Single-nucleus transcriptome profiling of prefrontal cortex induced by chronic methamphetamine treatment

Background Methamphetamine(METH)addiction causes a huge burden on society.The prefrontal cortex(PFC),associated with emotion and cognitive behaviours,is also involved in addiction neurocircuitry.Although bulk RNA sequencing has shown METH-induced gene alterations in the mouse PFC,the impact on different cell types remains unknown.Aims To clarify the effects of METH treatment on different cell types of the PFC and the potential pathways involved in METH-related disorders.Methods We performed single-nucleus RNA sequencing(snRNA-seq)to examine the transcriptomes of 20465 nuclei isolated from the PFC of chronic METH-treated and control mice.Main cell types and differentially expressed genes(DEGs)were identified and confirmed by RNA fluorescence in situ hybridization(FISH).Results Six main cell types were identified depending on the single-cell nucleus sequencing;of particular interest were the mature oligodendrocytes in the PFC.The DEGs of mature oligodendrocytes were enriched in the myelin sheath,adenosine triphosphate(ATP)metabolic process,mitochondrial function and components,and so on.The messenger RNA levels of Aldoc and Atp5l(FISH)and the protein level of the mitochondrial membrane pore subunit TOM40(immunofluorescence)decreased in the mature oligodendrocytes.Fast blue staining and transmission electron microscopy image indicated myelin damage,and the myelin thickness decreased in METH brains.Conclusions snRNA-seq reveals altered transcriptomes of different cell types in mouse PFC induced by chronic METH treatment,underscoring potential relationships with psychiatric disorders.

Dexmedetomidine alleviates oxygen and glucose deprivation-induced apoptosis in mesenchymal stem cell via downregulation of MKP-1

Bone marrow mesenchymal stem cell(MSC)-based therapy is a novel candidate for heart repair.But ischemiareperfusion injury leads to low viability of MSC.Dexmedetomidine(Dex)has been found to protect neurons against ischemia-reperfusion injury.It remains unknown if Dex could increase the viability of MSCs under ischemia.The present study is to observe the potential protective effect of Dex on MSCs under ischemia and its underlying mechanisms.Specific mRNAs related to myocardial ischemia in the GEO database were selected from the mRNA profiles assessed in a previous study using microarray.The most dysregulated mRNAs of the specific ones from the above study were subject to bioinformatics analysis at our laboratory.These dysregulated mRNAs possibly regulated apoptosis of cardiomyocytes and were validated in vitro for their protective effect on MSCs under ischemia.MSCs were pre-treated with Dex at 10μM concentration for 24 h under oxygen-glucose deprivation(OGD).Flow cytometry and TUNEL assay were carried out to detect apoptosis in Dex-pretreated MSCs under OGD.The relative expressions of mitogen-activated protein kinase phosphatase 1(MKP-1)and related genes were detected by quantitative polymerase chain reaction and western blotting.Microarray data analysis revealed that Dex regulates MAPK phosphatase activity.Dex significantly reduced in vitro apoptosis of MSCs under OGD,which suppressed the synthesis level of Beclin1 and light chain 3 proteins.Dex down-regulated MKP-1 expression and attenuated an OGDinduced change in the mitogen activated protein kinase 3(MAPK3)signaling pathway.Dex increases the viability of MSC and improves its tolerance to OGD in association with the MKP-1 signaling pathway,thus suggesting the potential of Dex as a novel strategy for promoting MSCs efficacy under ischemia.

Defective mitophagy and the etiopathogenesis of Alzheimer’s disease

Accumulation of impaired mitochondria and energy metabolism disorders are non-negligible features of both aging and age-related neurodegeneration,including Alzheimer’s disease(AD).A growing number of studies suggest that mitophagy disorders play an important role in AD occurrence and development.The interaction between mitophagy deficits and Aβor Tau pathology may form a vicious cycle and cause neuronal damage and death.Elucidating the molecular mechanism of mitophagy and its role in AD may provide insights into the etiology and mechanisms of AD.Defective mitophagy is a potential target for AD prevention and treatment.