A Study Of The Neural Mechanisms Of Chronic Stress-induced Olfactory Learning And Memory Deficits In Drosophila Melano Gaster

Stress often causes responsive changes in the animal's environment.Depending on the severity of the stress,this change has varying degrees of impact on the organism,ranging from a slight impact on quality of life to a serious life-threatening.Although the effects of stress on human health have been extensively studied,little is known about the molecular and neural mechanisms of stress-induced cognitive impairment.Genetic model organisms such as Drosophila melanogaster are rarely used to study the impacts of chronic stress on learning and memory.Our laboratory has previously established a Drosophila chronic stress model with vibration as the main stressor.Previous studies based on this model have found that olfactory learning and memory is significantly dampened after chronic unpredictable vibration treatment and the memory deficits are triggered by hyperdopaminergic signaling during treatmen.In this thesis,the following issues are investigated:1.Further characterize the impacts of chronic vibrati on stress.Chronic vibration stress induced learning deficits persists for at least three days,suggesting that chronic stress can induce a long-term internal state.In addition to olfactory learning and memory,this study examines the chronic vibration st ress treated flies with multiple behavioral tests,including forced wimming test,courtship behavior and stop-for-sweet tes.The results show that chronic vibration stress induces not only cognitive deficits in Drosophila,but also depression like behaviors,such as decreased sexual drive,anhedonia and behavioral despair.In addition,the levels of two important stress-related neuromodulators in the Drosophila brain,dopamine and octopamine,also decreased significantly after chronic vibration stress treatment.Octopamine is the insect norepinephrine analogue.Both dopamine and norepinephrine are closely related to depression.These experimental evidence suggests that the chronic vibration stress paradigm established in our laboratory can induce a depressio n-like state in Drosophila.2.Define the mushroom body neural circuits that mediate the impacts of vibration stress on olfactory learning.In this study,genetically encoded neural silencing and activation tools were used to screen dopamine neurons that p roject into mushroom bodies.The screen indetified MB-MP1/PPL1-?1pedc as the key dopaminergic neuron that mediates the deleterious effect of vibration stress on olfactory learning.Further studies have also found that the activity of MB-MVP2/MBON-?1pedc>?/? and KC?/? neurons that form synaptic connection with MB-MP1 is also important for chronic vibration stress-induced learning deficits.As pevious studies have shown that MP1 functionally inhibits the neuronal activity of MVP2 and MVP2 are inhibitory GABAergic neurons that project their axons to ?/? lobe,these experimental evidence thus supports the following model: In the process of chronic vibration treatment,vibraion induces hyperctivity in MB-MP1 neuron,and via a neural pathway composed of MB-MVP2 and KC ?/?,the MB-MP1 hyperdopaminergic signal modulates the mushroom body neural network to induce learning deficits.3.The deleterious effects of chronic carbon dioxide stress on olfactory learning and memory.A novel Drosophila chronic stress model was established with 2% carbon dioxide,an odorant that causes strong escape response in Drosophila,as the main stressor.Chronic carbon dioxide stress treatment specifically induces defects in olfactory learning and memory.Moreover,artificial activation of carbon dioxide olfactory receptor neurons can substitute carbon dioxide as a major stressor to cause chronic stress-induced learning deficits.Further behavioral and genetic analysis showed that chronic carbon dioxide stress specifically impairs anesthesia-sensitive memory(ASM).Moreover,the olfactory learning of ageing flies is resistant to chronic carbon dioxide stress,suggesting that chronic carbon dioxide stress and natural ageing process damages the same type of olfactory memory.4.Chronic sevoflurane stress impairs olfactory learning and memory.Chronic stress treatment with sevoflurane,an commonly used anesthetics that can paralyze fruit flies,as the major stressor also specifically causes olfactory learnin g deficits in Drosophila,suggesting that Drosophila can be a genetic model organisms for studying the cognitive dysfunction after repeated sevoflurane exposure.