Effect Of Orexin And Its Receptor On Learning And Memory In Chronic Sleep Deprivation Mice And Its Mechanism

Sleep is an essential for optimal health and performance in human life.Sleep disruption caused by occupational factors and/or sleep disorders results in the cognitive decline.It has substantial social and financial costs and is increasingly becoming a major public health and safety issue.The significant risk factors for developing mild cognitive impairment(MCI)and dementia,mostly Alzheimer's disease(AD)type have been special sleep problems.Chronic insomnia affects appromoximately 30-60%of older individuals.Therefore,the study of the relationship between sleep and cognitive aging has important public health implications for people at risk of cognitive decline to be a potential means to improve cognitive health.Although this type of sleep problem is very common in the elderly,there is not still enough attention.This study attempts to explore the effects and possible mechanisms of chronic sleep deprivation(CSD)on the behavior and cognition of aging population.The main research contents are as follows:1.Y-maze behavioral test was carried out on 6-month-old wild C57BL/6 female mice.The mice with similar cognitive level were randomly divided into groups to ensure that all mice had similar cognitive starting level,so as to ensure the smooth progress of the test.The model of chronic sleep deprivation was established in mice with gentle handling(GH),and the model of drug intervention was established in mice with dual orexic receptor antagonists(DORA).The results showed that female mice were more suitable to live in groups and fight less than male mice,which reduced unnecessary death.Compared with water platform sleep deprivation,GH sleep deprivation significantly reduced the fatigue and the death rate of mice.2.Morris water maze was used to detect the hippocampus-dependent spatial learning and memory ability of different groups of mice.It was found that CSD prolonged the escape latency and reduced the number of times to cross the platform in space exploration,while suvorexant shortened the escape latency and increased the number of times to cross the platform after treatment.The results showed that CSD damaged the learning and memory ability of mice,and suvorexant could reverse or inhibit the damage.3.The tau protein in CA1 area of hippocampus of different groups of mice was detected by immunohistochemistry and Western blotting,and statistical analysis showed that there was no significant accumulation of tau protein in sleep deprivation group.This suggests that sleep deprivation in female C57BL/6 mice can cause cognitive behavioral changes,but it does not reach the level of tau protein accumulation,which may be the reason for the mild cognitive decline of early dementia.4.Immunohistochemistry and Western blotting were used to detect astrocytes in CA1 area of hippocampus of different groups of mice,and statistical analysis was carried out.It was found that astrocytes in sleep deprivation group were significantly activated,while astrocytes in suvorexant treatment group were inhibited.This suggests that cognitive decline can cause astrocyte activation,which can be inhibited by orexin receptor antagonists.Therefore,orexin system and astrocytes are likely to participate in the regulation of cognitive function together.Whether the orexin system is involved in regulating the function of astrocytes in cognition remains to be further studied.To sum up,chronic sleep deprivation can cause mild decline of learning and memory function in aged wild-type mice.While sleep deprivation can not cause the accumulation of tau protein in CA1 area of hippocampus,it can obviously activate astrocytes.Suvorexant,a dual orexin receptor antagonist,improved cognition as well as sleep,and had a significant inhibitory effect on activation of astrocytes.