Short-chain fatty acids(SCFAs)have been increasingly evidenced to be important bioactive metabolites of the gut microbiota and transducers in controlling diverse psychiatric or neurological disorders via the microbiot...Short-chain fatty acids(SCFAs)have been increasingly evidenced to be important bioactive metabolites of the gut microbiota and transducers in controlling diverse psychiatric or neurological disorders via the microbiota-gut-brain axis.However,the precise mechanism by which brain SCFAs extert multiple beneficial effects is not completely understood.Our previous research has demonstrated that the acetyl-coenzyme A synthetase short-chain family member 2(ACSS2)is a novel target of the rapid and long-lasting antidepressant responses.Here,we show that micromolar SCFAs significantly augment both total cellular and nuclear ACSS2 to trigger tryptophan hydroxylase 2(TPH2)promoter histone acetylation and its transcription in SH-SY5Y cells.In chronic-restraint-stress-induced depression mice,neuronal ACSS2 knockdown by stereotaxic injection of adeno-associated virus in the hippocampus abolished SCFA-mediated improvements in depressive-like behaviors of mice,supporting that ACSS2 is required for SCFA-mediated antidepressant responses.Mechanistically,the peroxisome-proliferator-activated receptor gamma(PPARγ)is identified as a novel partner of ACSS2 to activate TPH2 transcription.Importantly,PPARγis also responsible for SCFA-mediated antidepressant-like effects via ACSS2-TPH2 axis.To further support brain SCFAs as a therapeutic target for antidepressant effects,d-mannose,which is a naturally present hexose,can significantly reverse the dysbiosis of gut microbiota in the chronic-restraint-stress-exposure mice and augment brain SCFAs to protect against the depressive-like behaviors via ACSS2-PPARγ-TPH2 axis.In summary,brain SCFAs can activate ACSS2-PPARγ-TPH2 axis to play the antidepressive-like effects,and d-mannose is suggested to be an inducer of brain SCFAs in resisting depression.展开更多
Objective To investigate the mechanism of Modified Shuyu Pills(MSP)in alleviating anxiety and depression behaviors in vascular dementia(VaD)mice.Methods For the pharmacological study,60 C57BL/6 mice were utilized to e...Objective To investigate the mechanism of Modified Shuyu Pills(MSP)in alleviating anxiety and depression behaviors in vascular dementia(VaD)mice.Methods For the pharmacological study,60 C57BL/6 mice were utilized to establish the VaD model through common carotid artery constriction/restraint stress(BCAS/CRS),with a sham operation serving as the control.Based on intervention conditions,the mice were divided into the control group(normal saline),model group(normal saline),MSP group(7,14,28 g·kg^(-1)),and fluoxetine group(10 mg·kg^(-1)).For the mechanism study,40 BCAS/CRS mice were treated with empty virus,MyRF overexpression virus,MSP(14 g·kg^(-1)),and MSP+MyRF knockdown virus,respectively.Behavioral changes were evaluated using the open-field test,elevated plus maze test,and tail suspension test.Western Blot analysis was employed to detect the expression of myelin-associated glycoprotein(MAG),myelin oligodendrocyteglycoprotein(MOG),myelin-basic protein(MBP)andmyelin-generegulatoryfactors(MyRF).MBP expression was also assessed through immunofluorescence staining.Compound action potential recordings in.the corpus callosum were conducted to evaluate the conductive efficacy of action potential in myelinated axons.Results Compared with the control group,the number/time of opening arms and the time/distance of the central area in the model groupwere significantly decreased,and the immobility time was prolonged(P<0.01).Expressions of MAG,MOG,MBP,and MyRF in mPFC and BLA were reduced,along with decreased MBP fluorescence intensity and action potential N1 amplitude(P<0.01).MSP and fluoxetine significantly increased the number/time of opening arms and the time/distance of the centra1l area,while shortening the immobility time(P<0.01,P<0.05).MSP and fluoxetine induced upregulation of myelin associated protein and MyRFexpression,as well as changes in MBP fluorescence intensity and action potential N1 amplitude(P<0.01,P<0.05).MyRF knockdown attenuated the improvement effect of MSP on the behavior,myelin-related protein expression,and action potential N1 amplitude of the model mice(P<0.01,P<0.05).Conclusion MSP ameliorates anxiety and depression behaviors in VaD mice by up-regulating the expression of MyRF and promoting myelin repair and signal transduction in the mPFC-BLA circuit.展开更多
基金supported by the National Natural Science Foundation of China(82101606,82173105,81771775,81971471,and 32270800)Shandong Excellent Young Scientists Fund Program(Overseas)(2022HWYQ-028)Shandong Provincial Natural Science Foundation(ZR2022MC012).
文摘Short-chain fatty acids(SCFAs)have been increasingly evidenced to be important bioactive metabolites of the gut microbiota and transducers in controlling diverse psychiatric or neurological disorders via the microbiota-gut-brain axis.However,the precise mechanism by which brain SCFAs extert multiple beneficial effects is not completely understood.Our previous research has demonstrated that the acetyl-coenzyme A synthetase short-chain family member 2(ACSS2)is a novel target of the rapid and long-lasting antidepressant responses.Here,we show that micromolar SCFAs significantly augment both total cellular and nuclear ACSS2 to trigger tryptophan hydroxylase 2(TPH2)promoter histone acetylation and its transcription in SH-SY5Y cells.In chronic-restraint-stress-induced depression mice,neuronal ACSS2 knockdown by stereotaxic injection of adeno-associated virus in the hippocampus abolished SCFA-mediated improvements in depressive-like behaviors of mice,supporting that ACSS2 is required for SCFA-mediated antidepressant responses.Mechanistically,the peroxisome-proliferator-activated receptor gamma(PPARγ)is identified as a novel partner of ACSS2 to activate TPH2 transcription.Importantly,PPARγis also responsible for SCFA-mediated antidepressant-like effects via ACSS2-TPH2 axis.To further support brain SCFAs as a therapeutic target for antidepressant effects,d-mannose,which is a naturally present hexose,can significantly reverse the dysbiosis of gut microbiota in the chronic-restraint-stress-exposure mice and augment brain SCFAs to protect against the depressive-like behaviors via ACSS2-PPARγ-TPH2 axis.In summary,brain SCFAs can activate ACSS2-PPARγ-TPH2 axis to play the antidepressive-like effects,and d-mannose is suggested to be an inducer of brain SCFAs in resisting depression.
文摘Objective To investigate the mechanism of Modified Shuyu Pills(MSP)in alleviating anxiety and depression behaviors in vascular dementia(VaD)mice.Methods For the pharmacological study,60 C57BL/6 mice were utilized to establish the VaD model through common carotid artery constriction/restraint stress(BCAS/CRS),with a sham operation serving as the control.Based on intervention conditions,the mice were divided into the control group(normal saline),model group(normal saline),MSP group(7,14,28 g·kg^(-1)),and fluoxetine group(10 mg·kg^(-1)).For the mechanism study,40 BCAS/CRS mice were treated with empty virus,MyRF overexpression virus,MSP(14 g·kg^(-1)),and MSP+MyRF knockdown virus,respectively.Behavioral changes were evaluated using the open-field test,elevated plus maze test,and tail suspension test.Western Blot analysis was employed to detect the expression of myelin-associated glycoprotein(MAG),myelin oligodendrocyteglycoprotein(MOG),myelin-basic protein(MBP)andmyelin-generegulatoryfactors(MyRF).MBP expression was also assessed through immunofluorescence staining.Compound action potential recordings in.the corpus callosum were conducted to evaluate the conductive efficacy of action potential in myelinated axons.Results Compared with the control group,the number/time of opening arms and the time/distance of the central area in the model groupwere significantly decreased,and the immobility time was prolonged(P<0.01).Expressions of MAG,MOG,MBP,and MyRF in mPFC and BLA were reduced,along with decreased MBP fluorescence intensity and action potential N1 amplitude(P<0.01).MSP and fluoxetine significantly increased the number/time of opening arms and the time/distance of the centra1l area,while shortening the immobility time(P<0.01,P<0.05).MSP and fluoxetine induced upregulation of myelin associated protein and MyRFexpression,as well as changes in MBP fluorescence intensity and action potential N1 amplitude(P<0.01,P<0.05).MyRF knockdown attenuated the improvement effect of MSP on the behavior,myelin-related protein expression,and action potential N1 amplitude of the model mice(P<0.01,P<0.05).Conclusion MSP ameliorates anxiety and depression behaviors in VaD mice by up-regulating the expression of MyRF and promoting myelin repair and signal transduction in the mPFC-BLA circuit.
