The special geographical environment and climate characteristics of the plateau can have many impacts on human physiology and psychology, and in severe cases, it can also endanger life and health. Previous studies have shown that as altitude increases, problems such as sleep disorders, changes in brain function, and anxiety continue to emerge among officers and soldiers stationed at high altitudes. Among them, sleep disorders and cognitive impairment are two particularly prominent issues, which have received much attention from military occupational medicine. Cognitive impairment (CI) often coexists with sleep disorders and is highly destructive, directly affecting the combat effectiveness of the military. Therefore, prevention and treatment measures can be sought to improve sleep disorders and cognitive impairment caused by altitude hypoxia through intervention. Existing research has clearly shown that enhancing the insulin effect of the central nervous system can improve learning and memory functions in both animals and humans, especially hippocampus dependent (declarative) memory. After intranasal administration of insulin, it can bypass the blood-brain barrier, pass through the extracellular nerve gap of the trigeminal nerve and the olfactory nerve pathway, and quickly reach the central nervous system through paracellular transport and endocytosis, increasing the central insulin concentration distributed in the space around cerebral blood vessels. It inhibits the secretion of the hypothalamic pituitary adrenal axis by acting on the hypothalamic nucleus and marginal structures (such as the hippocampus) that can express a large number of insulin receptors, improving sleep cycle disorders and cognitive impairment. This article will provide a review of nasal insulin, sleep awakening cycle, and cognitive impairment.

Huang Qingqing, Zeng Jingzheng, Lin Lu, Dai Xuemei, Shi Qin, Wu Xiao, Gong Gu. Research progress on reducing cognitive impairment under high-altitude hypoxia conditions by improving sleep awakening cycle through nasal insulin pretreatment. Frontiers in Medical Science Research (2023) Vol. 5, Issue 10: 1-7. https://doi.org/10.25236/FMSR.2023.051001.

[1] Xie Xinmin, Wen Yalan. The impact of long-term exposure to hypoxic environments on cognitive function [J]. China Public Health, 2008 (07): 814-815

[2] Yang Ying, Jing Linlin, Ma Huiping, et al. Research on the Mechanism and Prevention and Treatment of Hypoxia Induced Cognitive Dysfunction [J]. Medical Review, 2018, 24 (13): 2537-2542

[3] Zhao Houyu, Tu Zhihao, Qu Jingrui, et al. The impact of special environments on cognitive function in military personnel [J]. Journal of Second Military Medical University, 2021, 42 (04): 432-438. 

[4] Nedelcovych M T, Gadiano A J, Wu Y, et al. Pharmacokinetics of Intranasal versus Subcutaneous Insulin in the Mouse[J]. ACS Chem Neurosci, 2018, 9(4):809-816. 

[5] Benedict C, Frey W N, Schioth H B, et al. Intranasal insulin as atherapeutic option in the treatment of cognitive impairments [J]. Exp Gerontol, 2011, 46(2-3):112-115. 

[6] Renner D B, Svitak A L, Gallus N J, et al. Intranasal delivery of insulin via the olfactory nerve pathway[J]. J Pharm Pharmacol, 2012, 64(12):1709-1714. 

[7] Salameh T S, Bullock K M, Hujoel I A, et al. Central Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition [J]. J Alzheimers Dis, 2015, 47(3):715-728. 

[8] Liang Ningjian, Contemporary Cognitive Psychology (Revised Edition) [M] Shanghai: Shanghai Education Press, 2014, 3-5

[9] Zhang Renjing. A follow-up study on the psychological health of new recruits entering the plateau rapidly [D]. Chinese People's Liberation Army Army Military Medical University, 2020. 

[10] Morley JE. An Overview of Cognitive Impairment. Clin Geriatr Med. 2018, 34(4):505-513. 

[11] Wang Hong, Liu Shixiang, Liu Shuxiao, et al. The impact of different altitude environments on cognitive abilities and military operations of military personnel [J]. Journal of Clinical Military Medicine, 2013, 41 (01): 12-13. 

[12] Zhong Z, Zhou S, Xiang B, et al. Association of Peripheral Plasma Neurotransmitters with Cognitive Performance in Chronic High-altitude Exposure. Neuroscience. 2021, 463: 97-107. 

[13] Ji W, Zhang Y, Ge RL, et al. NMDA Receptor-Mediated Excitotoxicity Is Involved in Neuronal Apoptosis and Cognitive Impairment Induced by Chronic Hypobaric Hypoxia Exposure at High Altitude. High Alt Med Biol. 2021, 22(1):45-1457. 

[14] de Aquino Lemos V, Antunes HK, dos Santos RV, et al. High altitude exposure impairs sleep patterns, mood, and cognitive functions. Psychophysiology. 2012, 49(9):1298-306. 

[15] Shi Juhong, Ding Ding, Shi Jianping. Analysis of cognitive impairment and its risk factors in 237 soldiers stationed at high altitude [J]. Journal of the Second Military Medical University, 2017, 38 (09): 1214-1217

[16] Hu Keyan, Shi Qinghai, Fu Jianfeng. The mechanism and protective measures of cognitive impairment in the brain at high altitude [J]. Northwest Journal of National Defense Medicine, 2015, 36 (04): 247-250

[17] Zhang Na, Chen Xuewei, An Gaihong, et al. Comparison of sleep quality and cognitive function of officers and soldiers stationed at different altitudes in high-altitude areas [J]. Journal of Preventive Medicine of the People's Liberation Army, 2014, 32 (05): 406-408

[18] Wu Shizheng. Research Progress in High Altitude Brain Science [J]. Journal of High Altitude Medicine, 2019, 29 (01): 47-53

[19] Zhang Zhonghua, Zhu Xiquan. Sleep status and intervention of soldiers stationed at high altitude [J]. Journal of Hospital Management of the People's Liberation Army, 2014, 21 (06): 583-585

[20] Garske LA, Brown MG, Morrison SC. Acetazolamide reduces exercise capacity and increases leg fatigue under hypoxic conditions. J Appl Physiol (1985). 2003, 94(3):991-996. 

[21] Bradwell AR, Myers SD, Beazley M, et al. Exercise limitation of acetazolamide at altitude (3459 m). Wilderness Environ Med. 2014, 25(3):272-277. 

[22] Vochteloo A J, Moerman S, van der Burg B L, et al. Delirium risk screening and haloperidol prophylaxis program in hip fracture patients is a helpful tool in identifying high-risk patients, but does not reduce the incidence of delirium[J]. BMC Geriatr, 2011, 11:39. 

[23] Zhang Jianwei, Wang Junbo, Wang Mengyuan, et al The central regulatory effect of insulin on metabolism [J]. Progress in Physiological Science, 2018, 49 (06): 401-410. 

[24] Margolis R U, Altszuler N. Insulin in the cerebrospinal fluid [J]. Nature, 1967, 215(5108):1375-1376. 

[25] Havrankova J, Schmechel D, Roth J, et al. Identification of insulin in ratbrain[J]. Proc Natl Acad Sci USA, 1978, 75(11):5737-5741. 

[26] Stockhorst U, de Fries D, Steingrueber H J, et al. Insulin and the CNS: effects on food intake, memory, and endocrine parameters and the role of intranasal insulin administration in humans[J]. Physiol Behav, 2004, 83(1):47-54. 

[27] Shen Fang, Zhang Xiaoming, Liu Weiguo, et al Research progress on the role of insulin and insulin receptors in learning and memory [J]. Journal of Neuroanatomy, 2006 (03): 359-366. 

[28] Born J, Lange T, Kern W, et al. Sniffing neuropeptides: a transnasal approach to the human brain[J]. Nat Neurosci, 2002, 5(6):514-516. 

[29] Drejer K, Vaag A, Bech K, et al. Intranasal administration of insulin with phospholipid as absorption enhancer: pharmacokinetics in normal subjects[J]. Diabet Med, 1992, 9(4):335-340. 

[30] Schmid V, Kullmann S, Gfrorer W, et al. Safety of intranasal human insulin: A review[J]. Diabetes Obes Metab, 2018, 20(7):1563-1577. 

[31] Akintola A A, van Heemst D. Insulin, aging, and the brain: mechanisms and implications[J]. Front Endocrinol (Lausanne), 2015, 6:13. 

[32] Ji Yanqiu, Tao Lijun. The preventive effect of insulin intranasal administration on postoperative delirium in elderly patients [J]. Journal of Translational Medicine Electronics, 2018, 5 (10): 113-115

[33] Chen Yongsheng, Wang Shengsheng. The effect of high-altitude hypoxic environment on sleep and brain function [J]. Journal of Air Force Medicine, 2012, 28 (03): 150-153+158. 

[34] Zhang Zhonghua, Zhu Xiquan. Sleep status and intervention of soldiers stationed at high altitude [J]. Journal of Hospital Management of the People's Liberation Army, 2014, 21 (06): 583-585. 

[35] Nussbaumer-Ochsner Yvonne, Ursprung Justyna, Siebenmann Christoph, et al. Effect of short-term acclimatization to high altitude on sleep and nocturnal breathing. [J]. Sleep, 2012, 35(3):419-423. 

[36] Tian Lishan, Yao Yandong, Zhou Wei, Zhou Yanzhao, Fan Ming, Gao Yue. Research progress on the prevention and treatment of sleep disorders in high-altitude garrison training officers and soldiers [J]. Military Medicine, 2020, 44 (07): 546-551+558. 

[37] McManus M, Horvath SM, Bolduan N, et al. Metabolic and cardiorespiratory responses to long-term work under hypoxic conditions. J Appl Physiol. 1974, 36(2):177-182. 

[38] Fan Joline, Kudo Kiwamu, Ranasinghe Kamalini, et al. 073 Whole-brain network analysis of neural oscillations during light sleep [J]. Sleep, 2021, 44(Supplement2):A30-A31. 

[39] Dement W, Kleitman N. Cyclic variations in EEG during sleep and their relation to eye movements, body motility, and dreaming. Electroencephalogr Clin Neurophysiol. 1957, 9(4):673-690. 

[40] Li Yingxue, Ge Yijun, Kong Xiaoyi, et al. Changes in serum neurotrophic factors in patients with chronic insomnia and their relationship with sleep quality and cognitive function [J]. Chinese Journal of Neurology, 2020, 53 (2): 85-90. 

[41] Wang Chunye, Xing Jia. The relationship between insomnia and cognitive impairment [J]. Tianjin Traditional Chinese Medicine, 2016, 33 (6): 381-384. 

[42] Kreutzmann JC, Havekes R, Abel T, et al. Sleep deprivation and hippocampal vulnerability: changes in neuronal plasticity, neurogenesis and cognitive function[J], Neuroscience, 2015, 309:173-190. 

[43] Claxton A, Baker LD, Hanson A, et al. Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer's disease dementia. J Alzheimers Dis, 2015. 44(3): p. 897-906. 

[44] Farzampour, S., A. Majdi and S. Sadigh-Eteghad, Intranasal insulin treatment improves memory and learning in a rat amyloid-beta model of Alzheimer's disease. Physiol Int, 2016. 103(3): p. 344-353. 

[45] Chen Y, Zhao Y, Dai CL, et al. Intranasal insulin restores insulin signaling, increases synaptic proteins, and reduces Abeta level and microglia activation in the brains of 3xTg-AD mice. Exp Neurol, 2014. 261: p. 610-619. 

[46] Li X, Run X, Wei Z, et al. Intranasal Insulin Prevents Anesthesia-induced Cognitive Impairments in Aged Mice. Curr Alzheimer Res, 2019. 16(1): p. 8-18. 

[47] Zhang Y, Dai CL, Chen Y, et al. Intranasal Insulin Prevents Anesthesia-Induced Spatial Learning and Memory Deficit in Mice. Sci Rep, 2016. 6: p. 21186. 

[48] Mamik M K, Asahchop E L, Chan W F, et al. Insulin Treatment Prevents Neuroinflammation and Neuronal Injury with Restored Neurobehavioral Function in Models of HIV/AIDS Neurodegeneration[J]. J Neurosci, 2016, 36(41):10683-10695. 

[49] Ritze Y, Kern W, Ebner E M, et al. Metabolic and Cognitive Outcomes of Subchronic Once-Daily Intranasal Insulin Administration in Healthy Men[J]. Front Endocrinol (Lausanne), 2018, 9:663. 

[50] Feld G B, Wilhem I, Benedict C, et al. Central Nervous Insulin Signaling in Sleep-Associated Memory Formation and Neuroendocrine Regulation[J]. Neuropsychopharmacology, 2016, 41(6):1540-1550.