Role And Mechanism Of P75NTR In PTSD

Post traumatic stress disorder(PTSD)is a kind of mental disorder which is delayed and persistent for a long time after an individual experiences sudden,threatening or catastrophic life events.According to the diagnostic criteria of PTSD,the primary condition of the external factors(inducements)of PTSD is traumatic event experience,that is,the external environment of the individual is very important for the occurrence of PTSD.Special environment,such as plateau,explosion,earthquake,burn and other disaster environment,including sea disaster,mine disaster and debris flow,will increase the risk of PTSD.In recent years,with the frequent occurrence of accidental trauma and natural disasters,the incidence rate of PTSD has increased year by year,and the disease duration is long and the cure rate is low.PTSD can not only lead to the decline of individual quality of life and the impairment of social and occupational functions,but also often coexist with substance abuse,depression,anxiety,phobia and so on.In the case of lack of social support,PTSD can cause long-term negative impact on patients,families and society,and bring heavy economic burden.Therefore,it is of great significance to find an effective target for the treatment of PTSD.p75 neurotrophin receptor(p75NTR)is a low affinity receptor for nerve growth factor,which is highly expressed in the developing nervous system and the central nervous system of adult patients with injury or neurodegenerative diseases.As a pleiotropic neurotrophic factor receptor,p75 NTR plays different biological functions by forming a polymeric signal complex with other protein molecules.p75 NTR can act as a receptor of neurotrophin family members such as nerve growth factor(NGF)and play a role in neuronal survival and nerve regeneration.p75 NTR can also act as a co receptor of Nogo-66 receptor(Ng R)and participate in the inhibition of neurite outgrowth.In addition,p75 NTR is also the first member of tumor necrosis factor(TNF)receptor superfamily with intracellular deathdomain,which is involved in the regulation of neuronal apoptosis and autophagy.In the central nervous system,the effects of p75 NTR on nerve regeneration,neuronal apoptosis and regulation all affect the density of dendritic spines and synaptic plasticity.Therefore,p75 NTR has a variety of biological functions,including promoting neuronal survival,mediating apoptosis,participating in the process of synaptic plasticity,inducing autophagy and so on.There is evidence that p75 NTR may regulate the synaptic plasticity of hippocampal neurons through apoptosis and autophagy,and the changes of synaptic plasticity of hippocampal neurons can lead to a series of behavioral cognitive impairment,and it has been confirmed that p75 NTR is related to the occurrence of PTSD comorbidities such as depression and suicidal tendency.These results suggest that p75 NTR may be involved in the occurrence of PTSD and may be a potential therapeutic target for PTSD.In order to investigate the role and mechanism of p75 NTR in the pathogenesis of PTSD,p75 NTR knockout mice and p75 NTR overexpression AAV infected mice were treated with single prolonged stress(SPS),The effects of p75 NTR on the behavior of PTSD mice were detected by open field experiment,elevated cross maze and water maze.The pathological mechanism of p75 NTR was explored by HE,Nissl and Golgi staining.On this basis,the molecular mechanism of p75 NTR in the pathogenesis of PTSD was further explored by immunofluorescence and Western blot.The main research contents are as follows:1.Generation and identification of p75 NTR knockout / overexpression miceThe p75 NTR gene knockout heterozygous mice were mated to obtain the homozygous knockout p75 NTR offspring.The genotypes of p75 NTR were identified by multiplex PCR and further verified by detecting the expression of p75 NTR,The p75 NTR overexpression mice were obtained by intracerebroventricular injection of AAV into normal mice.The expression of p75 NTR and HA was detected by immunofluorescence and Western blot.2.Behavioral effects of p75 NTR at different expression levels on PTSD micep75NTR gene knockout/overexpression animals were used to establish PTSD mouse models by SPS.After two weeks of stress,the behavioral effects of p75 NTR on PTSD mice were detected by open field experiment,elevated cross maze and water maze.3.The pathological mechanism of p75 NTR in the pathogenesis of PTSDHE and Nissl staining were used to detect the number and morphology of hippocampal neurons,and Golgi staining was used to detect the density and morphology of dendritic spines.4.Molecular mechanism of p75 NTR in PTSDTUNEL staining,immunofluorescence and Western blot were used to explore the molecular mechanism of p75 NTR in PTSD.First,immunofluorescence and Western blot were used To investigate the role of p75 NTR in PTSD induced autophagy,the expression of Beclin-1,LC3A/B and other autophagy related genes in the hippocampus were detected by blot,and the apoptosis in the hippocampus was detected by TUNEL staining.Meanwhile,the expression of neuron specific markers Neu N and apoptosis-associated protein Bcl-2 were detected to explore the effect of p75 NTR on apoptosis in the hippocampus.Finally,synapsin I was used to detect the regulatory effect of p75 NTR on synaptic plasticity of hippocampal neurons in PTSD mice.The main results and conclusions are as follows:1.p75 NTR knockout / overexpression experimental animals were obtained,and PTSD animal model was prepared by SPS method.2.Behavioral test results showed that p75 NTR knockout / overexpression could effectively improve the symptoms of PTSD mice stimulated by SPS.3.The results of histopathological staining showed that p75 NTR was involved in the regulation of hippocampal neuronal apoptosis and synaptic plasticity,and affected the density of dendritic spines and the length of axons,which may be the histopathological mechanism of p75 NTR in the development of PTSD.4.The molecular mechanism of p75 NTR involved in PTSD may be through regulating the expression of autophagy,apoptosis and synaptic plasticity related molecules in hippocampal neurons.