General anesthesia severely affects the metabolites in the brain.Glycogen,principally stored in astrocytes and providing the short-term delivery of substrates to neurons,has been implicated as an affected molecule.How...General anesthesia severely affects the metabolites in the brain.Glycogen,principally stored in astrocytes and providing the short-term delivery of substrates to neurons,has been implicated as an affected molecule.However,whether glycogen plays a pivotal role in modulating anesthesia-arousal remains unclear.Here,we demonstrated that isoflurane-anesthetized mice exhibited dynamic changes in the glycogen levels in various brain regions.Glycogen synthase(GS)and glycogen phosphorylase(GP),key enzymes of glycogen metabolism,showed increased activity after isoflurane exposure.Upon blocking glycogenolysis with 1,4-dideoxy-1,4-imino-Darabinitol(DAB),a GP antagonist,we found a prolonged time of emergence from anesthesia and an enhancedδfrequency in the EEG(electroencephalogram).In addition,augmented expression of glycogenolysis genes in glycogen phosphorylase,brain(Pygb)knock-in(PygbH11/H11)mice resulted in delayed induction of anesthesia,a shortened emergence time,and a lower ratio of EEG-δ.Our findings revealed a role of brain glycogen in regulating anesthesiaarousal,providing a potential target for modulating anesthesia.展开更多
A growing number of studies have demonstrated that repeated exposure to sevoflurane during development results in persistent social abnormalities and cognitive impairment.Davunetide,an active fragment of the activity-...A growing number of studies have demonstrated that repeated exposure to sevoflurane during development results in persistent social abnormalities and cognitive impairment.Davunetide,an active fragment of the activity-dependent neuroprotective protein(ADNP),has been implicated in social and cognitive protection.However,the potential of davunetide to attenuate social deficits following sevoflurane exposure and the underlying developmental mechanisms remain poorly understood.In this study,ribosome and proteome profiles were analyzed to investigate the molecular basis of sevoflurane-induced social deficits in neonatal mice.The neuropathological basis was also explored using Golgi staining,morphological analysis,western blotting,electrophysiological analysis,and behavioral analysis.Results indicated that ADNP was significantly down-regulated following developmental exposure to sevoflurane.In adulthood,anterior cingulate cortex(ACC)neurons exposed to sevoflurane exhibited a decrease in dendrite number,total dendrite length,and spine density.Furthermore,the expression levels of Homer,PSD95,synaptophysin,and vglut2 were significantly reduced in the sevoflurane group.Patch-clamp recordings indicated reductions in both the frequency and amplitude of miniature excitatory postsynaptic currents(mEPSCs).Notably,davunetide significantly ameliorated the synaptic defects,social behavior deficits,and cognitive impairments induced by sevoflurane.Mechanistic analysis revealed that loss of ADNP led to dysregulation of Ca^(2+)activity via the Wnt/β-catenin signaling,resulting in decreased expression of synaptic proteins.Suppression of Wnt signaling was restored in the davunetide-treated group.Thus,ADNP was identified as a promising therapeutic target for the prevention and treatment of neurodevelopmental toxicity caused by general anesthetics.This study provides important insights into the mechanisms underlying social and cognitive disturbances caused by sevoflurane exposure in neonatal mice and elucidates the regulatory pathways involved.展开更多
Clinical researches including the Mayo Anesthesia Safety in Kids (MASK) study have found that children undergoing multiple anesthesia may have a higher risk of fne motor control difculties. However, the underlying mec...Clinical researches including the Mayo Anesthesia Safety in Kids (MASK) study have found that children undergoing multiple anesthesia may have a higher risk of fne motor control difculties. However, the underlying mechanisms remain elusive. Here, we report that erythropoietin receptor (EPOR), a microglial receptor associated with phagocytic activity, was signifcantly downregulated in the medial prefrontal cortex of young mice after multiple sevofurane anesthesia exposure. Importantly, we found that the inhibited erythropoietin (EPO)/EPOR signaling axis led to microglial polarization, excessive excitatory synaptic pruning, and abnormal fne motor control skills in mice with multiple anesthesia exposure, and those above-mentioned situations were fully reversed by supplementing EPO-derived peptide ARA290 by intraperitoneal injection. Together, the microglial EPOR was identifed as a key mediator regulating early synaptic development in this study, which impacted sevoflurane-induced fine motor dysfunction. Moreover, ARA290 might serve as a new treatment against neurotoxicity induced by general anesthesia in clinical practice by targeting the EPO/EPOR signaling pathway.展开更多
Background:The mechanisms underlying social dysfunction caused by repeated sevoflurane in early life remain unclear.Whether the gut microbiota-metabolite-brain axis is involved in the mechanism of sevoflurane developm...Background:The mechanisms underlying social dysfunction caused by repeated sevoflurane in early life remain unclear.Whether the gut microbiota-metabolite-brain axis is involved in the mechanism of sevoflurane developmental neurotoxicity still lacks report.Methods:Mice received 3%sevoflurane at postnatal day(PND)6,7,and 8 for 2 h per day.Metagenomic sequencing and untargeted metabolomic analysis were applied to investigate the effects of sevoflurane on gut microbiota and metabolism.The animal social behavior and the synaptic development were analyzed during PND 35.Subsequently,fecal microbiota transplantation(FMT)from the control group and bile acid administration were performed to see the expected rescuing effect on socially related behaviors that were impaired by repeated sevoflurane exposure in the mice.Results:In the 3-chamber test,sevoflurane-exposed mice spent less time with stranger mice compared with the control group.The density of both the apical and basal spine decreased in mice exposed to sevoflurane.In addition,repeated sevoflurane exposure led to a notable alteration in the gut microbiota and metabolite synthesis,particularly bile acid.FMT reduced the production of intestinal bile acid and attenuated the effect of sevoflurane exposure on social function and synaptic development.Cholestyramine treatment mimics the protective effects of FMT.Conclusions:The gut microbiota-metabolite-brain axis underlies social dysfunction caused by sevoflurane exposure in early age,and bile acid regulation may be a promising intervention to this impairment.展开更多
基金the Major Program of the National Natural Science Foundation of China(81590954)the International Cooperation and Exchange of the National Natural Science Foundation of China(81420108013)the State Key Program of National Natural Science Foundation of China(81730032)。
文摘General anesthesia severely affects the metabolites in the brain.Glycogen,principally stored in astrocytes and providing the short-term delivery of substrates to neurons,has been implicated as an affected molecule.However,whether glycogen plays a pivotal role in modulating anesthesia-arousal remains unclear.Here,we demonstrated that isoflurane-anesthetized mice exhibited dynamic changes in the glycogen levels in various brain regions.Glycogen synthase(GS)and glycogen phosphorylase(GP),key enzymes of glycogen metabolism,showed increased activity after isoflurane exposure.Upon blocking glycogenolysis with 1,4-dideoxy-1,4-imino-Darabinitol(DAB),a GP antagonist,we found a prolonged time of emergence from anesthesia and an enhancedδfrequency in the EEG(electroencephalogram).In addition,augmented expression of glycogenolysis genes in glycogen phosphorylase,brain(Pygb)knock-in(PygbH11/H11)mice resulted in delayed induction of anesthesia,a shortened emergence time,and a lower ratio of EEG-δ.Our findings revealed a role of brain glycogen in regulating anesthesiaarousal,providing a potential target for modulating anesthesia.
基金supported by the National Natural Science Foundation of China(82171170,81971076,82371277 to H.Z.,82101345 to L.R.L.)。
文摘A growing number of studies have demonstrated that repeated exposure to sevoflurane during development results in persistent social abnormalities and cognitive impairment.Davunetide,an active fragment of the activity-dependent neuroprotective protein(ADNP),has been implicated in social and cognitive protection.However,the potential of davunetide to attenuate social deficits following sevoflurane exposure and the underlying developmental mechanisms remain poorly understood.In this study,ribosome and proteome profiles were analyzed to investigate the molecular basis of sevoflurane-induced social deficits in neonatal mice.The neuropathological basis was also explored using Golgi staining,morphological analysis,western blotting,electrophysiological analysis,and behavioral analysis.Results indicated that ADNP was significantly down-regulated following developmental exposure to sevoflurane.In adulthood,anterior cingulate cortex(ACC)neurons exposed to sevoflurane exhibited a decrease in dendrite number,total dendrite length,and spine density.Furthermore,the expression levels of Homer,PSD95,synaptophysin,and vglut2 were significantly reduced in the sevoflurane group.Patch-clamp recordings indicated reductions in both the frequency and amplitude of miniature excitatory postsynaptic currents(mEPSCs).Notably,davunetide significantly ameliorated the synaptic defects,social behavior deficits,and cognitive impairments induced by sevoflurane.Mechanistic analysis revealed that loss of ADNP led to dysregulation of Ca^(2+)activity via the Wnt/β-catenin signaling,resulting in decreased expression of synaptic proteins.Suppression of Wnt signaling was restored in the davunetide-treated group.Thus,ADNP was identified as a promising therapeutic target for the prevention and treatment of neurodevelopmental toxicity caused by general anesthetics.This study provides important insights into the mechanisms underlying social and cognitive disturbances caused by sevoflurane exposure in neonatal mice and elucidates the regulatory pathways involved.
基金supported by grants from the National Natural Science Foundation of China(82101534,82171170,and 82201414)the Natural Science Foundation of Shaanxi Provence(2024JCYBMS659)the Science and Technology Plan in Xi’an of China(23YXYJ0134)。
文摘Clinical researches including the Mayo Anesthesia Safety in Kids (MASK) study have found that children undergoing multiple anesthesia may have a higher risk of fne motor control difculties. However, the underlying mechanisms remain elusive. Here, we report that erythropoietin receptor (EPOR), a microglial receptor associated with phagocytic activity, was signifcantly downregulated in the medial prefrontal cortex of young mice after multiple sevofurane anesthesia exposure. Importantly, we found that the inhibited erythropoietin (EPO)/EPOR signaling axis led to microglial polarization, excessive excitatory synaptic pruning, and abnormal fne motor control skills in mice with multiple anesthesia exposure, and those above-mentioned situations were fully reversed by supplementing EPO-derived peptide ARA290 by intraperitoneal injection. Together, the microglial EPOR was identifed as a key mediator regulating early synaptic development in this study, which impacted sevoflurane-induced fine motor dysfunction. Moreover, ARA290 might serve as a new treatment against neurotoxicity induced by general anesthesia in clinical practice by targeting the EPO/EPOR signaling pathway.
基金supported by National Natural Science Foundation of China to Y.Z.(grant no.82201414)H.Z.(grant nos.82371277 and 82171170)L.L.(grant no.82101345).
文摘Background:The mechanisms underlying social dysfunction caused by repeated sevoflurane in early life remain unclear.Whether the gut microbiota-metabolite-brain axis is involved in the mechanism of sevoflurane developmental neurotoxicity still lacks report.Methods:Mice received 3%sevoflurane at postnatal day(PND)6,7,and 8 for 2 h per day.Metagenomic sequencing and untargeted metabolomic analysis were applied to investigate the effects of sevoflurane on gut microbiota and metabolism.The animal social behavior and the synaptic development were analyzed during PND 35.Subsequently,fecal microbiota transplantation(FMT)from the control group and bile acid administration were performed to see the expected rescuing effect on socially related behaviors that were impaired by repeated sevoflurane exposure in the mice.Results:In the 3-chamber test,sevoflurane-exposed mice spent less time with stranger mice compared with the control group.The density of both the apical and basal spine decreased in mice exposed to sevoflurane.In addition,repeated sevoflurane exposure led to a notable alteration in the gut microbiota and metabolite synthesis,particularly bile acid.FMT reduced the production of intestinal bile acid and attenuated the effect of sevoflurane exposure on social function and synaptic development.Cholestyramine treatment mimics the protective effects of FMT.Conclusions:The gut microbiota-metabolite-brain axis underlies social dysfunction caused by sevoflurane exposure in early age,and bile acid regulation may be a promising intervention to this impairment.
