Behavioral Changes And Mechanisms Induced By Acetic Acid In Mice

Alcohol abuse is one of the most common mental disorders in the world,affecting more than 15 million adults in the United States,posing a serious public health threat.Alcohol abusers who stop consuming alcohol experience a negative emotional state resulting in a poor quality of life and decreased productivity.However,the current treatment for alcohol abuse mainly focuses on the addiction,but lacking research on the mechanism of alcoholism and treatment on brain damage in alcohol abuse patients.How to reverse the brain damage of patients who suffering from alcoholism,restore the cognitive function of patients,and make them return to normal life has become an important research field.This study focuses on exploring the possible molecule that causes brain nerve injury after alcohol exposure,the metabolic product of alcohol,acetate.Exploring the tagged site of acetate and its mechanism,revealing the mechanism of alcohol exposure affecting cognition,providing clues for the pathological mechanism,and looking for a new target for the treatment of patients is our intention.Based on previous studies,this study proposed that acetate,the metabolite of alcohol,was the molecule that really caused pathological damage on alcoholism,and exploring the biological function and regulatory mechanism of acetate on alcoholism.Primary hippocampal neurons and cortical neurons were cultured in vitro,and different concentration injury models were constructed.We found that compared with the same dose of alcohol,acetate caused more severe damage on neurons viability that from different brain regions,and showed a dose-dependent effect.Flow cytometry also verified that the apoptosis of neurons induced by acetate was significantly increased.We constructed mouse model of acute alcoholism,tested with open field test and Y maze test.We found that the same dose of acetate can induce more severe alcoholism symptoms,including instability gait,reduced activity,acute cognitive impairment,learning and memory deficit.After confirming that acetate can cause acute alcoholism symptoms,we also constructed a mouse model of chronic alcoholism.Open field test,Y maze,elevated plus maze and Novel object recognition task showed that compared with the same dose of alcohol,acetate induced a more severe memory and cognitive deficit and triggered anxiety behavior in chronic mouse model.Tail suspension test showed that the mice have depressive like behavior,which confirmed that acetate is the direct injury molecules in alcoholism.By testing apoptosis factor and inflammatory factor in hippocampus from chronic Mouse model,we found that acetate reduced the expression of antiapoptotic factor BCL-2 on neural cells of hippocampus,and increased expression of apoptosis factor BAX.The expression of inflammatory factors including TNF-α,TGF-β,IL-1,IL-4,IL-6 was increased.The results showed that acetate impaired mice hippocampal,elevated levels of neuron apoptosis,and causing inflammation storm.Immunofluorescence results showed that acetate reduced the number of microglia in cortical regions of brain tissue in chronic mouse models.Further,the hippocampus produced by established chronic mouse model of acetate and alcohol were analyzed using metabonomics.The results showed that the chronic mouse model of acetate and alcohol have adenosine synthesis and metabolism related pathways turbulence.There are lot of overlapping pathway on the synthesis and metabolism of adenosine in the hippocampus compare with chronic alcohol model.It hinted us that hippocampal metabolic disorders induced by acetate may have a close relationship with adenosine related pathways,and be the reason of brain damage in alcoholism.Based on this assumption we use DPCPX(adenosine A1A receptor inhibitor)on acute model.Then the result of open field test showed that DPCPX can rescue reduced activities and anxious caused by acute acetate.This result showed that the effect of acetate on alcoholism rely on activation of adenosine receptor A1A pathway.Then we also tested chronic acetate model intervened with DPCPX.Mice that given inhibitor of adenosine receptor A1A show alleviated depression behavior induced by acetate.This suggested that the key of depression on chronic mouse model induced by acetate is adenosine A1AR pathways.Therefore,this study showed that the activation of adenosine receptor pathway mediated by acetate is the reason cause acute and chronic learning and memory impairment,depression,anxiety behavior and inflammation storm after drinking.Blocking the interaction between acetate and adenosine receptor may be a new treatment plan for the prevention or treatment of alcoholism.