Astrocytes play critical roles in regulating neuronal synaptogenesis, maintaining blood–brain barrier integrity, and recycling neurotransmitters. Increasing numbers of studies have suggested astrocyte heterogeneity in morphology, gene profile, and function. However, metabolic phenotype of astrocytes in different brain regions have not been explored. In this paper, we investigated the metabolic signature of cortical and cerebellar astrocytes using primary astrocyte cultures. We observed that cortical astrocytes were larger than cerebellar astrocytes, whereas cerebellar astrocytes had more and longer processes than cortical astrocytes. Using a Seahorse extracellular flux analyzer, we demonstrated that cortical astrocytes had higher mitochondrial respiration and glycolysis than cerebellar astrocytes. Cerebellar astrocytes have lower spare capacity of mitochondrial respiration and glycolysis as compared with cortical astrocytes. Consistently, cortical astrocytes have higher mitochondrial oxidation and glycolysis-derived ATP content than cerebellar astrocytes. In addition, cerebellar astrocytes have a fuel preference for glutamine and fatty acid, whereas cortical astrocytes were more dependent on glucose to meet energy demands. Our study indicated that cortical and cerebellar astrocytes display distinct metabolic phenotypes. Future studies on astrocyte metabolic heterogeneity and brain function in aging and neurodegeneration may lead to better understanding of the role of astrocyte in brain aging and neurodegenerative disorders.
Estrogen receptors (ERs) are believed to be ligand-activated transcription factors belonging to the nuclear receptor superfamily, which on ligand binding translocate into the nucleus and activate gene transcription. To date, two ERs have been identified: ERα and ERβ. ERα plays major role in the estrogen-mediated genomic actions in both reproductive and nonreproductive tissue, whereas the function of ERβ is still unclear. In this study, we used immunocytochemistry, immunoblotting, and proteomics to demonstrate that ERβ localizes to the mitochondria. In immunocytochemistry studies, ERβ was detected with two ERβ antibodies and found to colocalize almost exclusively with a mitochondrial marker in rat primary neuron, primary cardiomyocyte, and a murine hippocampal cell line. The colocalization of ERβ and mitochondrial markers was identified by both fluorescence and confocal microscopy. No translocation of ERβ into the nucleus on 17β-estradiol treatment was seen by using immunocytochemistry. Immunoblotting of purified human heart mitochondria showed an intense signal of ERβ, whereas no signals for nuclear and other organelle markers were found. Finally, purified human heart mitochondrial proteins were separated by SDS/PAGE. The 50,000–65,000 M r band was digested with trypsin and subjected to matrix-assisted laser desorption/ionization mass spectrometric analysis, which revealed seven tryptic fragments that matched with those of ERβ. In summary, this study demonstrated that ERβ is localized to mitochondria, suggesting a role for mitochondrial ERβ in estrogen effects on this important organelle.
Neuroprotective strategies, including free radical scavengers, ion channel modulators, and anti-inflammatory agents, have been extensively explored in the last 2 decades for the treatment of neurological diseases. Unfortunately, none of the neuroprotectants has been proved effective in clinical trails. In the current study, we demonstrated that methylene blue (MB) functions as an alternative electron carrier, which accepts electrons from NADH and transfers them to cytochrome c and bypasses complex I/III blockage. A de novo synthesized MB derivative, with the redox center disabled by N-acetylation, had no effect on mitochondrial complex activities. MB increases cellular oxygen consumption rates and reduces anaerobic glycolysis in cultured neuronal cells. MB is protective against various insults in vitro at low nanomolar concentrations. Our data indicate that MB has a unique mechanism and is fundamentally different from traditional antioxidants. We examined the effects of MB in two animal models of neurological diseases. MB dramatically attenuates behavioral, neurochemical, and neuropathological impairment in a Parkinson disease model. Rotenone caused severe dopamine depletion in the striatum, which was almost completely rescued by MB. MB rescued the effects of rotenone on mitochondrial complex I-III inhibition and free radical overproduction. Rotenone induced a severe loss of nigral dopaminergic neurons, which was dramatically attenuated by MB. In addition, MB significantly reduced cerebral ischemia reperfusion damage in a transient focal cerebral ischemia model. The present study indicates that rerouting mitochondrial electron transfer by MB or similar molecules provides a novel strategy for neuroprotection against both chronic and acute neurological diseases involving mitochondrial dysfunction.
Meaningful and simplified representations of neural activity can yield insights into how and what information is being processed within a neural circuit. However, without labels, finding representations that reveal the link between the brain and behavior can be challenging. Here, we introduce a novel unsupervised approach for learning disentangled representations of neural activity called Swap-VAE. Our approach combines a generative modeling framework with an instance-specific alignment loss that tries to maximize the representational similarity between transformed views of the input (brain state). These transformed (or augmented) views are created by dropping out neurons and jittering samples in time, which intuitively should lead the network to a representation that maintains both temporal consistency and invariance to the specific neurons used to represent the neural state. Through evaluations on both synthetic data and neural recordings from hundreds of neurons in different primate brains, we show that it is possible to build representations that disentangle neural datasets along relevant latent dimensions linked to behavior.
Purpose: Intraplaque neovascularization, assessed using contrast-enhanced ultrasound (CEUS), is associated with ischemic stroke.It remains unclear whether detection of intraplaque neovascularization combined with color Doppler ultrasound (CDUS) provides additional value compared with CDUS alone in assessing ischemic stroke risk.Therefore, we investigated the clinical value of combined CEUS, CDUS, and clinical features for ischemic stroke risk stratification.Patients and Methods: We recruited 360 patients with ≥50% carotid stenosis between January 2019 and September 2022.Patients were examined using CDUS and CEUS.Covariates associated with ischemic stroke were identified using multivariate logistic regression analysis.The discrimination and calibration were verified using the C-statistic and Hosmer-Lemeshow test.The incremental value of intraplaque neovascularization in the assessment of ischemic stroke was analyzed using the Delong test.Results: We analyzed the data of 162 symptomatic and 159 asymptomatic patients who satisfied the inclusion and exclusion criteria, respectively.Based on multivariate logistic regression analysis, we constructed a nomogram using intraplaque neovascularization, degree of carotid stenosis, plaque hypoechoicity, and smoking status, with a C-statistic of 0.719 (95% confidence interval [CI]: 0.666-0.768)and a Hosmer-Lemeshow test p value of 0.261.The net reclassification index of the nomogram was 0.249 (95% CI: 0.138-0.359),and the integrated discrimination improvement was 0.053 (95% CI: 0.029-0.079).Adding intraplaque neovascularization to the combination of CDUS and clinical features (0.672; 95% CI: 0.617-0.723)increased the C-statistics (p=0.028).Conclusion: Further assessment of intraplaque neovascularization after CDUS may help more accurately identify patients at risk of ischemic stroke.Combining multiparametric carotid ultrasound and clinical features may help improve the risk stratification of patients with ischemic stroke with ≥50% carotid stenosis.Plain Language Summary: We studied whether using contrast-enhanced ultrasound (CEUS) to detect intraplaque neovascularization could help better determine the risk of ischemic stroke.We compared the combined use of color Doppler ultrasound (CDUS) and CEUS with CDUS alone in patients with more than 50% carotid narrowing.Our findings showed that combining clinical details, CDUS, and CEUS was more effective (0.719 vs 0.672).This means that CEUS provides extra insight when gauging ischemic stroke risk compared with CDUS alone.This could help in accurately identifying patients at high risk of stroke.However, more extensive studies are needed to fully understand the role of these tests in the evaluation of stroke risk.
Metformin is currently the most effective treatment for type-2 diabetes. The beneficial actions of metformin have been found even beyond diabetes management and it has been considered as one of the most promising drugs that could potentially slow down aging. Surprisingly, the effect of metformin on brain function and metabolism has been less explored given that brain almost exclusively uses glucose as substrate for energy metabolism. We determined the effect of metformin on locomotor and cognitive function in normoglycemic mice. Metformin enhanced locomotor and balance performance, while induced anxiolytic effect and impaired cognitive function upon chronic treatment. We conducted in vitro assays and metabolomics analysis in mice to evaluate metformin's action on the brain metabolism. Metformin decreased ATP level and activated AMPK pathway in mouse hippocampus. Metformin inhibited oxidative phosphorylation and elevated glycolysis by inhibiting mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) in vitro at therapeutic doses. In summary, our study demonstrated that chronic metformin treatment affects brain bioenergetics with compound effects on locomotor and cognitive brain function in non-diabetic mice.
Objective. We aim to conduct a comparison of the safety and effectiveness performance between left bundle branch area pacing (LBBAP) and right ventricular pacing (RVP) regimens for patients with atrioventricular block (AVB). Methods. This observational cohort study included patients who underwent pacemaker implantations with LBBAP or RVP for AVB indications from the 1st of January 2018 to the 18th of November 2021 at West China Hospital. The primary composite outcome included all-cause mortality, lead failure, or heart failure hospitalization (HFH). The secondary outcome included periprocedure complication, cardiac death, or recurrent unexplained syncope. A 1 : 1 propensity score–matched cohort was conducted for left ventricular (LV) function analysis. Results. A total of 903 patients met the inclusion criteria and completed clinical follow-up. After adjusting for the possible confounders, LBBAP was independently associated with a lower risk of the primary outcome (OR 0.48, 95% CI 0.28 to 0.83, ), including a lower risk of all-cause mortality and HFH. No significant difference in the secondary outcome was detected between the groups except that LBBAP was independently associated with a lower risk of recurrent unexplained syncope. In the propensity-score matching cohort of echocardiographic analysis, the LV systolic dyssynchrony index was lower in LBBAP compared with that in RVP ( vs. %, ). Conclusions. Compared to conventional RVP, LBBAP is a feasible novel pacing model associated with a significant reduction in the primary composite outcome. Moreover, LBBAP significantly reduces the risk of recurrent unexplained syncope and improves LV systolic synchrony. This study is registered with ClinicalTrials.gov NCT05722379.
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