Chronic Stress Affects Autophagy In The Drosophila Brain

When the body produces a series of reactions due to the external environment or internal environmental factors that cause the homeostasis to change,it is called stress.Stress promotes the imbalance of internal environment homeostasis,and the body maintains internal homeostasis through its own response mechanism.Long-term or more intense stress can induce homeostasis imbalances that cannot rehabilitate on their own,leading to the occurrence of various diseases.The brain is the organ most affected by stress,and chronic stress-induced cognitive impairment is the most common stress-related brain dysfunction.So far,scientists still know very little about the neural mechanisms of cognition-related complex behaviors.The neural molecular mechanisms of stress-regulating learning and memory are very complex and have not yet been fully elucidated.The regulatory mechanisms of many cell signaling pathways are highly conserved between the invertebrate model organism Drosophila melanogaster and mammals.In order to explore the neuromolecular and cellular mechanisms of stress-induced cognitive impairment,our laboratory established a set of Drosophila models of chronic stress-induced cognitive impairment in the previous work.After four days of chronic stress treatment on Drosophila,Its olfactory learning and memory ability is significantly reduced.Autophagy is an important way for the elimination of metabolic waste in organisms.Its abnormalities may directly or indirectly lead to the occurrence of many diseases,such as heart disease and premature aging.After the signal that induces autophagy is sent to the cell,autophagosomes are formed inside the cell,and then the autophagosomes fuse with lysosomes to degrade the substances inside the autophagosomes.Studies have found that up-regulating the autophagy level of Drosophila mushroom bodies can affect Drosophila ’ s olfactory memory ability by protecting neuronal synapses.This thesis mainly explores the molecular mechanism of chronic stress affecting the aversive olfactory learning ability of Drosophila at the biochemical level.Biochemical tests on the levels of Ref(2)p and Atg8a-II showed that after acute stress treatment,autophagy was first up-regulated and then down-regulated,and then returned to normal.After four days of chronic stress treatment,autophagy levels were significantly down-regulated.It implies that autophagy is related to olfactory learning disorder induced by chronic stress.Interestingly,after chronic stress treatment,while the levels of Ref(2)p and Atg8a-II were up-regulated,TOR activity was significantly down-regulated,suggesting that chronic stress may destroy a certain link downstream of the autophagy-lysosome pathway,leading to Autophagic flux is blocked;and the inhibition of TOR activity is a compensatory effect of autophagic flux blocking.Previous work has shown that overexpression of Atg1 and increasing the background level of autophagy of neurons can protect the olfactory learning ability of Drosophila from chronic stress.This study found that overexpression of Atg1 can effectively protect the autophagic flow from being blocked by chronic stress.And feeding chloroquine,a drug that can block the autophagy flow,also disrupts the olfactory learning of Drosophila.These results further verified the above hypothesis and proved that chronic stress impairs the olfactory learning ability of Drosophila by disrupting the autophagy flow.In this study,we also found that a PKC has an important regulatory effect on the olfactory learning ability of Drosophila.Overexpression or knockdown of a PKC by RNAi will damage the olfactory learning ability of Drosophila.Although there are reports showing that a PKC activity also has the effect of regulating autophagy,the data in this article show that chronic stress does not affect the activity of a PKC,and manipulation of a PKC function has no effect on chronic stress-induced learning disabilities.