Parvalbumin Interneurons Activation-dependent Adult Hippocampal Neurogenesis Is Required For Treadmill Running To Reverse Schizophrenia-like Phenotypes

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Aerobic exercise regulates adult neurogenesis,spatial and non-spatial learning by ErbB signalingObjective:To investigate the molecular mechanisms on adult hippocampal neurogenesis and memory improvement of aerobic exerciseMethods:(1)Inhibit ErbB signals was used by pharmacological means,and changes in total ErbB4 and phosphorylated ErbB4 protein levels was evaluate by western blot;spatial memory was used by open-field test,T-maze and Morris water maze(MWM);non-spatial memory analysis of cognitive memory was used by fear conditioning and pattern separation;(2)Ki67,NeuN,and BrdU immunostaining were used to evaluate the proliferation and survival of hippocampal neurons in DGResults:(1)AG1478 significantly reduced phosphorylated ErbB4 protein levels in the hippocampus of the running mice;AG1478 did not affect total ErbB4 protein level and body weight lose;which did not affect locomotor activity but increased anxiety-like behavior.AG1478 significantly weakened spatial learning and memory,contextual fear conditioning and discrimination learning paradigm's memory(non-spatial work and reference memory)of mice;(2)AG1478 enhanced the loss of neurogenesis,these defects can be reversed by aerobic exerciseConclusions:In summary,our study suggested that running enhances cognitive memory and neurogenesis via ErbB4 receptorsPart ? The effect of aerobic exercise on the behavioral phenotype of schizophrenia-like model miceObjective:To investigate the improvement of aerobic exercise on schizophrenia-like(SCZ-like)mice and provide a laboratory basis for aerobic exercise to prevent or delay schizophrenia.Methods:(1)MK801 was used to induce the SCZ-like model,spontaneous activity,sensory motor gating function and working memory were detected by open field test,PPI and T-maze test,respectively.(2)Since ErbB4 is a susceptibility gene of SCZ,knockout of ErbB4 in Gamma Amino Acid Butyric Acid(GABA)-PV-positive neurons can cause SCZ-related phenotypes,we then used PV-ErbB4-/-mice to detect aerobic exercise on the above three phenotypic improvement.Results:(1)Compared with vehicle+static mice,hyperactivity,impaired PPI,deficit lworking memory were observed in MK801+static mice;which were reversed by aerobic exercise.(2)Compared with ErbB4+/+mice,spontaneous activity were significantly increased,PPI was impaired,spatial working memory was decreased in PV-ErbB4-/-mice,however,these deficit behaviors were reversed by threadmill running.Conclusions:In summary,we found that aerobic exercise can improve hyperactivity,impaired PPI,and working memory in SCZ-like mice model induced by MK801 and PV-ErbB4-/-transgenic mice.These studies confirm aerobic exercise can improve SCZ disease.Part ? Aerobic exercise promotes adult neurogenesis in DG of schizophrenia-like model miceObjective:To investigate the effects of aerobic exercise on new born cells in DG of SCZ-like mice,and provide experimental evidence for aerobic exercise to improve schizophrenia.Methods:(1)Immunofluorescence and laser confocal technique were used to observe the expression of PV-positive neurons and the proliferation of neural cells(KI67+)and survival(NeuN+BrdU+)in hippocampal dentate gyrus.(2)Western Blot was used to detect the protein expression of PV and P-ErbB4 in the hippocampus of SCZ-like model mice.(3)Pattern separation was used to detect the ability of distinguishing similar scenes of SCZ-like model mice.Results:(1)Compared with the control mice,the expression of ErbB4 and PV in hippocampus of MK801-induced SCZ-like model mice was significantly down-regulated,both of which were significantly up-regulated by exercise;AG1478 significantly down-regulated the level of P-ErbB4.(2)Compared with the control mice,the numbers of PV+cells,KI67+and NeuN+BrdU+in DG were significantly decreased in the SCZ-like mice induced by MK801,which were significantly increased after exercise.(3)Compared with the control mice,the ability to distinguish similar scenes was significantly reduced in MK801-induced SCZ-like mice,which was significantly improved by exercise.(4)ErbB4 knockdown significantly reduced the number of PV positive cells in DG and significantly increased KI67 density;which were significantly impovedy by aerobic exercise.Conclusion:Aerobic exercise can significantly improve the proliferation and survival of neural stem cells in DG of two SCZ model mice,as well as the expression of PV+interneurons;and significantly improve the ability to distinguish similar scenes.These findings suggest adult hippocampal neurogenesis plays a very important role in mediating the mechanisms of exercise-improving schizophrenia.Part ? Parvalbumin interneurons-dependent adult hippocampal neurogenesis is required for treadmill running to reverse schizophrenia phenotypesObjective:To investigate the link between PV+ interneurons and neurogenesis of aerobic exercise on the effect of SCZ-like model mice,and provide a therapeutic target for SCZ.Methods:(1)Using retrovirus to label newborn neurons,combined with immunofluorescence technology,the interaction between PV-positive neurons and hippocampal dentate neurogenesis was observed.(2)Using the specific apoptotic virus,combined with immunofluorescence technique and behavioral experiments,the effect of PV-positive neurons in the DG on neurogenesis of SCZ model mice was observed.(3)Using transgenic and chemicalgenetic means to specifically activate PV-positive neurons in DG,the regulation of PV-positive neurons on newborn neurons in the dentate gyrus of hippocampus was observedResults:(1)Compared with the control mice,PV+ interneurons in DG of SCZ-like model mice were significantly reduced,GFP+cells were significantly decreased,and the number of branches near neuronal soma was significantly reduced.Exercise increased the number of GFP+cells and dendritic trees,complexity of the tree.(2)Compared with the control group,the PV interneuron were specifically apoptotic in DG of Casp3+ static mice,GFP+cells and dendritic branches were significantly reduced,which were not improved by aerobic exercise.(3)Compared with the control group,Casp3+ static mice showed significant hyperactivity,lower PPI and impaired working memory;aerobic exercise could not save these defective behaviors.(4)Compared with the control group,the CNO group specifically activated PV-positive interneurons in DG,accompanied by an increase in KI67+positive numbers,and decreased spontaneous activity distance,increased PPI and working memory.Conclusion:The increase of PV-positive GABAergic interneurons in DG by aerobic exercise is accompanied by an increase neonatal cells;PV interneurons ablation in DG lead to abnormal neurogenesis,and exercise cannot improve these deficits any more.Activation of PV+neurons in DG by chemical genetic techniques can mimic the benefit effects of exercise.These results indicate that PV interneurons play a crucial role in the maintenance and maturation of new born cells.PV interneurons in DG are a good target for saving SCZ phenotype.