The Establishment Of Environmental Stress Animal Models And Their Neurobiological Mechanisms

Environmental stress can damage the homeostasis of the organism,leading to serious diseases,including endocrine disorders,cardiovascular disease,obesity,depression or anxiety,drug addiction,schizophrenia and neurodegenerative diseases.Construction of animal models of such environmental stress can not only simulate the corresponding symptoms,but also help to study the pathogenesis with anatomy,cell and molecular biology methods.In this study,we investigated the effect of two kinds of environmental stress,24-hour restraint on mice and-6 degree head-down bed rest(HDBR)on monkey,and we want to explore the effects of environmental stress on behavior and brain functionFirst,we subject mice to 24-hour-restraint to simulate the situation that earthquake survivors being trapped under rubble during earthquake.We studied the short-term(2 days after the restraint)and long-term(35 days after the restraint)impaction of this single acute restraint stress,focusing on changes of physiology,behaviors,glucose uptake in brain and adult hippocampal neurogenesis and gene expressions in brain.The restraint mice displayed significant decreased weights and?2-fold increase of serum corticosterone level,demonstrating the 24-hour restraint is a strong stress.In the behavior tests,we found that the restraint mice displayed depressive-like behaviors,including anhedonia(reduced sucrose preference)and despair(increased immobility and decreased latency to abandon in force swim test).Also,in the contextual fear conditioning test,the restrained mice displayed less freezing time.Surprisingly,we found such depressive-like behaviors didn't disappear after 35 days,implying the long-lasting impact of the 24-hour restraint.Moreover,we found the restraint mice exhibited reduced hippocampal adult neurogenesis and decreased glucose uptake in brain.Microarray studies also suggested that genes related to depression and other mental disorders were differentially expressed after 24-hour restraint in both PFC and hippocampus,including neuroactive ligand-receptor(Drdla,Drd2,Adora2a,Htr1d)and myelination-related genes(Mbp,Plp1,Ugt8a,Ernm).At last,we demonstrated that the depression-like phenotypes induced by 24-hour restraint could be reversed by fluoxetine,a type of antidepressant drug.To summary,24-hour-restraint stress mice showed long-lasting dipressive-like behaviors and can be used as a mouse model of depression with both good face validity and predictive validity.This model is easily constructed and can be further used in the development of antidepressant drugs.Next,we established the monkey model of simulated weightlessness by subjecting monkeys to 42-day-60 HDBR.With the development of manned space flight technology,there will be increasing tasks of human exploration of outer space.However,the spatial microgravity of the environment will lead to not only physical changes to astronauts,including cardiovascular,bone,muscle,immune function and endocrine,but also mental changes affecting brain functions.In this thesis,we applied-6° HDBR to simulate the situation under microgravity that blood flows to head.First,we found that the weight of monkey was significantly decreased after HDBR.Then we used metabolomics method to study the changes of metabolite levels of the hippocampus after the HDBR.We found significant changes of abundance of more than 400 ions,including nervous-system-related metabolites like uridine 5'-diphosphate(UDP),adenosine,epinephrine,norepinephrine and serotonin,implying the metabolomic changes of the nervous system.Moreover,we demonstrated the decreased survival and decreased adult neurogenesis in hippocapus of HDBR monkeys.All above results provide possible explanation of how simulated weightlessness leads to abnormal cognition and decision making.In summary,in this thesis,we established two kinds of animal models experiencing environmental stress:mouse model under 24-hour-restraint and monkey model under simulated weightlessness.And we also studied the effects of such environmental stress on the brain functions and invovled molecular mechanisms.