Hippocampal Protein Expression Research Articles

Effect of ferric citrate on hippocampal iron accumulation and widespread molecular alterations associated with cognitive disorder in an ovariectomized mice model.

Nowadays, the prevalence of cognitive impairment in women has gradually increased, especially in postmenopausal women. There were few studies on the mechanistic effects of iron exposure on neurotoxicity in postmenopausal women. The aim of this study is to investigate the effect of iron accumulation on cognitive ability in ovariectomized mice and its possible mechanism and to provide a scientific basis for the prevention of cognitive dysfunction in postmenopausal women. Female C57BL/6N ovariectomized model mice were induced with ferric citrate (FAC). The mice were randomly divided into 5 groups: control, sham, ovariectomized (Ovx), Ovx + 50 mg/kg FAC (Ovx + l), and Ovx + 100 mg/kg FAC (Ovx + h). The impact of motor and cognitive function was verified by a series of behavioral tests. The levels of serum iron parameters, malondialdehyde, and superoxide dismutase were measured. The ultrastructure of mice hippocampal microglia was imaged by transmission electron microscopy. The differential expression of hippocampal proteins was analyzed by Tandem Mass Tag labeling. Movement and cognitive function in Ovx + l/Ovx + h mice were significantly decreased compared to control and Sham mice. Then, iron exposure caused histopathological changes in the hippocampus of mice. In addition, proteomic analysis revealed that 29/27/41 proteins were differentially expressed in the hippocampus when compared by Ovx vs. Sham, Ovx + l vs. Ovx, as well as Ovx + h vs. Ovx + l groups, respectively. Moreover, transferrin receptor protein (TFR1) and divalent metal transporter 1 (DMT1) protein expression were significantly increased in the iron accumulation mice model with ovariectomy. Iron exposure could cause histopathological damage in the hippocampus of ovariectomised mice and, by altering hippocampal proteomics, particularly the expression of hippocampal iron metabolism-related proteins, could further influence cognitive impairment in ovariectomized mice.

Aerobic exercise modulates RIPK1-mediated MAP3K5/JNK and NF-κB pathways to suppress microglia activation and neuroinflammation in the hippocampus of D-gal-induced accelerated aging mice

Microglia activation-induced neuroinflammation is a risk factor for cognitive dysfunction in the hippocampus during the early stages of neurodegenerative diseases. Exercise is an intrinsic remedy that plays a crucial role in enhancing the survival of neurons and reducing neuroinflammation in the brain. Among these theories, alterations in intracellular signaling pathways associated with neuronal growth and inflammation have been emphasized. Based on these observations and recent evidence demonstrating the beneficial effects of exercise on suppressing brain inflammation in the elderly, we examined cellular signaling pathways in the hippocampal formation of D-galactose-induced accelerated aging mice that underwent 8 weeks of treadmill exercise. To accomplish this, we utilized immunohistochemistry and Western blotting to detect the expression of hippocampal proteins, and qPCR to detect the expression of mRNA. We found that aerobic exercise significantly promoted the survival of hippocampal neurons, inhibited microglia activation, and decreased the expression of inflammatory cytokines TNF-α, IL-1α, IL-1β, and chemokines CXCL-1, CXCR-2 in D-galactose model mice. Furthermore, exercise contributed to decreasing the microglia activation marker Iba1-positive cell count and average optical density and increasing the number of NeuN-immunopositive cells. Exercise also reduced RIPK1 and MAP3K5 expression in the hippocampus. Surprisingly, aerobic exercise significantly decreased the expression ratios of p-p65/p65, p-IκBα/IκBα, and p-JNK/JNK. Therefore, we hypothesized that exercise has an anti-inflammatory effect on the hippocampus of mice in the D-galactose-induced aging model. This effect may be attributed to the ability of aerobic exercise to down-regulate the RIPK1-mediated NF-κB and JNK pathways.

DHA dietary intervention caused different hippocampal lipid and protein profile in ApoE-/- and C57BL/6J mice

BackgroundChanges in protein and lipid levels may occur in the Alzheimer’s disease brain, and DHA can have beneficial effects on it. To investigate the impact of DHA dietary intervention on brain protein and lipid profile in ApoE-/- mice and C57 mice. MethodThree-month-old ApoE-/- mice and C57 mice were randomly divided into two groups respectively, and fed with control diet and DHA-fortified diet for five months. Cortical TC, HDL-C and LDL-C levels and cholesterol metabolism-related protein expression were measured by ELISA or immunohistochemistry methods. Hippocampus were collected for proteomic and lipidomics analysis by LC-MS/MS and differential proteins and lipid metabolites were screened and further analyzed by GO functional annotation and KEGG pathway enrichment analysis. ResultsDHA intervention decreased cortical TC level in both C57 and ApoE-/- mice (P < 0.05), but caused different change of cortical HDL-C, LDL-C level and LDL-C/HDL-C ratio in C57 and ApoE-/- mice (P < 0.05). Discrepant cortical and hippocampal LDLR, ABCG1, Lox1 and SORT1 protein expression was found between C57 and ApoE-/- mice (P < 0.05), and DHA treatment caused different changes of these proteins in C57 and ApoE-/- mice (P < 0.05). Differential hippocampal proteins and lipids profile were found in C57 and ApoE-/- mice before and after DHA treatment, which were mainly involved in vesicular transport and phospholipid metabolic pathways. ConclusionApoE genetic defect caused abnormal cholesterol metabolism, and affected protein and lipid profile, as well as discrepant response of hippocampal protein and lipids profile in the brain of mice given DHA fortified diet intervention.

The improvement effect of exercise on rats with chronic stress-induced depression-like behavior: a discussion based on the kynurenine pathway.

To observe the effects of 4 weeks of voluntary wheel running on depressive-like behavior in a rat chronic stress-induced depression model to explore the anti-depressive mechanism of exercise. In this observational study, 36 Sprague-Dawley rats were randomly divided into control, stress model, and stress exercise groups (12 rats/group). The control group received no intervention, and the stress model and stress exercise group rats underwent chronic mild unpredictable stress and isolation. The stress exercise group rats also underwent 4 weeks of voluntary wheel running. Behavioral changes and hippocampal protein and mRNA expression levels were detected. Voluntary wheel running significantly increased horizontal and vertical movements, sucrose intake, and the sucrose preference percentage and reduced immobility time in the forced swimming test in depression model rats. The hippocampal tumor necrosis factor-α, interleukin (IL)-6, IL-1β, and quinolinic acid levels were significantly decreased, while the IL-4, IL-10, and kynurenic acid levels were significantly increased. Kynurenine-3-monooxygenase and 3-hydroxyanthranilate-3, 4-dioxygenase mRNA levels were downregulated, and kynurenine aminotransferase mRNA was upregulated. Voluntary wheel running improved depressive-like behavior in depression model rats. The mechanism may be related to a kynurenine pathway metabolite level imbalance, which has neurotoxic and neuroprotective effects, caused by long-term voluntary wheel running.

Glucose attenuates the long-term adverse neurodevelopment effect of neonate pain stimulus via CRF/GR in rats

BackgroundNeonates undergo numerous painful procedures throughout their hospitalization. Repeated procedural pain may cause adverse long-term effects. Glucose as a non-pharmacological analgesia, is used for neonate pain management. In this study, potential mechanism of attenuate pain induced by glucose in neurodevelopment effect of neonate pain stimulus was investigated. MethodsNeonatal rats to perform a repetitive injury model and glucose intervention model in the postnatal day 0–7(P0-7). Pain thresholds were measured by von Frey test weekly. The puberty behavioral outcome, tissue loss and protein expression in hippocampus were analyzed. ResultsOral administration of glucose after repeated pain stimulation can maintain the hippocampal structure in, and reduce the expressions of corticotropin releasing factor (CFR) and glucocorticoid receptor (GR), therefore, resulted in long-term threshold of pain and cognitive improvement. ConclusionExposure to neonatal repeated procedural pain causes persistent mechanical hypersensitivity and the dysfunction of spatial memory retention at puberty. In addition, glucose can relieve these adverse effects, possibly via decreasing CRF/GR levels to change the hypothalamus-pituitary-adrenal (HPA) axis.

Improving dietary patterns in obese mice: Effects on body weight, adiposity, anhedonia-like behavior, pro-BDNF expression and 5-HT system

IntroductionThe excessive fat accumulation in obesity, resulting from an unbalanced diet, can lead to metabolic and neurological disorders and increase the risk of developing anxiety and depression. AimAssess the impact of dietary intervention (DI) on the serotonergic system, brain-derived neurotrophic factor (BDNF) expression and behaviors of obese mice. MethodsMale C57BL/6 mice, 5 weeks old, received a high-fat diet (HFD) for 10 weeks for the induction of obesity. After this period, for 8 weeks, half of these animals received a control diet (CD), group obese (OB) + control diet (OB + CD, n = 10), and another half continued being fed HFD, group obese + HFD (OB + HFD, n = 10). At the end of the eighth week of intervention, behavioral tests were performed (sucrose preference test, open field, novel object recognition, elevated plus maze and tail suspension). Body weight and food intake were assessed weekly. Visceral adiposity, the hippocampal and hypothalamic protein expression of BDNF, 5-HT1A (5-HT1A serotonin receptor) and TPH2 (key enzyme in serotonin synthesis), were evaluated after euthanasia. ResultsThe dietary intervention involved changing from a HFD to a CD over an 8-week period, effectively reduced body weight gain, adiposity, and anhedonia-like behavior. In the OB + HFD group, we saw a lower sucrose preference and shorter traveled distance in the open field, along with increased pro-BDNF expression in the hypothalamus compared to the OB + CD mice. However, the levels of TPH2 and 5-HT1A remained unchanged. ConclusionThe HFD model induced both obesity and anhedonia, but the dietary intervention successfully improved these conditions.

Modulation of hippocampal protein expression by a brain penetrant biologic TNF-α inhibitor in the 3xTg Alzheimer’s disease mice

BackgroundBiologic TNF-α inhibitors (bTNFIs) can block cerebral TNF-α in Alzheimer’s disease (AD) if these macromolecules can cross the blood–brain barrier (BBB). Thus, a model bTNFI, the extracellular domain of type II TNF-α receptor (TNFR), which can bind to and sequester TNF-α, was fused with a mouse transferrin receptor antibody (TfRMAb) to enable brain delivery via BBB TfR-mediated transcytosis. Previously, we found TfRMAb-TNFR to be protective in a mouse model of amyloidosis (APP/PS1) and tauopathy (PS19), and herein we investigated its effects in mice that combine both amyloidosis and tauopathy (3xTg-AD).MethodsEight-month-old female 3xTg-AD mice were injected intraperitoneally with saline (n = 11) or TfRMAb-TNFR (3 mg/kg; n = 11) three days per week for 12 weeks. Age-matched wild-type (WT) mice (n = 9) were treated similarly with saline. Brains were processed for immunostaining and high-resolution multiplex NanoString GeoMx spatial proteomics.ResultsWe observed regional differences in proteins relevant to Aβ, tau, and neuroinflammation in the hippocampus of 3xTg-AD mice compared with WT mice. From 64 target proteins studied using spatial proteomics, a comparison of the Aβ-plaque bearing vs. plaque-free regions in the 3xTg-AD mice yielded 39 differentially expressed proteins (DEP) largely related to neuroinflammation (39% of DEP) and Aβ and tau pathology combined (31% of DEP). Hippocampal spatial proteomics revealed that the majority of the proteins modulated by TfRMAb-TNFR in the 3xTg-AD mice were relevant to microglial function (⁓ 33%). TfRMAb-TNFR significantly reduced mature Aβ plaques and increased Aβ-associated microglia around larger Aβ deposits in the 3xTg-AD mice. Further, TfRMAb-TNFR increased mature Aβ plaque-associated microglial TREM2 in 3xTg-AD mice.ConclusionOverall, despite the low visual Aβ load in the 11-month-old female 3xTg-AD mice, our results highlight region-specific AD-relevant DEP in the hippocampus of these mice. Chronic TfRMAb-TNFR dosing modulated several DEP involved in AD pathology and showed a largely microglia-centric mechanism of action in the 3xTg-AD mice.

Exercise-Induced Reduction of IGF1R Sumoylation Attenuates Neuroinflammation in APP/PS1 Transgenic Mice

IntroductionAlzheimer's Disease (AD), a progressive neurodegenerative disorder, is marked by cognitive deterioration and heightened neuroinflammation. The influence of Insulin-like Growth Factor 1 Receptor (IGF1R) and its post-translational modifications, especially sumoylation, is crucial in understanding the progression of AD and exploring novel therapeutic avenues. ObjectivesThis study investigates the impact of exercise on the sumoylation of IGF1R and its role in ameliorating AD symptoms in APP/PS1 mice, with a specific focus on neuroinflammation and innovative therapeutic strategies. MethodsAPP/PS1 mice were subjected to a regimen of moderate-intensity exercise. The investigation encompassed assessments of cognitive functions, alterations in hippocampal protein expressions, neuroinflammatory markers, and the effects of exercise on IGF1R and SUMO1 nuclear translocation. Additionally, the study evaluated the efficacy of KPT-330, a nuclear export inhibitor, as an alternative to exercise. ResultsExercise notably enhanced cognitive functions in AD mice, possibly through modulations in hippocampal proteins, including Bcl-2 and BACE1. A decrease in neuroinflammatory markers such as IL-1β, IL-6, and TNF-α was observed, indicative of reduced neuroinflammation. Exercise modulated the nuclear translocation of SUMO1 and IGF1R in the hippocampus, thereby facilitating neuronal regeneration. Mutant IGF1R (MT IGF1R), lacking SUMO1 modification sites, showed reduced SUMOylation, leading to diminished expression of pro-inflammatory cytokines and apoptosis. KPT-330 impeded the formation of the IGF1R/RanBP2/SUMO1 complex, thereby limiting IGF1R nuclear translocation, inflammation, and neuronal apoptosis, while enhancing cognitive functions and neuron proliferation. ConclusionModerate-intensity exercise effectively mitigates AD symptoms in mice, primarily by diminishing neuroinflammation, through the reduction of IGF1R Sumoylation. KPT-330, as a potential alternative to physical exercise, enhances the neuroprotective role of IGF1R by inhibiting SUMOylation through targeting XPO1, presenting a promising therapeutic strategy for AD.

A single 24 h maternal separation at PND 9 promotes behavioral resilience of female C57BL/6J mice and the possible role of hippocampal Homer1a

Early life stress (ELS) has been thought to increase vulnerability to developing psychiatric disorders later in life, while some researchers have found that adversity early in life may promote stress resilience. Studies investigating the resilient effect of maternal separation (MS) are still relatively few, and the underlying mechanisms remain unknown. In the current study, the effect of a single 24 h MS paradigm at postnatal day 9 (PND 9) in female C57BL/6J mice was investigated by assessing behavioral performance in middle adolescence. We demonstrated that, mice in MS group displayed decreased anxiety-like behavior and increased exploratory behavior than controls in the open field test and elevated plus maze test. Furthermore, MS mice exhibited improved hippocampal-dependent spatial learning in the Morris water maze test. This performance indicated behavioral resilience to early life stress. The protein expression levels of Homer1 isoforms, which are implicated in a variety of neuropsychiatric disorders, were evaluated using Western blot analysis. A significant increase in hippocampal Homer1a protein expression was observed immediately after MS, which subsequently decreased until adolescence (PND 27–42), when a significant increase was observed again. This distinctive change of hippocampal Homer1a protein expression pattern indicated that hippocampal Homer1a might play a role in behavioral resilience to MS in female C57BL/6J mice. In conclusion, this study demonstrated that exposure to a single 24 h MS at PND 9 promoted behavioral resilience of female C57BL/6J mice in middle adolescence. This behavioral resilience might be related to increased expression of hippocampal Homer1a.

Artemisinin reduces PTSD-like symptoms, improves synaptic plasticity, and inhibits apoptosis in rats subjected to single prolonged stress.

Post-Traumatic Stress Disorder (PTSD) is a chronic mental disorder characterized by symptoms of panic and anxiety, depression, impaired cognitive functioning, and difficulty in social interactions. While the effect of the traditional Chinese medicine artemisinin (AR) on PTSD is unknown, its therapeutic benefits have been demonstrated by studies on models of multiple neurological disorders. This study aimed to extend such findings by investigating the effects of AR administration on a rat model of PTSD induced by a regimen of single prolonged stress (SPS). After rats were subjected to the SPS protocol, AR was administered and its impact on PTSD-like behaviors was evaluated. In the present study, rats were subjected to a multitude of behavioral tests to evaluate behaviors related to anxiety, memory function, and social interactions. The expression of hippocampal synaptic plasticity-related proteins was detected using Western blot and immunofluorescence. The ultrastructure of synapses was observed under transmission electron microscopy. The apoptosis of hippocampal neurons was examined with Western blot, TUNEL staining, and HE staining. The results showed that AR administration alleviated the PTSD-like phenotypes in SPS rats, including behavior indicative of anxiety, cognitive deficits, and diminished sociability. AR administration was further observed to improve synaptic plasticity and inhibit neuronal apoptosis in SPS rats. These findings suggest that administering AR after the onset of severe traumatic events may alleviate anxiety, cognitive deficits, and impaired social interaction, improve synaptic plasticity, and diminish neuronal apoptosis. Hence, the present study provides evidence for AR's potential as a multi-target agent in the treatment of PTSD.

Protective effect of functional food containing Dendrobium officinale via mediation of the FSHR/PI3K/AKT signaling pathway on menopausal syndrome in rats

Menopausal symptoms are age-related disorders related to the deficiency of estrogen that can be influenced by emotional and dietary habits. Guocaoyin superior-national-functional food (GSNF), a traditional Chinese medicine primarily containing Dendrobium officinale, offers notable benefits for mitigating metabolic disorders caused by unhealthy diet. Currently, there is limited research on the impact of GSNF on menopausal syndrome, and its underlying pharmacological mechanisms remain poorly understood. The aim of this study was to evaluate the ameliorative effect of GSNF on menopausal syndrome and to investigate its effect on endocrine metabolic disorders induced by ovarian failure. The findings demonstrate that GSNF raised levels of serum estradiol (E2), anti-mullerian hormone (AMH), and inhibin B (INHB), reduced levels of serum gonadotropin-releasing hormone (GnRH) and follicle-stimulating hormone (FSH), and ameliorated ovarian pathological damage in rats experiencing menopausal syndrome. It was discovered that GSNF enhanced ovarian FSHR and ERα protein expression, stimulated follicular development by activating the PI3K/AKT pathway, and hindered ovarian follicular apoptosis while improving ovarian function through the regulation of apoptosis-related proteins Bcl-2, BAX, and Caspase-3 expression. Furthermore, GSNF augmented the expression of hippocampal FSHR protein and upregulated the expression of hippocampal PI3K and AKT proteins. Additionally, it reduced serum corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels, facilitated the release of 5-hydroxytryptamine (5-HT), dopamine (DA), and norepinephrine (NE), and boosted hippocampal tissue neuron count, thereby ameliorating depression-like symptoms during menopause. Moreover, GSNF supplementation improved glucose-lipid metabolism disorders and mitigated hepatic steatosis in model rats. Overall, our research revealed a new function for GSNF in mitigating the adverse impact of negative emotion and unhealthy dietary habits on menopausal symptoms. These findings indicate that GSNF may be a viable option for treating menopausal syndrome.

Hippocampal subregion‐specific proteomic differences between Alzheimer disease (AD) and primary age‐related tauopathy (PART)

AbstractBackgroundAlthough Alzheimer disease (AD) and primary age‐related tauopathy (PART) both harbor 3R/4R‐tau immunopositive Alzheimer‐type neurofibrillary degeneration, they differ in the spatial development of neurofibrillary tangles (NFTs) in the hippocampus. PART displays an early predilection for neurofibrillary degeneration in the CA2 subregion of the hippocampus, whereas AD typically develops NFTs in the entorhinal cortex and CA1 subregion initially (Figures 1‐2).MethodUsing Nanostring’s GeoMx™ Digital Spatial Profiling (DSP), we compared hippocampal subregion protein expression differences between AD and PART. The DSP panel allows for spatial analysis of the level of expression of 73 different proteins in multiple regions of interest (ROIs) on formalin‐fixed paraffin embedded sections. Our ROIs were NFT‐bearing neurons and non‐NFT‐bearing neurons in the entorhinal cortex, CA1 and CA2 hippocampal subregions, as well as the neuronal microenvironments in these regions.ResultAnalyses identified several proteins displaying differential expression in tangle‐bearing neurons when comparing AD to PART. These included higher levels of synaptic and neuronal markers in PART, such as Synaptophysin, MAP2, Calbindin and NRGN, as well as higher levels of proteins involved in degradation pathways, such as CTSD, GPNMB, Park7 and FUS. PART also displayed higher levels of Neprilysin in CA2, and higher IDE in CA1, which are proteins that help degrade β‐amyloid (Figure 3). Many of these proteins were also differentially expressed in the non‐tangle bearing neurons. In addition, AD demonstrated higher levels of p‐tau T231, S214, S199, and S396 in non‐tangle bearing neurons of CA1, as well as higher expression of Aβ1‐40. In the microenvironment, NEFL, NRGN, CLEC7a, GPNMB, and CTSD were higher in PART, while p‐tau S396 and BACE1 were higher in AD.ConclusionIn conclusion, PART cases displayed higher levels of neuronal and synaptic markers, suggesting better maintenance of neuronal and synaptic integrity than AD, as well as higher levels of proteins important for degradation of detrimental proteins. AD cases expressed higher levels of certain p‐tau epitopes, especially in and around CA1 non‐tangle bearing neurons. In addition, AD displayed higher levels of BACE1, whereas PART displayed higher levels of CTSD, Neprilysin and IDE, which could explain the differences in β‐amyloid deposition in these cases.

Modulation of hippocampal protein expression by a brain penetrant biologic TNF‐α inhibitor in the 3xTg Alzheimer’s disease mice

AbstractBackgroundAlzheimer’s disease (AD) is a chronic neuroinflammatory condition and the proinflammatory cytokine, tumor necrosis factor alpha (TNF‐α), is a key mediator of neuroinflammation in AD. Biologic TNF‐α inhibitors (bTNFIs) can block cerebral TNF‐α if these large molecules cross the blood‐brain barrier (BBB). Thus, a model bTNFI, the extracellular domain of type II TNF‐α receptor (TNFR) which can bind to and sequester TNF‐α, has been reengineered to enable brain delivery by fusion with a mouse transferrin receptor antibody (TfRMAb). TfRMAb binds to the BBB TfR to deliver the TNFR into the brain via receptor‐mediated transcytosis. Previously, we found the TfRMAb‐TNFR to be protective in a mouse model of amyloidosis (APP/PS1) and tauopathy (PS19), and the aim of the current study was to investigate its effects in a mouse model that combines both amyloidosis and tauopathy (3xTg‐AD mice).MethodEight‐month‐old female triple transgenic 3xTg‐AD mice were injected intraperitoneally with saline (n = 11) or TfRMAb‐TNFR (3 mg/kg; n = 11) three days per week for 12 weeks. At the end of treatment, brains were processed for hippocampal immunohistochemistry and high‐resolution multiplex NanoString spatial proteomics using the GeoMx protein assays for neuroscience.ResultTfRMAb‐TNFR treatment significantly reduced mature β‐sheet rich Aβ plaques and increased plaque‐associated microglial localization around larger plaques in the 3xTg mice. Further, TfRMAb‐TNFR increased plaque‐associated microglial TREM2 compared with saline‐treated 3xTg mice. From a total of 64 target proteins studied using spatial proteomics (comparing protein expression in the Aβ‐plaque bearing vs. plaque‐free regions), 39 (61%) differentially expressed proteins (DEP) were identified in the 11‐month‐old 3xTg mice, comprising of proteins related to neurodegeneration (10% of DEP), neuroinflammation (41% of DEP), amyloid (21% of DEP) and tau (10% of DEP) pathology, autophagy (10% of DEP) and other pathways (8% of DEP). TfRMAb‐TNFR treatment modulated proteins involved in Aβ clearance and processing, microglial function, RNA processing, and neurodegeneration. Majority of these proteins were relevant to microglial function (∼ 40%).ConclusionThe study highlights that TfRMAb‐TNFR modulates several proteins involved in AD pathology and progression and largely suggests a microglia‐centric mechanism of action of this treatment in the 3xTg mice.

Anti-epileptic and Neuroprotective Effects of Ultra-low Dose NADPH Oxidase Inhibitor Dextromethorphan on Kainic Acid-induced Chronic Temporal Lobe Epilepsy in Rats.

Neuroinflammation mediated by microglia and oxidative stress play pivotal roles in the development of chronic temporal lobe epilepsy (TLE). We postulated that kainic acid (KA)-Induced status epilepticus triggers microglia-dependent inflammation, leading to neuronal damage, a lowered seizure threshold, and the emergence of spontaneous recurrent seizures (SRS). Extensive evidence from our laboratory suggests that dextromethorphan (DM), even in ultra-low doses, has anti-inflammatory and neuroprotective effects in many animal models of neurodegenerative disease. Our results showed that administration of DM (10 ng/kg per day; subcutaneously via osmotic minipump for 4 weeks) significantly mitigated the residual effects of KA, including the frequency of SRS and seizure susceptibility. In addition, DM-treated rats showed improved cognitive function and reduced hippocampal neuronal loss. We found suppressed microglial activation-mediated neuroinflammation and decreased expression of hippocampal gp91phox and p47phox proteins in KA-induced chronic TLE rats. Notably, even after discontinuation of DM treatment, ultra-low doses of DM continued to confer long-term anti-seizure and neuroprotective effects, which were attributed to the inhibition of microglial NADPH oxidase 2 as revealed by mechanistic studies.

Differential expression of Hdac2 in male and female mice of differing social status

Mice naturally form social hierarchies, and their experiences as subordinate or dominant mice inform future behavioural strategies. To better understand the neural bases of social dominance, we investigated hippocampal gene and protein expression of histone deacetylase 2 (HDAC2), an epigenetic regulator that decreases expression of synaptic plasticity genes and reduces excitatory synaptic function. Hdac2 in hippocampus was associated with social status. The gene for a closely related histone deacetylase (Hdac1), and HDAC2 protein expression, were not associated with social rank in hippocampus. These findings suggest that Hdac2 expression in hippocampus is distinctly linked with social status.

Manganese-enhanced magnetic resonance assessment of changes in hippocampal neural function after the treatment of radiation-induced brain injury with bone marrow mesenchymal stem cells

The role of bone marrow mesenchymal stem cells (BMSCs) in treating radiation-induced brain injury (RIBI) is not completely understood, and assessment methods to directly characterize neurological function are lacking. In this study, we aimed to evaluate the effects of BMSCs treatment on changes in hippocampal neural function in Sprague–Dawley(SD) rats with RIBI, and to evaluate the therapeutic effect of BMSCs by manganese-enhanced magnetic resonance imaging (MEMRI). First, we assessed cognitive function after RIBI treatment with BMSCs using the Morris water maze. Next, we used MEMRI at two time points to observe the treatment effect and explore the correlation between MEMRI and cognitive function. Finally, we evaluated the expression of specific hippocampal neurofunctional proteins, the ultrastructure of hippocampal nerves, and the histological changes in the hippocampus. After BMSCs treatment of RIBI, cognitive dysfunction improved significantly, the expression of hippocampal neurofunctional proteins was increased, the integrity of the hippocampal neural structure was protected, and nerve cell survival was enhanced. The improvement in neurological function was successfully detected by MEMRI, and MEMRI was highly correlated with cognitive function and histological changes. These results suggest that BMSCs treatment of RIBI is an optional modality, and MEMRI can be used for treatment evaluation.

Pioglitazone ameliorates DOX-induced cognitive impairment by mitigating inflammation, oxidative stress, and apoptosis of hippocampal neurons in rats

Doxorubicin (DOX) is broadly used as a medication for cancer treatment. However, DOX has been connected with chemotherapy-related complications, for instance, cognitive impairment (chemobrain). Chemobrain developed in up to 70% of cancer patients; therapeutic is unavailable. This study investigated the preventive effect of pioglitazone (PIO) on neurotoxicity caused by (DOX) in the hippocampus. Forty rats were separated into four groups; control (normal saline 10 ml/kg), DOX (5 mg/kg, intraperitoneally every 3rd day, equivalent to 20 mg/kg cumulative dose), PIO (2 mg/kg in drinking water), and DOX+PIO (DOX, 5 mg/kg, intraperitoneally every 3rd day concurrently PIO, 2 mg/kg in drinking water) and duration of drug treatment lasted for 14 days. The animals were subjected to contextual fear memory tests to characterize the cognitive impairment following DOX treatment. ELISA assessed hippocampal protein expression related to inflammation, oxidative damage, and apoptosis. DOX-treatment produced significant reduction in freezing duration in contextual fear memory tests, which was reversed by PIO co-administration. DOX increased neuroinflammation, oxidative stress, apoptosis, and mitochondrial activity by increasing NF-κB and COX-2 levels, reducing SOD levels, and increasing Bax, caspase-3, and lipid peroxidation. However, DOX did not affect GSH or catalase levels. PIO co-administration reduces NF-κB, COX-2, MDA, Bax, and caspase-3 levels and improves mitochondrial activity and SOD expression. To sum up, DOX therapy accelerates cognitive decline in rats by increasing neuroinflammation, oxidative stress, mitochondrial dysfunction, lipid peroxidation, and apoptosis. PIO is a promising treatment for DOX-induced cognitive impairment.

Long-term exercise training inhibits inflammation by suppressing hippocampal NLRP3 in APP/PS1 mice

Behavioral experiments have demonstrated that long-term physical exercise can be beneficial for learning and memory dysfunction caused by neuroinflammation in Alzheimer's disease (AD). However, the molecular mechanism remains poorly understood due to a lack of sufficient pertinent biochemical evidence. We investigated the potential effect of long-term physical exercise on cognition and hippocampal gene and protein expression changes in a transgenic AD mouse model. Following twenty weeks of treadmill exercise, transgenic AD mice showed improvement in cognitive functions and downregulation of Nod-like receptor protein 3 (NLRP3) (p ​< ​0.01), interleukin-1beta (IL-1β) (p ​< ​0.05), and amyloid-β1-42 (Aβ1-42) (p ​< ​0.05) expression levels. In addition, we observed significant reductions of microglial activation and hippocampal neuronal damage in the exercised AD mice (p ​< ​0.01), which might be a result of the downregulation of NLRP3-mediated signaling and neuro-inflammatory responses. As neuronal damage due to inflammation might be a likely cause of AD-associated cognitive dysfunction. Our results suggested that the anti-inflammatory effects of exercise training involved downregulating the expression of key inflammatory factors and might play an important role in protecting hippocampal neurons against damage during the course of AD.

The Involvement of PGRMC1 Signaling in Cognitive Impairment Induced by Long-Term Clozapine Treatment in Rats

Introduction: Progesterone receptor component 1 (PGRMC1) has been identified as a potential target in atypical antipsychotic drug-induced metabolic disturbances as well as neuroprotection in the central nervous system. In our study, we aimed to figure out the essential role of PGRMC1 signaling pathway underlying clozapine-induced cognitive impairment. Methods: In male SD rats, we utilized recombinant adeno-associated viruses (BBB 2.0) and the specific inhibitor of PGRMC1 (AG205) to regulate the expression of PGRMC1 in the brain, with a special focus on the hippocampus. Treatments of clozapine and AG205 were conducted for 28 days, and subsequent behavioral tests including modified elevated plus maze and Morris water maze were conducted to evaluate the cognitive performance. Hippocampal protein expressions were measured by Western blotting. Results: Our study showed that long-term clozapine administration led to cognitive impairment as confirmed by behavioral tests as well as histopathological examination in the hippocampus. Clozapine inhibited neural survival through the PGRMC1/EGFR/GLP1R-PI3K-Akt signaling pathway, leading to a decrease in the downstream survival factor, brain-derived neurotrophic factor (BDNF), and simultaneously promoted neural apoptosis in the rat hippocampus. Intriguingly, by targeting at the hippocampal PGRMC1, we found that inhibiting PGRMC1 mimics, while its upregulation notably mitigates clozapine-induced cognitive impairment through PGRMC1 and its downstream signaling pathways. Conclusion: PGRMC1-overexpression could protect hippocampus-dependent cognitive impairment induced by clozapine. This effect appears to arise, in part, from the upregulated expression of PGRMC1/EGFR/GLP1R and the activation of downstream PI3K-Akt-BDNF and caspase-3 signaling pathways.

The needle in the haystack: Identifying and validating common genes of depression, insomnia, and inflammation

BackgroundInsomnia, inflammation, and depression are often co-occurring conditions. The mechanisms underlying these conditions remain unclear. Materials and methodsWe collected microarray datasets of depression and insomnia from GEO and analyzed them for differentially expressed genes (DEGs). We then overlapped the DEGs with a list of inflammatory response-related genes to identify genes associated with all three conditions. We next performed analyses of enrichment analyses, KEGG mapping, and protein-protein interaction to identify hub genes. Furthermore, we established a depression rat model with inflammation and insomnia to validate the potential genes. At last, a two-sample Mendelian randomization (MR) study was conducted to confirm the association of identified target genes with depression outcomes. ResultsWe obtained 32 common DEGs associated with the depression, insomnia and inflammatory, and found that the PI3K-AKT signaling pathway might be involved in the inflammatory response in insomnia and depression. CREB1, CYBB, FYN, and CCR5 were identified as targets for the next validation. In model rats, the CCR5 and PI3K-AKT pathways were significantly up-regulated, while the model group exhibited significantly lower hippocampal p-CREB protein expression. The MR study suggested a potential causal relationship between CREB1 and the risk of depression (OR = 1.11, p = 0.013). LimitationsThe identified potential genes and pathways require further laboratory and clinical evidence verification. ConclusionWe identified four potential inflammatory related-genes (CREB1, CYBB, FYN, and CCR5). CREB1 may be a potential inflammatory response-related biomarker and drug target for depression and insomnia, as validated by the followed rat model and MR study.