spatial learning and memory were tested using the Radial Arm Water Maze (RAWM). Hippocampal BDNF protein level, and oxidative stress biomarkers (GPx, SOD, GSH, GSSG, GSH/GSSG ratio) were also assessed. Results: ECIG aerosol exposure for 4 and 12 weeks impaired both short- and long- term memory and induced reductions in the hippocampus BDNF, SOD and GPx activities, and GSH/GSSG ratio (p < 0.05). No changes in any examined biomarkers were observed after 1-week exposure to ECIG aerosol (p > 0.05). Conclusions: ECIG aerosol exposure impaired functional memory and elicited changes in brain chemistry that are consistent with reduced function and oxidative stress.

High glucose exacerbates neuroinflammation and apoptosis at the intermediate stage after post-traumatic brain injury.

Traumatic brain injury (TBI) is a highly lethal event with a poor prognosis. Recovering residual neuronal function in the intermediate stage of TBI is important for treatment; however, neuroinflammation and neuronal apoptosis impede residual neuronal repair processes. Considering that hyperglycemia influences inflammatory processes and neuronal survival, we examined the effects of high glucose on neuroinflammation and neuronal death during the intermediate phase of TBI. Rat models of type 2 diabetes mellitus and/or TBI were developed and behaviorally assessed. Neurological function and cognitive abilities were impaired in TBI rats and worsened by type 2 diabetes mellitus. Histopathological staining and analyses of serum and hippocampal mRNA and protein levels indicated that neuroinflammation and apoptosis were induced in TBI rats and exacerbated by hyperglycemia. Hyperglycemia inhibited hippocampal mitogen-activated protein kinase kinase 5 (MEK5) phosphorylation in TBI rats. In vitro assays were used to assess inflammatory factor expression, apoptotic protein levels and neuronal survival after MEK5 activation in TBI- and/or high-glucose-treated neurons. MEK5/extracellular signal-regulated kinase 5 (ERK5) pathway activation reduced the inflammation, cleaved caspase-3 expression, Bax/Bcl-2 ratio and apoptosis of TBI neurons, even under high-glucose conditions. Thus, high glucose exacerbated neuroinflammation and apoptosis in the intermediate stage post-TBI by inhibiting the MEK5/ERK5 pathway.

Sericin protects against acute sleep deprivation-induced memory impairment via enhancement of hippocampal synaptic protein levels and inhibition of oxidative stress and neuroinflammation in mice

Sleep deprivation (SD) induces learning and memory deficits via inflammatory responses and oxidative stress. On the other hand, sericin (Ser) possesses potent antioxidant and neuroprotective effects. We investigated the effect of different doses of Ser on the SD-induced cognitive impairment. Ser (100, 200, and 300 mg/kg) was administered to animals via oral gavage for 8 days, 5 days before to SD, and during SD. SD was induced in mice using a modified multiple platform model, starting on the 6th day for 72 h. Spatial learning and memory were assessed using the Lashley III maze. Serum corticosterone level, and hippocampal malondialdehyde (MDA), total antioxidant capacity (TAC), and the activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzymes were evaluated. The expression of growth‐associated protein 43 (GAP-43), post‐synaptic density‐95 (PSD-95), synapsin 1 (SYN-1), and synaptophysin (SYP), and inflammation markers were detected by western blotting. SD caused cognitive impairment, while Ser pretreatment prevented such an effect. Serum corticosterone also increased with SD, but its levels were suppressed in SD mice receiving Ser. Furthermore, Ser normalized SD-induced reduction in the hippocampus activity of SOD and GPx, increased TAC, and decreased MDA levels. Besides, Ser pretreatment increased GAP-34, SYP, SYN-I, and PSD-95 and reduced IL1-β and TNF-α in the hippocampus. SD induced memory impairment and pretreatment with Ser improved memory via its antioxidant, anti-inflammation, and up-regulation of synaptic proteins in the hippocampus.

A preliminary study of sex differences and histopathological observations in experimentally-induced Alzheimer’s disease albino rats with Letrozole administration

Background: Letrozole is an aromatase inhibitor with conflicting studies reporting its effects on memory in male and female animals, and whether the observed memory impairments become exacerbated with an additional insult such as Alzheimer's disease (AD); an illness in which beta-amyloid and hyperphosphorylated Tau (p-Tau) protein accumulate. We examined Letrozole effects on memory, hippocampal p-Tau and histopathology in animals treated with Letrozole only or on top of induced AD, and investigated whether there would be any sex-based differences in memory status and/or p-Tau.Methods: 51 adult male and female Sprague Dawley rats were divided into: Control groups: Intact, Letrozole Vehicle, CSF, and CSF+Letrozole Vehicle, Letrozole group, Streptozotocin (STZ) group; with induced AD via cerebroventricular STZ injection in artificial CSF and, STZ+Letrozole (STZ-L) group. Memory was tested in a T-maze to measure alternation percentage. Hippocampal p-Tau protein levels were estimated using ELISA, and histopathology was documented in sections stained with Hematoxylin and Eosin.Results: There were significant reductions in alternation percentage in the STZ, Letrozole and STZ-L groups; most severe in the STZ-L group and least severe in the Letrozole group. Significant elevation in p-Tau concentration was observed in the STZ, Letrozole and STZ-L groups compared to the controls. No differences were found between males and females in all groups in any of the studied parameters. Histopathological examination showed neurodegeneration and inflammation in the Letrozole, STZ and STZ-L groups. Conclusion: Letrozole alters memory, more so in experimentally-induced AD, increases p-Tau and may cause hippocampal pathological changes, with no sex-based differences.

Hippocampal mitogen-activated protein kinase phosphatase-1 regulates behavioral and systemic effects of chronic corticosterone administration

Clinical reports indicate a bidirectional relationship between mental illness and chronic systemic diseases. However, brain mechanisms linking chronic stress and development of mood disorders to accompanying peripheral organ dysfunction are still not well characterized in animal models. In the current study, we investigated whether activation of hippocampal mitogen-activated protein kinase phosphatase-1 (MKP-1), a key factor in depression pathophysiology, also acts as a mediator of systemic effects of stress. First, we demonstrated that treatment with the glucocorticoid receptor (GR) agonist dexamethasone or acute restraint stress (ARS) significantly increased Mkp-1 mRNA levels within the rat hippocampus. Conversely, administration of the GR antagonist mifepristone 30 min before ARS produced a partial blockade of Mkp-1 upregulation, suggesting that stress activates MKP-1, at least in part, through upstream GR signaling. Chronic corticosterone (CORT) administration evoked comparable increases in hippocampal MKP-1 protein levels and produced a robust increase in behavioral emotionality. In addition to behavioral deficits, chronic CORT treatment also produced systemic pathophysiological effects. Elevated levels of renal inflammation protein markers (NGAL and IL18) were observed suggesting tissue damage and early kidney impairment. In a rescue experiment, the effects of CORT on development of depressive-like behaviors and increased NGAL and IL18 protein levels in the kidney were blocked by CRISPR-mediated knockdown of hippocampal Mkp-1 prior to CORT exposure. In sum, these findings further demonstrate that MKP-1 is necessary for development of enhanced behavioral emotionality, while also suggesting a role in stress mechanisms linking brain dysfunction and systemic illness such as kidney disease.

Osthole Ameliorates Estrogen Deficiency-Induced Cognitive Impairment in Female Mice.

Loss of endogenous estrogen and dysregulation of the estrogen receptor signaling pathways are associated with an increase in risk for cognitive deficit and depression in women after menopause. Estrogen therapy for menopause increases the risk of breast and ovarian cancers, and stroke. Therefore, it is critical to find an alternate treatment for menopausal women. Osthole (OST), a coumarin, has been reported to have neuroprotective effects. This study examined whether OST improves ovariectomy (OVX)-induced cognitive impairment, and alleviates anxiety- and depression-like behaviors induced by OVX in mice. Adult female C57BL/6J mice were ovariectomized and then treated with OST at a dose of 30 mg/kg for 14 days. At the end of the treatment period, behavioral tests were used to evaluate spatial learning and memory, recognition memory, anxiety- and depression-like behaviors. A cohort of the mice were sacrificed after 14 days of OST treatment and their hippocampi were collected for measurement of the proteins of interest using western blot. OVX-induced alteration in the levels of proteins was accompanied by cognitive deficit, anxiety- and depression-like behaviors. OST treatment improved cognitive deficit, alleviated anxiety- and depression-like behaviors induced by OVX, and reversed OVX-induced alterations in the levels of synaptic proteins and ERα, BDNF, TrKB, p-CREB, p-Akt and Rac1 in the hippocampus. Therefore, reversal of OVX-induced decrease in the levels of hippocampal proteins by OST might contribute to the effects of OST on improving cognitive deficit and alleviating anxiety- and depression-like behaviors induced by OVX.

Adverse Maternal Environment Alters MicroRNA-10b-5p Expression and Its Epigenetic Profile Concurrently with Impaired Hippocampal Neurogenesis in Male Mouse Hippocampus

An adverse maternal environment (AME) predisposes adult offspring toward cognitive impairment in humans and mice. However, the underlying mechanisms remain poorly understood. Epigenetic changes in response to environmental exposure may be critical drivers of this change. Epigenetic regulators, including microRNAs, have been shown to affect cognitive function by altering hippocampal neurogenesis which is regulated in part by brain-derived neurotropic factor (BDNF). We sought to investigate the effects of AME on miR profile and their epigenetic characteristics, as well as neurogenesis and BDNF expression in mouse hippocampus. Using our mouse model of AME which is composed of maternal Western diet and prenatal environmental stress, we found that AME significantly increased hippocampal miR-10b-5p levels. We also found that AME significantly decreased DNA methylation and increased accumulations of active histone marks H3 lysine (K) 4me3, H3K14ac, and ­H3K36me3 at miR-10b promoter. Furthermore, AME significantly decreased hippocampal neurogenesis by decreasing cell numbers of Ki67⁺ (proliferation marker), NeuroD1⁺ (neuronal differentiation marker), and NeuN⁺ (mature neuronal marker) in the dentate gyrus (DG) region concurrently with decreased hippocampal BDNF protein levels. We speculate that the changes in epigenetic profile at miR-10b promoter may contribute to upregulation of miR-10b-5p and subsequently lead to decreased BDNF levels in a model of impaired offspring hippocampal neurogenesis and cognition in mice.

Effect of blood-letting puncture of "Well-points" on hippocampal mitophagy-related protein expression in rats with acute brain injury due to hypobaric hypoxia

To study the effect of blood-letting puncture at "Well-points" of the twelve meridians on hippocampal mitophagy of hypobaric hypoxia-induced brain injury (HHIBI) rats, so as to explore its biological mechanisms underlying improvement of high altitude hypoxia-induced brain injury. Male SD rats were randomly divided into normal control group （n=9）， and model and blood-letting groups which were further divided into 6, 12, 24, 48 and 72 h subgroups (n=9 in each subgroup). The HHIBI model was established by putting the rats into a hypobaric hypoxia chamber (equivalent to 5 000 m above sea level).The blood-letting groups were given blood-letting therapy at "Shaoshang"(LU11), "Shangyang"(LI1), "Zhongchong"(PC9), "Guanchong"(SJ1), "Shaochong"(HT9), "Shaoze"(SI9), once a day for 7 days. H.E. staining was used to observe the histopatholo-gical changes of hippocampus tissue. Serum hypoxia inducible factor(HIF)-1α and vascular endothelial growth factor(VEGF) contents were assayed using ELISA, and the expression levels of hippocampal Beclin-1 and LC3-Ⅱ proteins detected using Western blot. Compared with the normal control group, the levels of serum HIF-1α and VEGF at each time point, and the expressions of hippocampal Beclin-1 at 12 and 24 h, LC3-Ⅱat each time point were significantly increased in the model group (P<0.05, P<0.01); while in comparison with the model group, the levels of serum HIF-1α and VEGF contents, and the expressions of Beclin-1 at 12 h, LC3-Ⅱ at 24, 48 and 72 h were further significantly up-regulated in the blood-letting group (P<0.01, P<0.05). H.E. staining revealed that the pyramidal cells in the hippocampal CA1 region had a disordered arrangement, and some of them presented swelling with loose and pale cytoplasm or vacuolation at 6, 12 and 24 h, and showed indistinct nucleolus, irregular shape, pyknosis and deep staining and an obvious edema at 48 and 72 h, which was relatively milder in the blood-letting group. Blood-letting of "Well-points" can up-regulate serum HIF-1α and VEGF contents and hippocampal Beclin-1 and LC3-Ⅱ (mitophagy related proteins) expressions in HHIBI rats, which may contribute to its effect in reducing hypoxic brain injury.

RNA sequencing and proteomic profiling reveal different alterations by dietary methylmercury in the hippocampal transcriptome and proteome in BALB/c mice.

Methylmercury (MeHg) is a highly neurotoxic form of mercury (Hg) present in seafood. Here, we recorded and compared proteomic and transcriptomic changes in hippocampus of male BALB/c mice exposed to two doses of MeHg. Mice were fed diets spiked with 0.28 mg MeHg kg–1, 5 mg MeHg kg–1, or an unspiked control diet for 77 days. Total mercury content was significantly (P < 0.05) increased in brain tissue of both MeHg-exposed groups (18 ± 2 mg Hg kg–1 and 0.56 ± 0.06 mg Hg kg–1). Hippocampal protein and ribonucleic acid (RNA) expression levels were significantly altered both in tissues from mice receiving a low dose MeHg (20 proteins/294 RNA transcripts) and a high dose MeHg (61 proteins/876 RNA transcripts). The majority but not all the differentially expressed features in hippocampus were dose dependent. The combined use of transcriptomic and proteomic profiling data provided insight on the influence of MeHg on neurotoxicity, energy metabolism, and oxidative stress through several regulated features and pathways, including RXR function and superoxide radical degradation.