Changes In Mouse Brain Research Articles

Sphingolipid changes in mouse brain and plasma after mild traumatic brain injury at the acute phases

BackgroundTraumatic brain injury (TBI) causes neuroinflammation and can lead to long-term neurological dysfunction, even in cases of mild TBI (mTBI). Despite the substantial burden of this disease, the management of TBI is precluded by an incomplete understanding of its cellular mechanisms. Sphingolipids (SPL) and their metabolites have emerged as key orchestrators of biological processes related to tissue injury, neuroinflammation, and inflammation resolution. No study so far has investigated comprehensive sphingolipid profile changes immediately following TBI in animal models or human cases. In this study, sphingolipid metabolite composition was examined during the acute phases in brain tissue and plasma of mice following mTBI.MethodsWildtype mice were exposed to air-blast-mediated mTBI, with blast exposure set at 50-psi on the left cranium and 0-psi designated as Sham. Sphingolipid profile was analyzed in brain tissue and plasma during the acute phases of 1, 3, and 7 days post-TBI via liquid-chromatography-mass spectrometry. Simultaneously, gene expression of sphingolipid metabolic markers within brain tissue was analyzed using quantitative reverse transcription-polymerase chain reaction. Significance (P-values) was determined by non-parametric t-test (Mann–Whitney test) and by Tukey’s correction for multiple comparisons.ResultsIn post-TBI brain tissue, there was a significant elevation of 1) acid sphingomyelinase (aSMase) at 1- and 3-days, 2) neutral sphingomyelinase (nSMase) at 7-days, 3) ceramide-1-phosphate levels at 1 day, and 4) monohexosylceramide (MHC) and sphingosine at 7-days. Among individual species, the study found an increase in C18:0 and a decrease in C24:1 ceramides (Cer) at 1 day; an increase in C20:0 MHC at 3 days; decrease in MHC C18:0 and increase in MHC C24:1, sphingomyelins (SM) C18:0, and C24:0 at 7 days. Moreover, many sphingolipid metabolic genes were elevated at 1 day, followed by a reduction at 3 days and an absence at 7-days post-TBI. In post-TBI plasma, there was 1) a significant reduction in Cer and MHC C22:0, and an increase in MHC C16:0 at 1 day; 2) a very significant increase in long-chain Cer C24:1 accompanied by significant decreases in Cer C24:0 and C22:0 in MHC and SM at 3 days; and 3) a significant increase of C22:0 in all classes of SPL (Cer, MHC and SM) as well as a decrease in Cer C24:1, MHC C24:1 and MHC C24:0 at 7 days.ConclusionsAlterations in sphingolipid metabolite composition, particularly sphingomyelinases and short-chain ceramides, may contribute to the induction and regulation of neuroinflammatory events in the early stages of TBI, suggesting potential targets for novel diagnostic, prognostic, and therapeutic strategies in the future.

Mir125b-1 is not imprinted in human brain and shows developmental expression changes in mouse brain.

Genomic imprinting is a predominantly brain and placenta-specific epigenetic process that contributes to parent-of-origin-specific gene expression. While microRNAs are highly expressed in the brain, their imprinting status in this tissue remains poorly studied. Previous research demonstrated that Mir125b-2 is imprinted in the human brain and regulates hippocampal circuits and functions in mice. However, the imprinting status of another isoform of miR125b, Mir125b-1, in the human brain, as well as its spatiotemporal expression patterns in mice, have not been elucidated. Here, we show MIR125B1 is not imprinted in the human brain. Moreover, miR-125b-1 was highly expressed in the brains of mice. Furthermore, miR-125b-1 was down-regulated during brain development in mice. Specifically, miR-125b-1 displayed preferential expression in the olfactory bulb, thalamus, and hypothalamus of the mouse brain. Notably, miR-125b-1 was enriched in GABAergic neurons, particularly somatostatin-expressing GABAergic neurons, compared with glutamatergic neurons. Taken together, our findings provide the imprinting status and comprehensive spatiotemporal expression profiling of Mir125b-1 in the brain.

Characterization of Radiographic and Molecular Changes in Mouse Brain after FLASH Irradiation

Despite refinements in treatment platforms such as incorporation of high-resolution imaging and real time motion tracking, the amount of radiation dose delivered safely to a particular tissue type is limited by both tissue intrinsic and extrinsic factors. FLASH radiotherapy (RT), delivery of relatively high radiation dose at dose rates several orders of magnitude higher than that of conventional (CONV) dose-rates, may change that paradigm due to normal tissue sparing characteristics of FLASH RT. Our Radiation Oncology Physics division developed a novel FLASH kV x-ray cabinet system for preclinical laboratory research. Here we utilize this technology to establish optimal radiation parameters for FLASH effect in brain tissue of a murine model. A range of total radiation dose and dose rates that are considered to be within the window for FLASH effect are being investigated. We have identified several measurable and clinically meaningful toxicity outcomes, including radiation necrosis and blood brain barrier integrity, to assess FLASH effects in brain tissue. A high-capacity rotating anode x-ray tube was implemented for FLASH irradiation, operating at 150 kVp with 0.025 mm Cu added filtration. A custom 3D printed immobilization tool was designed to reproducibly position animals for stereotactic irradiation of the brain. Dose and dose rate measurements were performed with calibrated radiographic film in kV solid water. Conventional dose rate irradiations were delivered using a standard laboratory irradiator (SARRP) operating at the same kVp and filtration. The depth-dose gradients in solid water were compared between the irradiators. Healthy 8-week-old C57BL6J mice were then irradiated with graded doses of FLASH and CONV x-rays (10- 60 Gy) using a single 1-cm wide AP field. Dose was prescribed to the center of the brain, at a depth of 3.25 mm. RT-induced necrosis is being monitored by serial biweekly MR imaging using a 7-T preclinical MRI machine. Histopathological changes will be assessed through H&E staining of harvested brain at 3-months post-irradiation (n = 5 per arm). FITC-Dextran infusion will be performed prior to necropsy to assess blood-brain barrier integrity. Animal setup for stereotactic FLASH brain irradiation was reproducible to within 0.5mm. Measured dose rates were 75.6 Gy/s for FLASH and 3.8 Gy/min for conventional irradiations. At 5-mm depth in solid water, the PDDs agreed to within 4% between SARRP and FLASH Irradiator. Biweekly T1 post and T2 weighted image acquisition is currently underway. Histology and FITC-Dextran data will be presented when available. We have successfully designed a high-precision platform to study x-ray FLASH effects in mice brain model. Evaluation of dose window for brain FLASH effect and molecular mechanisms of this phenomenon is an important step in the potential translation of FLASH RT for brain irradiation.

Ketamine triggers rapid antidepressant effects by modulating synaptic plasticity in a new depressive-like mouse model based on astrocyte glutamate transporter GLT-1 knockdown in infralimbic cortex

ObjectiveRecently, we reported on a new MDD-like mouse model based on a regionally selective knockdown of astroglial glutamate transporters, GLAST/GLT-1, in infralimbic cortex (IL) which evokes widespread changes in mouse brain associated with the typical alterations found in MDD patients. To further characterize this new MDD-like mouse model, here we examine some transcriptional elements of glutamatergic/GABAergic neurotransmission and neuroplasticity in forebrain regions in the GLT-1 knockdown mice. Furthermore, we assess the acute ketamine effects on these transcriptional processes. Material and methodsWe used a small interfering RNA (siRNA) pool targeting GLT-1 mRNA to disrupt the GLT-1 transcription in mouse IL. Histological assays were performed to examine postsynaptic density protein-95 (PSD95), neuritin (NRN), glutamine acid descarboxilase-65 (GAD65), and GLT-1 mRNA expression in IL and hippocampus. ResultsKnockdown of GLT-1 in mouse IL leads to decreased expression of PSD95 and NRN neuroplasticity mRNAs in IL and hippocampus, which was reversed by an acute dose of ketamine antidepressant. Likewise, a single dose of ketamine also increased the mRNA levels of GAD65 and GLT-1 in IL of GLT-1 knockdown mice, reaching the basal values of control mice. ConclusionsThe glutamatergic neuronal hyperactivity and deficits in the GABA system resulting from siRNA-induced astroglial glutamate transporter knockdown in IL can compromise the integrity/plasticity of neurocircuits affected in MDD. Suitable depressive-like animal models to address the neurobiological changes in MDD are an unmet need and the development of the GLAST/GLT-1 knockdown mouse model may represent a better option to understand the rapid-acting antidepressant effects of ketamine.

Effect of Dietary Grapes on Female C57BL6/J Mice Consuming a High-Fat Diet: Behavioral and Genetic Changes

(1) Background: Adverse effects of a chronic high-fat diet (HFD) on murine behavior, cognition, and memory are well established. Polyphenols such as resveratrol, anthocyanins, and flavonoids, that are known for antioxidative and anti-inflammatory properties, are present in grapes. The objective of this work was to determine if the dietary intake of grapes has the potential of alleviating HFD-induced deficiencies. (2) Methods: The effect of dietary grape intake was studied using behavioral assays and high throughput genome-wide RNA transcriptome analyses with female C57BL6/J mice. (3) Results: Mice that were fed a HFD from 3-weeks of age showed anxiety-like behaviors compared with the standard diet (STD). This HFD-induced effect was attenuated by supplementing the HFD with 1% grape powder (HF1G) (open field test). Similar results were observed with the novel object recognition test; there was a significant difference in time spent exploring a novel object between the HFD and the HF1G groups. There was no significant difference between the HFD1G and the STD groups. Based on the RNA-Seq analysis, genetic expression in the brain varied as a result of diet, with 210, 360, and 221 uniquely expressed genes in the STD, HFD, and HF1G groups, respectively. Cluster analysis revealed that the HFIG group mapped more closely with the STD group than the HFD group. Focusing on some specific areas, based on genetic expression, Dopamine receptor 2 (Drd2) was increased in the HFD group and normalized in the HF1G group, relative to the STD group. In addition, as judged by cluster hierarchy, the expression of genes that are associated with the dopamine receptor 2 pathway were increased in the HFD group, whereas the pattern that was derived from mouse brain from the HF1G group showed greater similarity to the STD group. KEGG pathway analyses were consistent with these results. For example, neuroactive ligand-receptor interaction (KEGG ID: mmu04080) was altered due to HFD compared with STD, but normalized by grape supplementation or the HFD; there was no significant difference between the STD and HF1G groups. In addition, the expression of genes related to feeding behavior, such as Adora2a, Th, and Trh, were also increased in the HFD group compared with the STD group, and attenuated by grape supplementation. (4) Conclusions: Dietary grape consumption has positive effects on behavior and cognition that are impaired by a HFD. Attenuation of these effects correlates with global transcriptional changes in mouse brain.

The effects of antimony on Alzheimer's disease-like pathological changes in mice brain

We have previously identified antimony (Sb) as a newly nerve poison which leads to neuronal apoptosis. However, the relationship between Sb exposure and Alzheimer's disease (AD) process lacks direct evidence. HE staining and Nissl staining showed significant nerve damage after Sb exposure. Therefore, we further evaluated Sb-associated AD risk by detecting accumulation of β-amyloid protein (Aβ) and neurofibrillary tangles (NFTs) in the brains of mice exposed to Sb for 4 and 8 weeks, and even 1 year. The results showed that dose of 20 mg/kg induced Aβ accumulation, but not tau hyperphosphorylation after exposure for 4 week. Eight weeks later, both 10 and 20 mg/kg dramatically triggered Aβ accumulation and increased tau phosphorylation at ser199. At the same time, 20 mg/kg could also increase tau phosphorylation at ser396 and number of NFTs. One years later, we found all of AD hallmarks detected in present study showed positive results in the brains of mice exposed to Sb at 10 and 20 mg/kg. In summary, our data provided direct evidence of Sb-associated AD risk, drawing more attention to Sb-triggered neurotoxicity.

Characterization of small metabolites alteration in mice brain tissues after infected by rabies virus.

Rabies, caused by rabies virus (RABV), is still one of the deadliest infectious diseases. Host metabolomic changes against RABV infection has not yet been fully understood. We performed untargeted metabolomics to discover the metabolites associated with RABV infection. The brain tissues from 20 RABV infected mice and 10 mock infected mice were used for this method. A total of 1352 differential metabolites were identified after the first-run screen, and the number reduced to 75 after second-run screen. Multivariate analysis using PLS-DA and OPLS-DA clearly discriminated the RABV infected samples from controls. Pathways enrichment analysis revealed that most differential metabolites were associated with metabolism of nucleotide and amino acid, and aminoacyl - tRNA biosynthesis and purine metabolism were the most active pathways. The findings presented in our study would promote the understanding of metabolomics changes in brains of mice after RABV infection as well as a new perspective to study the relationship between RABV and host.

Dietary phytochemicals modulate experience-dependent changes in Neurexin gene expression and alternative splicing in mice after chronic variable stress exposure

Neurexins (NRXNs) are cell-adhesion molecules important in the formation and remodeling of neural circuits. It has been shown that aversive environmental stimuli can affect the expression pattern of Neurexin genes (Nrxns) impacting the regulation of synaptic strength. Accumulated evidence suggests that, after chronic exposure to psychological stress, the triggered changes in gene expression and splicing patterns of Nrxns may be involved in aversive conditioning. Previously, we have demonstrated that a novel treatment using dietary phytochemicals can modulate the response to chronic variable stress (CVS) in mice. Here, we aimed to further investigate the long-term plasticity changes after CVS by focusing on the regulation of NRXNs at synapses. We found that CVS differentially triggers the region-specific gene expression of Nrxns in mice Nucleus Accumbens (NAc) and Hippocampus (HIPP). The prophylactic treatment with the combination of two phytochemicals dihydrocaffeic acid (DHCA) and Malvidin-3-O-glucoside (Mal-gluc) differentially modulated the stress-induced effects on Nrxn1 and 3 mRNA expression in these brain areas and promoted the alternative splicing of Nrxn3 in HIPP.Overall, our data supports the prophylactic effect of dietary phytochemicals in the restoration of stress-induced plasticity changes in mouse brain. By intervening in activity-dependent plasticity at synapses, these compounds may attenuate the effects of chronic aversive conditioning. We propose that an early therapeutic intervention may help with disorders of negative affect, such as depression or post-traumatic stress disorder. Our future studies will address how DHCA/Mal-gluc might serve as a potential complement for current therapies in depression and other mood disorders.

Brain response after treatment of Trypanosoma evansi-infected mice with Indigofera oblongifolia

Trypanosomiasis is one of the most important diseases affecting economic development for humans and livestock. The current research aimed to assess the in vitro antitrypanosomal effect of methanol extracts of Indigofera oblongifolia leaf (IME) and to examine the brain response after IME treatment of infected mice. In the in vitro method, IME (1.25 mg/ml) was able to kill all parasites after 30 min of exposure. The percentage of the parasite inhibition reached 100% after 180 min of the IME application. Swiss albino mice were infected with 103Trypanosoma evansi then were daily treated with 100 mg/Kg IME for four days. IME was able to significantly decrease the number of trypanosomes in mice blood. In addition, IME improved the histopathological changes in mice brain induced by the infection. Furthermore, following treatment with IME, the level of epinephrine and nitric oxide in the mice brain homogenate decreased significantly. Taken together, I. Oblongifolia has antitrypanosomal activity and might enhance the brain response to T. evansi.

Neuroprotective effect of the essential oil of Lavandula officinalis against hydrogen peroxide-induced toxicity in mice

Background: Brain is the main organ that manages all other organs and has significant oxygen requirements, which makes it vulnerable to reactive oxygen species, thus causing different neurological disorders. The aim of this work is the evaluation of Lavandula officinalis essential oil neuroprotective effect against hydrogen peroxide (HP)-induced toxicity in mice. Materials and Methods: Essential oil was extracted by hydrodistillation using a Clevenger-type apparatus. Essential oil analysis is performed using gas chromatography-mass spectrometry (GC-MS). Biological activity evaluation carried out the ferric reducing antioxidant power test, deoxyribonucleic acid (DNA) fragmentation assay, the histopathological study of the brain, and determination of antioxidant enzyme activities. Results: Chemical characterization of essential oil using GC-MS identified 47 compounds, accounting for almost 80% of the total oil and indicates the occurrence of monoterpenes and sesquiterpenes. The identified major compounds are pentanone (16.55%), propanal (15.89%), methyl ethyl ketone (13.51%), naphthalene (10.81%), terpinen-4-ol (6.55%), cyclopentanecarboxylic acid (4.77%), and isoborneol (2.27%). This study allowed us to investigate the effects of HP on brain function in Mus musculus adult mice by assessing DNA degradation, cell morphology, oxidative balance and brain weight variation. Furthermore, we have highlighted the beneficial effects of L. officinalis essential oil, which could significantly counteract all these alterations by its active compounds, which are endowed with potent biological activities. Conclusion: We can conclude that HP-induced damage in histomorphological changes in mice brain, significant atrophy, as well as an important alteration of the genetic expression.

Dynamic c‐Fos changes in mouse brain during acute and protracted withdrawal from chronic intermittent ethanol exposure and relapse drinking

Alcohol dependence promotes neuroadaptations in numerous brain areas, leading to escalated drinking and enhanced relapse vulnerability. We previously developed a mouse model of ethanol dependence and relapse drinking in which repeated cycles of chronic intermittent ethanol (CIE) vapor exposure drive a significant escalation of voluntary ethanol drinking. In the current study, we used this model to evaluate changes in neuronal activity (as indexed by c‐Fos expression) throughout acute and protracted withdrawal from CIE (combined with or without a history of ethanol drinking). We analyzed c‐Fos protein expression in 29 brain regions in mice sacrificed 2, 10, 26, and 74 hours or 7 days after withdrawal from 5 cycles of CIE. Results revealed dynamic time‐ and brain region‐dependent changes in c‐Fos activity over the time course of withdrawal from CIE exposure, as compared with nondependent air‐exposed control mice, beginning with markedly low expression levels upon removal from the ethanol vapor chambers (2 hours), reflecting intoxication. c‐Fos expression was enhanced during acute CIE withdrawal (10 and 26 hours), followed by widespread reductions at the beginning of protracted withdrawal (74 hours) in several brain areas. Persistent reductions in c‐Fos expression were observed during prolonged withdrawal (7 days) in prelimbic cortex, nucleus accumbens shell, dorsomedial striatum, paraventricular nucleus of thalamus, and ventral subiculum. A history of ethanol drinking altered acute CIE withdrawal effects and caused widespread reductions in c‐Fos that persisted during extended abstinence even without CIE exposure. These data indicate that ethanol dependence and relapse drinking drive long‐lasting neuroadaptations in several brain regions.

Anesthesia and Preconditioning Induced Changes in Mouse Brain [18F] FDG Uptake and Kinetics.

2-Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) has been widely used for imaging brain metabolism. Tracer injection in anesthetized animals is a prerequisite for performing dynamic positron emission tomography (PET) scanning. Since preconditioning, as well as anesthesia, has been described to potentially influence brain [18F] FDG levels, this study evaluated how these variables globally and regionally affect both [18F] FDG uptake and kinetics in murine brain. Sixty-minute dynamic [18F] FDG PET scans were performed in adult male C57BL/6 mice anesthetized with isoflurane [control (in 100% O2), in medical air, in 100% O2 + insulin pre-treatment, and in 100% O2 after 18h fasting], ketamine/xylazine, sevoflurane, and chloral hydrate. An additional group was scanned after awake uptake. Blood glucose levels were determined, and data was analyzed by comparing percent injected dose per cc tissue (%ID/cc) and glucose influx rate and metabolic rate (MRGlu) calculated by Patlak plot. Ketamine/xylazine and chloral hydrate anesthesia induced a lower whole-brain uptake of [18F] FDG (2.86 ± 0.67%ID/cc, p < 0.001; 4.25 ± 0.28%ID/cc, p = 0.0179, respectively) compared to isoflurane anesthesia (5.04 ± 0.19%ID/cc). In addition, protocols affected differently distribution of [18F] FDG uptake in brain regions. Ketamine/xylazine reduced [18F] FDG influx rate in murine brain (0.0135 ± 0.0009 vs 0.0247 ± 0.0014ml/g/min; p < 0.005) and chloral hydrate increased MRGlu (66.72 ± 3.75 vs 41.55 ± 3.06μmol/min/100ml; p < 0.01) compared to isoflurane. Insulin-pretreated animals showed a higher influx rate (0.0477 ± 0.0101ml/min/g; p < 0.05) but a reduced MRGlu (21.92 ± 3.12μmol/min/100ml; p < 0.01). Blood glucose levels were negatively correlated to [18F] FDG uptake and influx rate, but positively correlated to MRGlu. Choice of anesthesia and pre-conditioning affect not only [18F] FDG uptake but also kinetics and regional distribution in the mouse brain. Both anesthesia and pre-conditioning should be carefully considered in the interpretation of [18F] FDG studies due to its great influence on the uptake and distribution of the tracer along the brain regions.

Longitudinal FDG-PET scan study of brain changes in mice with cancer-induced bone pain and after morphine analgesia.

Morphine is the most commonly used drug for treating physical and psychological suffering caused by advanced cancer. Although morphine is known to elicit multiple supraspinal analgesic effects, its behavioral correlates with respect to the whole-brain metabolic activity during cancer-induced bone pain have not been elucidated. We injected 4T1 mouse breast cancer cells into the left femur bone marrow cavity of BALB/c mice. All mice developed limb use deficits, mechanical allodynia, and hypersensitivity to cold, which were effectively suppressed with morphine. Serial 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) was performed for each mouse before cancer induction (0 day), after cancer-induced bone pain was established (14 days), and during effective morphine treatment (16 days). The longitudinal FDG-PET imaging analysis demonstrated that cancer-induced bone pain increased glucose uptake in the insular cortex and hypothalamus and decreased the activity of the retrosplenial cortex. Morphine reversed the activation of the insular cortex and hypothalamus. Furthermore, morphine activated the amygdala and rostral ventromedial medulla and suppressed the activity of anterior cingulate cortex. Our findings of hypothalamic and insular cortical activation support the hypothesis that cancer-induced bone pain has strong inflammatory and affective components in freely moving animals. Morphine may provide descending inhibitory and facilitatory actions in the treatment of cancer-induced bone pain in a clinical setting.

Alterations to the Intestinal Microbiome and Metabolome of Pimephales promelas and Mus musculus Following Exposure to Dietary Methylmercury.

Mercury is a global contaminant, which may be microbially transformed into methylmercury (MeHg), which bioaccumulates. This results in potentially toxic body burdens in high trophic level organisms in aquatic ecosystems and maternal transfer to offspring. We previously demonstrated effects on developing fish including hyperactivity, altered time-to-hatch, reduced survival, and dysregulation of the dopaminergic system. A link between gut microbiota and central nervous system function in teleosts has been established with implications for behavior. We sequenced gut microbiomes of fathead minnows exposed to dietary MeHg to determine microbiome effects. Dietary exposures were repeated with adult CD-1 mice. Metabolomics was used to screen for metabolome changes in mouse brain and larval fish, and results indicate effects on lipid metabolism and neurotransmission, supported by microbiome data. Findings suggest environmentally relevant exposure scenarios may cause xenobiotic-mediated dysbiosis of the gut microbiome, contributing to neurotoxicity. Furthermore, small-bodied teleosts may be a useful model species for studying certain types of neurodegenerative diseases, in lieu of higher vertebrates.

At seeming safe concentrations, synergistic effects of PM2.5 and formaldehyde co-exposure induces Alzheimer-like changes in mouse brain.

Alzheimer's disease (AD) is a serious, common, global disease, yet its etiology and pathogenesis are incompletely understood. Air pollution is a multi-pollutants co-exposure system, which may affect brain. The indoor environment is where exposure to both air particulate matter (<2.5 μm in diameter) (PM2.5) and formaldehyde (FA) can occur simultaneously. Whether exposure to such a multi-pollutant (PM2.5 plus FA) mixture contributes to the development of AD, and whether there is a difference between exposure to PM2.5 or FA alone needs to be investigated. To determine the objective, C57BL/6J mice were exposed daily to PM2.5 (0.193 mg/Kg/day), FA (0.155 mg/Kg/day) or multi-pullutants (0.193 mg/Kg/day PM2.5 plus 0.155 mg/Kg/day FA) for one week. AD-like changes and upstream events were investigated after exposure. The results showed that exposure to PM2.5 or FA alone in this study had little or no adverse effects on the mouse brain. However, some AD-like pathologies were detected after multi-pullutants co-exposure. This work suggested PM2.5 plus FA co-exposure has more potential to induce AD-like pathologies than exposure alone. Oxidative stress and inflammation may be involved into the toxic mechanisms. Synergistic effects of co-exposure may induce the hygienic or safety standards of each pollutant not safe.

Acute formaldehyde exposure induced early Alzheimer-like changes in mouse brain

Alzheimer’s disease (AD) is a serious, common, global disease, yet its etiology and pathogenesis are incompletely understood. Although an association between AD and exposure to air pollutants has been discussed, the effects of pollutants on the functioning of the brain remain unclear. The indoor environment is where exposure to formaldehyde (FA) can occur. Whether exposure to FA contributes to the development of AD needs to be investigated. To determine the objective, C57BL/6 mice were exposed daily to FA (0, 0.155, 1.55 and 15.5 mg/kg/day) for 1 week. After acute FA exposure, some early AD-like changes [cognitive deficits, pathological alterations in the mouse brain, accumulation of total β-amyloid plaques 1-42 (Aβ1-42) and hyper-phosphorylated tau (Tau-P) in the cerebral cortex] were detected after exposure to high concentrations of FA (1.55 or 15.5 mg/kg/day). The permeability of the blood–brain barrier (BBB), activation of astrocyte and microglia, oxidative stress (OS) and inflammation were analyzed to explore the toxicity mechanisms behind the development of early AD-like changes. While exposed to a low concentration of FA (0.155 mg/kg/day) had little or no adverse effects on the mouse brain. The results indicated that acute FA exposure induced early AD-like changes in mouse brain, increased the susceptibility of AD in mouse.

Sleep Deprivation Is Not Only Unpleasant but Also Harmful

Sleep deprivation makes us tired, but is it physically harmful? These researchers examined brain changes in mice that were sleeping normally, had woken

The acute exposure of tetrachloro-p-benzoquinone (a.k.a. chloranil) triggers inflammation and neurological dysfunction via Toll-like receptor 4 signaling: The protective role of melatonin preconditioning.

This study is aimed to investigate the inflammation and neurological dysfunction induced by tetrachloro-p-benzoquinone (TCBQ) through Toll-like receptor 4 (TLR4) signaling. We also investigated the protective role of melatonin as an antioxidant and anti-inflammatory agent. In vitro model was established by rat pheochromocytoma PC12 cells, meanwhile, TLR4 wild-type (C57BL/6) and knockout mice (C57BL/10ScNJ TLR4-/-) were used as in vivo model. In vitro study showed TCBQ exposure enhanced the expression of TLR4, myeloid differentiation factor 88 (MyD88) at both transcriptional and post-transcriptional levels. By contrast, melatonin decreased TLR4 and MyD88 expressions. Moreover, our result indicated that melatonin disrupted the formation of TLR4/MyD88/MD2/CD14 complex. In addition, melatonin terminated TCBQ-mediated phosphorylation of c-Jun N-terminal kinase (JNK), p38, and extracellular regulated protein kinase (ERK) signaling and hampered its downstream pro-inflammatory cytokine releases. In vivo result also indicated TLR4 deficiency partially protected against TCBQ-induced morphological and neuropathological changes in mice brain, suggested the role of TLR4. In conclusion, melatonin modulates TCBQ-mediated inflammatory genes through TLR4/MyD88-dependent signaling pathway. Our current study, to the best of our knowledge, is the first time show melatonin not only disrupt the binding of TLR4 and MyD88, but also restricted the formation of TLR4/MD2/CD14 complex, suggesting that melatonin supplementary may represent a valuable therapeutic strategy for inflammatory neurological dysfunction.

The gene expression of the neuronal protein, SLC38A9, changes in mouse brain after in vivo starvation and high-fat diet.

SLC38A9 is characterized as a lysosomal component of the amino acid sensing Ragulator-RAG GTPase complex, controlling the mechanistic target of rapamycin complex 1 (mTORC1). Here, immunohistochemistry was used to map SLC38A9 in mouse brain and staining was detected throughout the brain, in cortex, hypothalamus, thalamus, hippocampus, brainstem and cerebellum. More specifically, immunostaining was found in areas known to be involved in amino acid sensing and signaling pathways e.g. piriform cortex and hypothalamus. SLC38A9 immunoreactivity co-localized with both GABAergic and glutamatergic neurons, but not with astrocytes. SLC38A9 play a key role in the mTORC1 pathway, and therefore we performed in vivo starvation and high-fat diet studies, to measure gene expression alterations in specific brain tissues and in larger brain regions. Following starvation, Slc38a9 was upregulated in brainstem and cortex, and in anterior parts of the brain (Bregma 3.2 to -2.1mm). After high-fat diet, Slc38a9 was specifically upregulated in hypothalamus, while overall downregulation was noticed throughout the brain (Bregma 3.2 to -8.6mm).

Early and progressive microstructural brain changes in mice overexpressing human α-Synuclein detected by diffusion kurtosis imaging

Diffusion kurtosis imaging (DKI) is sensitive in detecting α-Synuclein (α-Syn) accumulation-associated microstructural changes at late stages of the pathology in α-Syn overexpressing TNWT-61 mice. The aim of this study was to perform DKI in young TNWT-61 mice when α-Syn starts to accumulate and to compare the imaging results with an analysis of motor and memory impairment and α-Syn levels. Three-month-old (3mo) and six-month-old (6mo) mice underwent DKI scanning using the Bruker Avance 9.4T magnetic resonance imaging system. Region of interest (ROI) analyses were performed in the gray matter; tract-based spatial statistics (TBSS) analyses were performed in the white matter. In the same mice, α-Syn expression was evaluated using quantitative immunofluorescence.Mean kurtosis (MK) was the best differentiator between TNWT-61 mice and wildtype (WT) mice. We found increases in MK in 3mo TNWT-61 mice in the striatum and thalamus but not in the substantia nigra (SN), hippocampus, or sensorimotor cortex, even though the immunoreactivity of human α-Syn was similar or even higher in the latter regions. Increases in MK in the SN were detected in 6mo mice. These findings indicate that α-Syn accumulation-associated changes may start in areas with a high density of dopaminergic nerve terminals. We also found TBSS changes in white matter only at 6mo, suggesting α-Syn accumulation-associated changes start in the gray matter and later progress to the white matter.MK is able to detect microstructural changes induced by α-Syn overexpression in TNWT-61 mice and could be a useful clinical tool for detecting early-stage Parkinson’s disease in human patients.