低温低氧对学习记忆的影响及药物防护研究
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摘要
我国高原面积广阔，具有重要军事及经济意义的青藏高原平均海拔在4000米以上。空气稀薄、低温干燥等特殊的高原环境对进入人群的身心健康产生严重威胁。大脑对低温、低氧刺激尤为敏感，以脑水肿为病理基础的急性高原病在以往得到了广泛研究。近年来，高原低氧环境引起的记忆能力下降，反应速度下降，错误判断增加和感觉异常等认知能力损伤成为特殊环境医学关注的焦点。认知能力的损伤严重影响高原地区官兵与居民的作业效能与生命健康，如何防护高原低氧环境引起的学习记忆能力下降成为亟待解决的重要问题。目前高原低温低氧损伤学习记忆的特点与医学防护研究仍处于起步阶段，有关高原环境损伤学习记忆的相关基础与应用研究主要集中在动物模型水平，人群研究主要为模拟环境下的实验室研究，并不能有效反应现实条件下的暴露情况及生物学效应。此外，现有研究往往只关注低压低氧单一因素对认知功能产生的影响，而忽略了高原地环境区的另一主要因素——环境低温，高原低温低氧复合环境对认知功能造成的影响有待探讨。在药物防护方面，神经兴奋药物与激素类药物如安非他命、地塞米松等对高原低氧认知功能损伤具有一定的保护作用，但由于其副作用较大，无法作为常规预防药物。最近的研究发现，中药银杏叶的多种成分对脑功能具有良好的保护作用，其标准提取物EGb-761能够调节脑血流，降低氧化损伤，并被认为具有促进高原习服的作用。乙酰唑胺作为预防急性高原反应（AMS）的首选药物，能够加快机体低氧适应。但银杏叶提取物EGb-761及乙酰唑胺对高原认知损伤的预防作用尚不明确。因此，乙酰唑胺及银杏叶提取物EGb-761对高原低温低氧记忆损伤的预防效果及作用机制有待证实。
目的
通过人群现场研究及动物模型研究，观察高原低温低氧复合环境对学习记忆能力的影响，初步评价乙酰唑胺及银杏叶提取物EGb-761对急进高原人群学习记忆能力的影响，探讨银杏叶提取物活性成分单体银杏内酯B（GKB）对小鼠低温低氧暴露学习记忆损伤的防护作用，阐明GluR1蛋白磷酸化水平在GKB防护低温低氧学习记忆能力损伤中的作用，为急进高原引起的学习记忆损伤药物防护提供实验依据和理论基础。
方法
1.受试者分组、药物干预及试验流程
招募年龄17至20岁的男性志愿者进行人群现场研究，随机分为两组，在夏季与冬季分别进行研究。每组按药物干预不同随机分为乙酰唑胺组（125mgBID）、银杏叶组（120mg BID）和安慰剂组。药物干预在进入高原前3天开始，共持续4天。研究对象乘飞机在3小时内从海拔396m上升到海拔3658m。试验地点为西藏拉萨市，平均气温为：夏季18-21℃，冬季0-3℃。
2.受试者记忆能力评价
利用记忆能力测试评价受试者在夏季及冬季急进高原前后记忆水平的变化情况。主要测试包括瞬时回忆测试（瞬时单词回忆测试、瞬时图形回忆测试）、定速视觉相加测试（Paced visual serial addition test，PVSAT）、数符转换测试（Digital symbolsubstitution test，DSST）和延迟回忆测试（延迟单词回忆测试、延迟图形回忆测试）。
3.受试者AMS发病情况
利用Lake Louise评分标准进行评价，其中Lake Louise评分标准包括自我评分（Self-reported score, S-LLS）和临床评分（Clinical assessment score, C-LLS）两部分。
4.低温低氧暴露模型建立
雄性C57J小鼠（18-24g）经不同海拔低温低氧暴露后，以5000m/4℃暴露2h为暴露条件建立低温低氧暴露模型。动物随机分为对照组、GKB预处理组、低温低氧暴露组和GKB预处理低温低氧暴露组。GKB通过腹腔注射方式于暴露开始前1h给药，剂量为40mg/kg bodyweight。
5.低温低氧暴露小鼠学习记忆测试
通过新物体识别测试（Novel object recognition test）及回避离开平台实验（Step-dwoninhibitoryavoidance task）观察小鼠短期记忆与工作记忆能力。主要观察小鼠在新物体识别实验中对新物体的探索时间与鉴别指数（DI）及回避离开平台实验中小鼠离开平台的潜伏期。
6.低温低氧暴露小鼠记忆相关蛋白表达的检测
通过westernblot方法检测NMDA、GluR1、Akt、GSK、PKC等蛋白的表达与活化水平。
7.低温低氧暴露小鼠海马蛋白激酶A（PKA）活性的检测
通过ELISA试剂盒方法检测小鼠海马组织PKA活性水平。结果
1.低氧环境对学习记忆的影响及药物的防护效果
（1）低氧环境对各组AMS发生情况的影响
各组受试对象在高原停留期间均有AMS发生，乙酰唑胺组S-LLS评分（1.5）显著低于安慰剂组（3.0）和银杏叶组（2.8）（p<0.05）。
（2）低氧环境对学习记忆的影响
各组学习测试成绩在急进高原后与平原水平相比均呈现下降趋势，并以急进高原后8h最为显著（p<0.05）。
（3）乙酰唑胺对低氧环境学习记忆能力的影响
在高原3天的测试中，乙酰唑胺组在DSST、PVSAT及延迟回忆测试中的成绩显著低于安慰剂组（p<0.05），通过对急进高原8h后测试成绩的进一步比较后我们发现，乙酰唑胺组在瞬时回忆及PVSAT测试中的成绩显著低于安慰剂组（p<0.05）。
（4）银杏叶对低氧环境学习记忆能力的影响
在高原3天的测试中，银杏叶组在DSST、PVSAT及延迟回忆测试中的成绩显著高于安慰剂组（p<0.05）。通过对急进高原8h后测试成绩的进一步比较后我们发现，银杏叶组受试对象在延迟回忆测试中的成绩显著高于安慰剂组（p<0.05）。
（5）AMS对学习记忆的影响
各药物干预组中发生AMS的受试对象测试成绩与未发生AMS的受试对象相比无显著差别。
2.低温低氧复合环境对学习记忆的影响及药物的防护效果
（1）低温低氧复合环境对AMS发生情况的影响
各组受试对象在高原停留期间均有AMS发生，乙酰唑胺组S-LLS评分（2.2）显著低于安慰剂组（3.9）和银杏叶组（3.3）（p<0.05）。
（2）低温低氧复合环境对学习记忆的影响
各组学习测试成绩在急进高原后与平原水平相比均呈现下降趋势，并以急进高原后8h最为显著（p<0.05）。
（3）乙酰唑胺对低温低氧复合环境学习记忆能力的影响
在高原3天的测试中，乙酰唑胺组在PVSAT测试中的成绩显著低于安慰剂组（p<0.05），通过对急进高原8h后测试成绩的进一步比较后我们发现，乙酰唑胺组受试对象在DSST及PVSAT测试中的成绩显著低于安慰剂组（p<0.05）。
（4）银杏叶对低温低氧复合环境学习记忆能力的影响
在高原3天的测试中，银杏叶组受试对象在PVSAT及延迟回忆测试中的成绩显著高于安慰剂组（p<0.05）。通过对急进高原8h后测试成绩的进一步比较后我们发现，银杏叶组在延迟回忆测试中显著高于安慰剂组（p<0.05）。
（5）AMS对学习记忆能力的影响
各药物干预组中发生AMS的受试对象测试成绩与未发生AMS的受试对象相比无显著差别。
（6）低温低氧复合环境与低氧环境学习记忆能力的比较
通过对夏季和冬季两组急进高原人群安慰剂组测试成绩的比较后发现，冬季低温低氧暴露组在瞬时/延时回忆、DSST和PVSAT测试中的成绩显著低于夏季低氧暴露组（p<0.05）。
3. GKB在低温低氧损伤学习记忆中的作用及机制
（1）低温低氧暴露对小鼠记忆能力的影响
在新物体识别测试和回避离开平台测试中我们发现，在新物体识别测试中，5000m海拔暴露组小鼠与对照组相比，对新物体的探索时间及鉴别指数（DI）显著降低（p<0.05）；在回避离开平台测试中，5000m海拔暴露组小鼠与对照组相比，离开平台的潜伏期显著缩短（p<0.05）。
（2）GKB对低温低氧暴露损伤小鼠学习记忆的影响
在新物体识别测试中，GKB能够显著提高低温低氧暴露后小鼠对新物体的探索时间（p<0.05）及鉴别指数（DI）（p<0.05）。GKB注射组小鼠在回避离开平台测试中离开平台的潜伏期显著多于生理盐水注射低温低氧暴露组（p<0.05）。
（3）低温低氧暴露及GKB干预对学习记忆相关蛋白的影响
通过western blot检测我们发现小鼠海马组织Akt、GSK-3β、Erk的磷酸化水平及PKCα/β、NMDA的表达水平在低温低氧暴露后无明显变化趋势，而GluR1蛋白ser831/845位点磷酸化水平及PKA活性在暴露后显著低于对照组（p<0.05）。
GKB能够缓解低温低氧暴露引起的GluR1蛋白磷酸化水平及PKA活性的下降，在低温低氧暴露后，GKB组GluR1蛋白ser831/845位点磷酸化水平及PKA活性显著高于生理盐水组（p<0.05）。
结论
本研究通过人群现场研究发现急进高原能够引起学习记忆能力下降，而环境低温能够显著加重这种损伤效应。乙酰唑胺对低氧及低温低氧复合环境引起的学习记忆能力下降无防护效果，并能够加重学习记忆能力的损伤，但乙酰唑胺能有效预防AMS的发生。银杏叶提取物EGb-761在急进高原情况下能显著改善急进高原引起的学习记忆能力下降，但对预防AMS无明显效果。银杏叶单体GKB可能在银杏叶提取物EGb-761保护学习记忆水平下降过程中起到关键作用，其作用机制可能是通过调节小鼠海马组织PKA活性及GluR1蛋白磷酸化水平实现的。
The high-altitude areas cover a quarter of land area in China. The special natureenvironment of cold and hypoxia in Qinghai-Tibet Plateau, which has an average elevationof4000m, seriously endangers people’s physical and mental health. Brain is one of themost sensitive organs to cold and hypoxia. Previous studies paid much attention aboutacute mountain sickness (AMS) which was caused by cerebral edema during acuteexposure of altitude. However, the impairments of higher-order brain functions caused by cold and hypoxia complex environment were rarely reported. Recently, the cognitiveability of learning and memory, reaction capacity, reasoning and judgments were reportedto be impaired during acute altitude exposure, which was becoming the focus in thisresearch field. The impairment of cognition may exert widespread impacts on the lifequality and working efficacy of peoples who were living in the high land or taking part inthe military assignments. So, how to prevent people from cognitive impairment duringacute cold and hypoxia exposure was one of the most important questions.
The mechanisms leading to cognitive impairment and specific chemoprophylaxisduring acute cold and hypoxia exposure remain largely unknown. As its limitedexperimental conditions of temperature and atmospheric pressure control, most studiesabout altitude exposure using hypobaric chamber for animal and human experiments.However, the results from such studies under simulated environment may not provide awhole picture of actual situation because there are many more factors that may haveeffects on cognitive performance in high-altitude areas. It was reported that some analepticand steroids such as amphetamine and dexamethasone could improve cognitiveperformance during altitude exposure. However, in view of the side effects of these drugs,they could not be used as conventional medications. As preferred prophylactic drug inprevention of AMS, acetazolamide could promote hypoxia adaptation and relievesymptoms of AMS. Recently, it has been reported that the extract of ginkgo biloba,EGb-761, could protect brain from impairment through its regulative effects on cerebralblood flow during hypoxia exposure. Though may have some beneficial effects, theprotective effects of the two drugs mentioned above remain to be clarified during cold andhypoxia exposure. We hypothesize that acetazolamide and EGb-761might protect peoplefrom impairment of learning and memory during acute cold and hypoxia exposure.
Objective.
The objectives of our study are to determine the impairment effects of acute cold andhypoxia exposure on learning and memory, and assess the protective effects of acetazolamide and EGb-761in human field tests. In animal experiments, we will furtherexplore the protective and regulative effects of Ginkgolide B (GKB), monomer of ginkgobiloba extract, on prevention of learning and memory impairment during acute cold andhypoxia exposure.
Methods.
1. Subjects and experimental procedure.
Male volunteers aging17-20were recruited. And they were randomized into twogroups that ascent to Lhasa in summer and winter separately. And subjects in each groupwere treated with acetazolamide (125mg BID), EGb-761(120mg BID) and placeborandomly. The medication was started3days before ascent and lasted for4days. All thesubjects were lifted from Xianyang (396m) to Lhasa (3658m) where the cognitive testswere performed. The ambient temperature in Lhasa was18-21°C in summer and0-3°Cin winter。
2. Incidence of acute mountain sickness
Lake Louise scoring system was used to assess the incidence of AMS, which isconsisted of the self-reported score (S-LLS) and clinical assessment score (C-LLS).
3. Assessment of learning and memory capacity
Neurocognitive test battery was used to assess the effects of acute altitude exposureon learning and memory in summer and winter. The test battery was consists of immediaterecall (immediate word recall/immediate figure recall), PVSAT (paced visual serialaddition task), DSST (digit symbol substitution test) and delayed recall (delayed wordrecall/delayed figure recall).
4. Cold and hypoxia exposure model
Male C57J mice weighing18-24g was used and exposed to5000m/4°C for2hours.Animals were randomized into control group (Norm), GKB treated control group (Norm+GKB), cold and hypoxia exposure group (Hypo) and GKB treated cold and hypoxiaexposure group (Hypo+GKB). GKB (40mg/kg body weight) was injectedintraperitoneally (i.p.)1hour before the onset of exposure.
5. Behavior tests
Novel object recognition test and step-down inhibitory avoidance test were used toassess the impact of cold and hypoxia exposure on learning and memory.
6. Molecular biological study
The expression and activation level of NMDA, GluR1, Akt, GSK-3β and PKC wasdetected by western blot.
Results.
1. Effects of acetazolamide and EGb-761on learning and memory during acutehypoxia exposure
(1) Incidence of AMS among groups during acute hypoxia exposure
During the stay in Lhasa, all the drug treatment groups were reported to have AMS,but the mean score of S-LLS in acetazolamide group (1.5) was significantly lower thanthat in the placebo (3.0) and EGb-761(2.8) group (p<0.05).
(2) Effects of acute hypoxia exposure on learning and memory
The capacity of learning and memory was severely impaired8h after exposure andgot to be recovered in the following time.
(3) Effects of acetazolamide on learning and memory during hypoxia exposure
During the stay in Lhasa, the subjects in acetazolamide group performed significantl yworse in the delayed recall, DSST and PVSAT tests when compared with placebo group(p<0.05). And further analysis showed that the subjects in acetazolamide group performedsignificantly worse in the immediate recall and PVSAT tests after8h of exposure whencompared with placebo group (p<0.05).
(4) Effects of EGb-761on learning and memory during hypoxia exposure
During the stay in Lhasa, the subjects in EGb-761group performed significantl ybetter in delayed recall, PVSAT and DSST tests when compared with placebo group(p<0.05). And further analysis showed that the subjects in EGb-761group performedsignificantly better in delayed recall test after8h of exposure when compared withplacebo group (p<0.05).
(5) Effects of AMS on learning and memory during hypoxia exposure
There were no significant differences between the subjects with and without AMSwhen compared of their scores in all the neurocognitive tests, no matter what drug theywere treated with.
2. Effects of acetazolamide and EGb-761on learning and memory during acutecold and hypoxia exposure
(1) Incidence of AMS among groups during acute cold and hypoxia exposure
During the stay in Lhasa, all the groups were reported to have AMS, but the meanscore of S-LLS in acetazolamide group (2.2) was significantly lower than that in theplacebo (3.9) and group EGb-761(3.3)(p<0.05).
(2) Effects of acute cold and hypoxia exposure on learning and memory
The capacity of learning and memory was severely impaired8h after exposure andgot to be recovered as the exposure time prolonged in all the groups. After8hours ofhypoxia exposure, subjects in each group performed significantly worse in theimmediate/delayed recall, DSST and PVSAT tests (p<0.05).
(3) Effects of acetazolamide on learning and memory during cold and hypoxiaexposure
During the stay in Lhasa, the subjects in acetazolamide group performed significantl yworse in PVSAT test when compared with placebo group (p<0.05). And further analysisshowed that the subjects in acetazolamide group performed significantly worse in theDSST and PVSAT tests after8h of exposure when compared with placebo group(p<0.05).
(4) Effects of EGb-761on learning and memory during cold and hypoxia exposure
During the stay in Lhasa, the subjects in EGb-761group performed significantl ybetter in PVSAT and delayed recall tests when compared with placebo group (p<0.05).And further analysis showed that subjects in EGb-761group performed significantlybetter in delayed recall test when compared with placebo group (p<0.05).
(5) Effects of AMS on learning and memory during hypoxia exposure
There were no significant differences between the subjects with and without AMS when compared of their scores in all the neurocognitive tests, no matter what drug theywere treated with.
(6) Effects of cold temperature on the impairment effects of hypoxia exposure onlearning and memory
The cognitive performances of the subjects in placebo group in the summer trail andwinter trial were compared. And we found that the performance of subjects in the wintertrail was significantly worse than those in the summer trail (p<0.05).
3. Effects of GKB on learning and memory performance of mouse after coldand hypoxia exposure
(1) Effects of acute cold and hypoxia exposure on learning and memory performance
The time spent in exploring of the novel object as well as the discrimination indexwere significantly reduced in the novel object recognition test (p<0.05), and the latency ofstep down of the platform was significantly shorter in the step-down inhibitory avoidancetask (p<0.05) after2h of cold and hypoxia exposure at5000m.
(2) Effects of GKB on learning and memory performance after cold and hypoxiaexposure
GKB significantly increased the time spent in exploring of the novel object as well asthe discrimination index (p<0.05), and it also significantly increased the latency of stepdown of the platform (p<0.05) when compared with those treated with saline.
(3) Effects of cold and hypoxia exposure and GKB on the expression andphosphorylation level of proteins relative with learning and memory
The expression level of NMDA and PKCα/β and the phosphorylation level of Akt,GSK-3β and Erk were not affected by cold and hypoxia exposure. However, thephosphorylation level of GluR1at ser831/845and the activity of PKA decreasedsignificantly after2h of cold and hypoxia exposure at5000m. This change could bereversed by GKB treatment1h before exposure.
Conclusion.
1. Acute hypoxia exposure could impair learning and memory, and cold temperature could aggravate the impairment effects.
2. Acetazolamide impaired learning and memory during hypoxia as well as cold andhypoxia exposure. However, it could prevent people from AMS.
3. EGb-761could potently protect people from impairment of learning and memory.But it has no protective effects on AMS.
4. GKB might be the key component of EGb-761in prevention of learning andmemory impairment by regulating the phosphorylation of GluR1during cold andhypoxia exposure.
目的
通过人群现场研究及动物模型研究，观察高原低温低氧复合环境对学习记忆能力的影响，初步评价乙酰唑胺及银杏叶提取物EGb-761对急进高原人群学习记忆能力的影响，探讨银杏叶提取物活性成分单体银杏内酯B（GKB）对小鼠低温低氧暴露学习记忆损伤的防护作用，阐明GluR1蛋白磷酸化水平在GKB防护低温低氧学习记忆能力损伤中的作用，为急进高原引起的学习记忆损伤药物防护提供实验依据和理论基础。
方法
1.受试者分组、药物干预及试验流程
招募年龄17至20岁的男性志愿者进行人群现场研究，随机分为两组，在夏季与冬季分别进行研究。每组按药物干预不同随机分为乙酰唑胺组（125mgBID）、银杏叶组（120mg BID）和安慰剂组。药物干预在进入高原前3天开始，共持续4天。研究对象乘飞机在3小时内从海拔396m上升到海拔3658m。试验地点为西藏拉萨市，平均气温为：夏季18-21℃，冬季0-3℃。
2.受试者记忆能力评价
利用记忆能力测试评价受试者在夏季及冬季急进高原前后记忆水平的变化情况。主要测试包括瞬时回忆测试（瞬时单词回忆测试、瞬时图形回忆测试）、定速视觉相加测试（Paced visual serial addition test，PVSAT）、数符转换测试（Digital symbolsubstitution test，DSST）和延迟回忆测试（延迟单词回忆测试、延迟图形回忆测试）。
3.受试者AMS发病情况
利用Lake Louise评分标准进行评价，其中Lake Louise评分标准包括自我评分（Self-reported score, S-LLS）和临床评分（Clinical assessment score, C-LLS）两部分。
4.低温低氧暴露模型建立
雄性C57J小鼠（18-24g）经不同海拔低温低氧暴露后，以5000m/4℃暴露2h为暴露条件建立低温低氧暴露模型。动物随机分为对照组、GKB预处理组、低温低氧暴露组和GKB预处理低温低氧暴露组。GKB通过腹腔注射方式于暴露开始前1h给药，剂量为40mg/kg bodyweight。
5.低温低氧暴露小鼠学习记忆测试
通过新物体识别测试（Novel object recognition test）及回避离开平台实验（Step-dwoninhibitoryavoidance task）观察小鼠短期记忆与工作记忆能力。主要观察小鼠在新物体识别实验中对新物体的探索时间与鉴别指数（DI）及回避离开平台实验中小鼠离开平台的潜伏期。
6.低温低氧暴露小鼠记忆相关蛋白表达的检测
通过westernblot方法检测NMDA、GluR1、Akt、GSK、PKC等蛋白的表达与活化水平。
7.低温低氧暴露小鼠海马蛋白激酶A（PKA）活性的检测
通过ELISA试剂盒方法检测小鼠海马组织PKA活性水平。结果
1.低氧环境对学习记忆的影响及药物的防护效果
（1）低氧环境对各组AMS发生情况的影响
各组受试对象在高原停留期间均有AMS发生，乙酰唑胺组S-LLS评分（1.5）显著低于安慰剂组（3.0）和银杏叶组（2.8）（p<0.05）。
（2）低氧环境对学习记忆的影响
各组学习测试成绩在急进高原后与平原水平相比均呈现下降趋势，并以急进高原后8h最为显著（p<0.05）。
（3）乙酰唑胺对低氧环境学习记忆能力的影响
在高原3天的测试中，乙酰唑胺组在DSST、PVSAT及延迟回忆测试中的成绩显著低于安慰剂组（p<0.05），通过对急进高原8h后测试成绩的进一步比较后我们发现，乙酰唑胺组在瞬时回忆及PVSAT测试中的成绩显著低于安慰剂组（p<0.05）。
（4）银杏叶对低氧环境学习记忆能力的影响
在高原3天的测试中，银杏叶组在DSST、PVSAT及延迟回忆测试中的成绩显著高于安慰剂组（p<0.05）。通过对急进高原8h后测试成绩的进一步比较后我们发现，银杏叶组受试对象在延迟回忆测试中的成绩显著高于安慰剂组（p<0.05）。
（5）AMS对学习记忆的影响
各药物干预组中发生AMS的受试对象测试成绩与未发生AMS的受试对象相比无显著差别。
2.低温低氧复合环境对学习记忆的影响及药物的防护效果
（1）低温低氧复合环境对AMS发生情况的影响
各组受试对象在高原停留期间均有AMS发生，乙酰唑胺组S-LLS评分（2.2）显著低于安慰剂组（3.9）和银杏叶组（3.3）（p<0.05）。
（2）低温低氧复合环境对学习记忆的影响
各组学习测试成绩在急进高原后与平原水平相比均呈现下降趋势，并以急进高原后8h最为显著（p<0.05）。
（3）乙酰唑胺对低温低氧复合环境学习记忆能力的影响
在高原3天的测试中，乙酰唑胺组在PVSAT测试中的成绩显著低于安慰剂组（p<0.05），通过对急进高原8h后测试成绩的进一步比较后我们发现，乙酰唑胺组受试对象在DSST及PVSAT测试中的成绩显著低于安慰剂组（p<0.05）。
（4）银杏叶对低温低氧复合环境学习记忆能力的影响
在高原3天的测试中，银杏叶组受试对象在PVSAT及延迟回忆测试中的成绩显著高于安慰剂组（p<0.05）。通过对急进高原8h后测试成绩的进一步比较后我们发现，银杏叶组在延迟回忆测试中显著高于安慰剂组（p<0.05）。
（5）AMS对学习记忆能力的影响
各药物干预组中发生AMS的受试对象测试成绩与未发生AMS的受试对象相比无显著差别。
（6）低温低氧复合环境与低氧环境学习记忆能力的比较
通过对夏季和冬季两组急进高原人群安慰剂组测试成绩的比较后发现，冬季低温低氧暴露组在瞬时/延时回忆、DSST和PVSAT测试中的成绩显著低于夏季低氧暴露组（p<0.05）。
3. GKB在低温低氧损伤学习记忆中的作用及机制
（1）低温低氧暴露对小鼠记忆能力的影响
在新物体识别测试和回避离开平台测试中我们发现，在新物体识别测试中，5000m海拔暴露组小鼠与对照组相比，对新物体的探索时间及鉴别指数（DI）显著降低（p<0.05）；在回避离开平台测试中，5000m海拔暴露组小鼠与对照组相比，离开平台的潜伏期显著缩短（p<0.05）。
（2）GKB对低温低氧暴露损伤小鼠学习记忆的影响
在新物体识别测试中，GKB能够显著提高低温低氧暴露后小鼠对新物体的探索时间（p<0.05）及鉴别指数（DI）（p<0.05）。GKB注射组小鼠在回避离开平台测试中离开平台的潜伏期显著多于生理盐水注射低温低氧暴露组（p<0.05）。
（3）低温低氧暴露及GKB干预对学习记忆相关蛋白的影响
通过western blot检测我们发现小鼠海马组织Akt、GSK-3β、Erk的磷酸化水平及PKCα/β、NMDA的表达水平在低温低氧暴露后无明显变化趋势，而GluR1蛋白ser831/845位点磷酸化水平及PKA活性在暴露后显著低于对照组（p<0.05）。
GKB能够缓解低温低氧暴露引起的GluR1蛋白磷酸化水平及PKA活性的下降，在低温低氧暴露后，GKB组GluR1蛋白ser831/845位点磷酸化水平及PKA活性显著高于生理盐水组（p<0.05）。
结论
本研究通过人群现场研究发现急进高原能够引起学习记忆能力下降，而环境低温能够显著加重这种损伤效应。乙酰唑胺对低氧及低温低氧复合环境引起的学习记忆能力下降无防护效果，并能够加重学习记忆能力的损伤，但乙酰唑胺能有效预防AMS的发生。银杏叶提取物EGb-761在急进高原情况下能显著改善急进高原引起的学习记忆能力下降，但对预防AMS无明显效果。银杏叶单体GKB可能在银杏叶提取物EGb-761保护学习记忆水平下降过程中起到关键作用，其作用机制可能是通过调节小鼠海马组织PKA活性及GluR1蛋白磷酸化水平实现的。
The high-altitude areas cover a quarter of land area in China. The special natureenvironment of cold and hypoxia in Qinghai-Tibet Plateau, which has an average elevationof4000m, seriously endangers people’s physical and mental health. Brain is one of themost sensitive organs to cold and hypoxia. Previous studies paid much attention aboutacute mountain sickness (AMS) which was caused by cerebral edema during acuteexposure of altitude. However, the impairments of higher-order brain functions caused by cold and hypoxia complex environment were rarely reported. Recently, the cognitiveability of learning and memory, reaction capacity, reasoning and judgments were reportedto be impaired during acute altitude exposure, which was becoming the focus in thisresearch field. The impairment of cognition may exert widespread impacts on the lifequality and working efficacy of peoples who were living in the high land or taking part inthe military assignments. So, how to prevent people from cognitive impairment duringacute cold and hypoxia exposure was one of the most important questions.
The mechanisms leading to cognitive impairment and specific chemoprophylaxisduring acute cold and hypoxia exposure remain largely unknown. As its limitedexperimental conditions of temperature and atmospheric pressure control, most studiesabout altitude exposure using hypobaric chamber for animal and human experiments.However, the results from such studies under simulated environment may not provide awhole picture of actual situation because there are many more factors that may haveeffects on cognitive performance in high-altitude areas. It was reported that some analepticand steroids such as amphetamine and dexamethasone could improve cognitiveperformance during altitude exposure. However, in view of the side effects of these drugs,they could not be used as conventional medications. As preferred prophylactic drug inprevention of AMS, acetazolamide could promote hypoxia adaptation and relievesymptoms of AMS. Recently, it has been reported that the extract of ginkgo biloba,EGb-761, could protect brain from impairment through its regulative effects on cerebralblood flow during hypoxia exposure. Though may have some beneficial effects, theprotective effects of the two drugs mentioned above remain to be clarified during cold andhypoxia exposure. We hypothesize that acetazolamide and EGb-761might protect peoplefrom impairment of learning and memory during acute cold and hypoxia exposure.
Objective.
The objectives of our study are to determine the impairment effects of acute cold andhypoxia exposure on learning and memory, and assess the protective effects of acetazolamide and EGb-761in human field tests. In animal experiments, we will furtherexplore the protective and regulative effects of Ginkgolide B (GKB), monomer of ginkgobiloba extract, on prevention of learning and memory impairment during acute cold andhypoxia exposure.
Methods.
1. Subjects and experimental procedure.
Male volunteers aging17-20were recruited. And they were randomized into twogroups that ascent to Lhasa in summer and winter separately. And subjects in each groupwere treated with acetazolamide (125mg BID), EGb-761(120mg BID) and placeborandomly. The medication was started3days before ascent and lasted for4days. All thesubjects were lifted from Xianyang (396m) to Lhasa (3658m) where the cognitive testswere performed. The ambient temperature in Lhasa was18-21°C in summer and0-3°Cin winter。
2. Incidence of acute mountain sickness
Lake Louise scoring system was used to assess the incidence of AMS, which isconsisted of the self-reported score (S-LLS) and clinical assessment score (C-LLS).
3. Assessment of learning and memory capacity
Neurocognitive test battery was used to assess the effects of acute altitude exposureon learning and memory in summer and winter. The test battery was consists of immediaterecall (immediate word recall/immediate figure recall), PVSAT (paced visual serialaddition task), DSST (digit symbol substitution test) and delayed recall (delayed wordrecall/delayed figure recall).
4. Cold and hypoxia exposure model
Male C57J mice weighing18-24g was used and exposed to5000m/4°C for2hours.Animals were randomized into control group (Norm), GKB treated control group (Norm+GKB), cold and hypoxia exposure group (Hypo) and GKB treated cold and hypoxiaexposure group (Hypo+GKB). GKB (40mg/kg body weight) was injectedintraperitoneally (i.p.)1hour before the onset of exposure.
5. Behavior tests
Novel object recognition test and step-down inhibitory avoidance test were used toassess the impact of cold and hypoxia exposure on learning and memory.
6. Molecular biological study
The expression and activation level of NMDA, GluR1, Akt, GSK-3β and PKC wasdetected by western blot.
Results.
1. Effects of acetazolamide and EGb-761on learning and memory during acutehypoxia exposure
(1) Incidence of AMS among groups during acute hypoxia exposure
During the stay in Lhasa, all the drug treatment groups were reported to have AMS,but the mean score of S-LLS in acetazolamide group (1.5) was significantly lower thanthat in the placebo (3.0) and EGb-761(2.8) group (p<0.05).
(2) Effects of acute hypoxia exposure on learning and memory
The capacity of learning and memory was severely impaired8h after exposure andgot to be recovered in the following time.
(3) Effects of acetazolamide on learning and memory during hypoxia exposure
During the stay in Lhasa, the subjects in acetazolamide group performed significantl yworse in the delayed recall, DSST and PVSAT tests when compared with placebo group(p<0.05). And further analysis showed that the subjects in acetazolamide group performedsignificantly worse in the immediate recall and PVSAT tests after8h of exposure whencompared with placebo group (p<0.05).
(4) Effects of EGb-761on learning and memory during hypoxia exposure
During the stay in Lhasa, the subjects in EGb-761group performed significantl ybetter in delayed recall, PVSAT and DSST tests when compared with placebo group(p<0.05). And further analysis showed that the subjects in EGb-761group performedsignificantly better in delayed recall test after8h of exposure when compared withplacebo group (p<0.05).
(5) Effects of AMS on learning and memory during hypoxia exposure
There were no significant differences between the subjects with and without AMSwhen compared of their scores in all the neurocognitive tests, no matter what drug theywere treated with.
2. Effects of acetazolamide and EGb-761on learning and memory during acutecold and hypoxia exposure
(1) Incidence of AMS among groups during acute cold and hypoxia exposure
During the stay in Lhasa, all the groups were reported to have AMS, but the meanscore of S-LLS in acetazolamide group (2.2) was significantly lower than that in theplacebo (3.9) and group EGb-761(3.3)(p<0.05).
(2) Effects of acute cold and hypoxia exposure on learning and memory
The capacity of learning and memory was severely impaired8h after exposure andgot to be recovered as the exposure time prolonged in all the groups. After8hours ofhypoxia exposure, subjects in each group performed significantly worse in theimmediate/delayed recall, DSST and PVSAT tests (p<0.05).
(3) Effects of acetazolamide on learning and memory during cold and hypoxiaexposure
During the stay in Lhasa, the subjects in acetazolamide group performed significantl yworse in PVSAT test when compared with placebo group (p<0.05). And further analysisshowed that the subjects in acetazolamide group performed significantly worse in theDSST and PVSAT tests after8h of exposure when compared with placebo group(p<0.05).
(4) Effects of EGb-761on learning and memory during cold and hypoxia exposure
During the stay in Lhasa, the subjects in EGb-761group performed significantl ybetter in PVSAT and delayed recall tests when compared with placebo group (p<0.05).And further analysis showed that subjects in EGb-761group performed significantlybetter in delayed recall test when compared with placebo group (p<0.05).
(5) Effects of AMS on learning and memory during hypoxia exposure
There were no significant differences between the subjects with and without AMS when compared of their scores in all the neurocognitive tests, no matter what drug theywere treated with.
(6) Effects of cold temperature on the impairment effects of hypoxia exposure onlearning and memory
The cognitive performances of the subjects in placebo group in the summer trail andwinter trial were compared. And we found that the performance of subjects in the wintertrail was significantly worse than those in the summer trail (p<0.05).
3. Effects of GKB on learning and memory performance of mouse after coldand hypoxia exposure
(1) Effects of acute cold and hypoxia exposure on learning and memory performance
The time spent in exploring of the novel object as well as the discrimination indexwere significantly reduced in the novel object recognition test (p<0.05), and the latency ofstep down of the platform was significantly shorter in the step-down inhibitory avoidancetask (p<0.05) after2h of cold and hypoxia exposure at5000m.
(2) Effects of GKB on learning and memory performance after cold and hypoxiaexposure
GKB significantly increased the time spent in exploring of the novel object as well asthe discrimination index (p<0.05), and it also significantly increased the latency of stepdown of the platform (p<0.05) when compared with those treated with saline.
(3) Effects of cold and hypoxia exposure and GKB on the expression andphosphorylation level of proteins relative with learning and memory
The expression level of NMDA and PKCα/β and the phosphorylation level of Akt,GSK-3β and Erk were not affected by cold and hypoxia exposure. However, thephosphorylation level of GluR1at ser831/845and the activity of PKA decreasedsignificantly after2h of cold and hypoxia exposure at5000m. This change could bereversed by GKB treatment1h before exposure.
Conclusion.
1. Acute hypoxia exposure could impair learning and memory, and cold temperature could aggravate the impairment effects.
2. Acetazolamide impaired learning and memory during hypoxia as well as cold andhypoxia exposure. However, it could prevent people from AMS.
3. EGb-761could potently protect people from impairment of learning and memory.But it has no protective effects on AMS.
4. GKB might be the key component of EGb-761in prevention of learning andmemory impairment by regulating the phosphorylation of GluR1during cold andhypoxia exposure.
引文
[1] Imray, C, Wright, A, Subudhi, A and Roach, R. Acute Mountain Sickness: Pathophysiology,Prevention, and Treatment. Progress in Cardiovascular Diseases,2010,52:467–484.
[2] Imray, C, Booth, A, Wright, a. and Bradwell, a. Acute altitude illnesses. Bmj,2011,343:d4943–d4943.
[3] Bahrke, MS and Shukitt-Hale, B. Effects of altitude on mood, behaviour and cognitivefunctioning. A review. Sports medicine (Auckland, N.Z.),1993,16:97–125.
[4] Richardson, C, Hogan, AM, Bucks, RS, Baya, A, Virues-Ortega, J, Holloway, JW,Rose-Zerilli, M, Palmer, LJ, Webster, RJ, Kirkham, FJ and Baldeweg, T.Neurophysiological evidence for cognitive and brain functional adaptation in adolescentsliving at high altitude. Clinical neurophysiology: official journal of the InternationalFederation of Clinical Neurophysiology,2011,122:1726–34.
[5] Dykiert, D, Hall, D, Van Gemeren, N, Benson, R, Der, G, Starr, JM and Deary, IJ. Theeffects of high altitude on choice reaction time mean and intra-individual variability:Results of the Edinburgh Altitude Research Expedition of2008. Neuropsychology,2010,24:391–401.
[6] Mineo, PM, Cassell, E a, Roberts, ME and Schaeffer, PJ. Chronic cold acclimationincreases thermogenic capacity, non-shivering thermogenesis and muscle citrate synthaseactivity in both wild-type and brown adipose tissue deficient mice. Comparativebiochemistry and physiology. Part A, Molecular&integrative physiology,2012,161:395–400.
[7] Aggarwal, S, Negi, S, Jha, P, Singh, PK, Stobdan, T and Pasha, MAQ. EGLN1involvementin high-altitude adaptation revealed through genetic analysis of extreme constitution typesdefined in Ayurveda. PNAS,2010,107(44):18961–6.
[8] Janssen, J. Club Alpin Francais, Annuaire,1890,1882–1887.
[9] Barhwal, K, Singh, SB, Hota, SK, Jayalakshmi, K and Ilavazhagan, G. Acetyl-L-carnitineameliorates hypobaric hypoxic impairment and spatial memory deficits in rats. Europeanjournal of pharmacology,2007,570:97–107.
[10] Muthuraju, S, Maiti, P, Solanki, P, Sharma, AK, Pati, S, Singh, SB, Prasad, D andIlavazhagan, G. Possible role of cholinesterase inhibitors on memory consolidationfollowing hypobaric hypoxia of rats. The International journal of neuroscience,2011,121:279–88.
[11] Maiti, P, Singh, SB, Muthuraju, S, Veleri, S and Ilavazhagan, G. Hypobaric hypoxiadamages the hippocampal pyramidal neurons in the rat brain. Brain research,2007,1175:1–9.
[12] Karinen, HM and Tikkanen, HO. Acute mountain sickness, two cases and their treatment inthe field. International journal of occupational medicine and environmental health,2012,25:304–9.
[13] Kayser, B, Hulsebosch, R and Bosch, F. Low-Dose Acetylsalicylic Acid Analog andAcetazolamide for Prevention of Acute Mountain Sickness. High Altitude Medicine&Biology,2008,9:1,15–23.
[14] White, AJ. Cognitive impairment of acute mountain sickness and acetazolamide. Aviation,space, and environmental medicine,1984,55:598–603.
[15] Esbaugh, AJ and Tufts, BL. The structure and function of carbonic anhydrase isozymes inthe respiratory system of vertebrates. Respiratory physiology&neurobiology,2006,154:185–98.
[16] Roncin, JP, Schwartz, F and D’Arbigny, P. EGb761in control of acute mountain sicknessand vascular reactivity to cold exposure. Aviation, space, and environmental medicine,1996,67:445–52.
[17] Leadbetter, G, Keyes, LE, Maakestad, KM, Olson, S, Tissot van Patot, MC and Hackett, PH.Ginkgo biloba does-and does not-prevent acute mountain sickness. Wilderness&environmental medicine,2009,20:66–71.
[18] Gilbert, DL. The first documented report of mountain sickness: the China or HeadacheMountain story. Respiration physiology,1983,52:315–26.
[19] Plutarch. Lives, Volume VII Demosthenes and Cicero. Alexander and Caesar. HarvardUniversity Press,1919, US.
[20] McFarland, RA. Psycho-physiological studies at high altitude in the Andes. II. Sensory andmotor responses during acclimatization. Journal of Comparative Psychology,1937,23:227–258.
[21] THE INTERNAL ENVIRONMENT AND BEHAVIOR Part I. Introduction and the R le ofOxygen. American Journal of Psychiatry,1941,97.
[22] Sutton, JR, Houston, CS, Mansell, AL, McFadden, MD, Hackett, PM, Rigg, JR and Powles,AC. Effect of acetazolamide on hypoxemia during sleep at high altitude. The New Englandjournal of medicine,1979,301:1329–31.
[23] Moore, LG. Comparative human ventilatory adaptation to high altitude. Respirationphysiology,2000,121:257–76.
[24] Schoene, RB. Control of ventilation in climbers to extreme altitude. Journal of appliedphysiology: respiratory, environmental and exercise physiology,1982,53:886–90.
[25] Hackett, PH, Rennie, D, Hofmeister, SE, Grover, RF, Grover, EB and Reeves, JT. Fluidretention and relative hypoventilation in acute mountain sickness. Respiration; internationalreview of thoracic diseases,1982,43:321–9.
[26] Richalet, JP, Souberbielle, JC, Antezana, AM, Déchaux, M, Le Trong, JL, Bienvenu, A,Daniel, F, Blanchot, C and Zittoun, J. Control of erythropoiesis in humans duringprolonged exposure to the altitude of6,542m. The American journal of physiology,1994,266:R756–64.
[27] Baumgartner, RW, Spyridopoulos, I, B rtsch, P, Maggiorini, M and Oelz, O. Acutemountain sickness is not related to cerebral blood flow: a decompression chamber study.Journal of applied physiology (Bethesda, Md.:1985),1999,86:1578–82.
[28] Jensen, JB, Wright, AD, Lassen, NA, Harvey, TC, Winterborn, MH, Raichle, ME andBradwell, AR. Cerebral blood flow in acute mountain sickness. Journal of appliedphysiology (Bethesda, Md.:1985),1990,69:430–3.
[29] Morganti, A, Giussani, M, Ghio, F, Pierini, A, Savoia, MT and Cogo, A.Endothelin-releasing stimuli and calcium antagonists in normal and pathological conditions.Journal of hypertension. Supplement: official journal of the International Society ofHypertension,1994,12:S27–31.
[30] Karliner, JS, Sarnquist, FF, Graber, DJ, Peters, RM and West, JB. The electrocardiogram atextreme altitude: experience on Mt. Everest. American heart journal,1985,109:505–13.
[31] Milledge, JS. ELECTROCARDIOGRAPHIC CHANGES AT HIGH ALTITUDE. Britishheart journal,1963,25:291–8.
[32] PENALOZA, D and ECHEVARRIA, M. Electrocardiographic observations on ten subjectsat sea level and during one year of residence at high altitudes. American heart journal,1957,54:811–22.
[33] West, JB and Mathieu-Costello, O. High altitude pulmonary edema is caused by stressfailure of pulmonary capillaries. International journal of sports medicine,1992,13Suppl1:S54–8.
[34] Janssen, J. Club Alpin Francais, Annuaire,1890,1882–1887.
[35] Dunlap, K. Medical studies in aviation: IV. Psychologic observations and metho ds.1918.Aviation, space, and environmental medicine,1989,60:819–21.
[36] Shipton, E. Upon that Mountain, Hodder and Stoughton,London,1943, p.129.
[37] Ruttledge,H. Everest1933: TheUnfinished Adventure,1934,164–166, Hodder andStoughton, London.
[38] THE RESPONSE OF PSYCHONEUROTICS TO VARIATIONS IN OXYGEN TENSION.American Journal of Psychiatry,1937,93.
[39] McFarland, R. A. The internal environment and behavior. Am.J. Psychiatry,1941,97:868–877.
[40] McFarland, R. A. Psycho-physiological studies at high altitudein the Andes: III. Mental andpsycho-somatic responses duringgradual adaptation. Comp. Psychol,1937,24:147–187.
[41] Denison, DM, Ledwith, F and Poulton, EC. Complex reaction times at simulated cabinaltitudes of5,000feet and8,000feet. Aerospace medicine,1966,37:1010–3.
[42] McFarland, RA. Human factors in relation to the development of pressurized cabins.Aerospace medicine,1971,42:1303–18.
[43] Ryn, Z. Psychopathology in alpinism. Acta medica Polona,1971,12:453–67.
[44] Garrido, E, Segura, R, Capdevila, A, Aldomá, J, Rodríguez, FA, Javierra, C and Ventura, JL.New evidence from magnetic resonance imaging of brain changes after climbs at extremealtitude. European journal of applied physiology and occupational physiology,1995,70:477–81.
[45] Hornbein, TF, Townes, BD, Schoene, RB, Sutton, JR, Houston, CS and Ph, D. The cost tothe central nervous system of climbing to extremely high altitude. The New Englandjournal of medicine,1989,321:1714–9.
[46] Regard, M, Oelz, O, Brugger, P and Landis, T. Persistent cognitive impairment in climbersafter repeated exposure to extreme altitude. Neurology,1989,39:210–3.
[47] West, J. Human physiology at extreme altitudes on Mount Everest. Science,1984,223:784–788.
[48] Brierley, J. B. CerebralHypoxia (Chapter II). In: Blackwood,W.,and Corsellis, J. A.(eds.),Greenfield’s Neuropathology,1976, Arnold,London.
[49] Pichiule, P, Chávez, JC, Boero, J and Arregui, A. Chronic hypoxia induces modification ofthe N-methyl-D-aspartate receptor in rat brain. Neuroscience letters,1996,218:83–6.
[50] Reed, LJ, Marsden, P, Lasserson, D, Sheldon, N, Lewis, P, Stanhope, N, Guinan, E andKopelman, MD. FDG-PET analysis and findings in amnesia resulting from hypoxia.Memory (Hove, England),7:599–612.
[51] Adams, R. A., Victor, M., and Ropper, A. H. Trastornosmetab′olicos adquiridos del sistemanervioso [Acquired metabolicnervous system disorders]. Principios de Neurolog′a (7thed.),1999,961–967, McGraw Hill, Mexico DF.
[52] Schulze, G, Coper, H and F hndrich, C. Adaptation capacity of biogenic amines turnover tohypoxia in different brain areas of old rats. Neurochemistry international,1990,17:281–9.
[53] Shukitt-Hale, B, Stillman, MJ, Levy, A, Devine, JA and Lieberman, HR. Nimodipineprevents the in vivo decrease in hippocampal extracellular acetylcholine produced byhypobaric hypoxia. Brain research,1993,621:291–5.
[54] Shukitt-Hale, B, Kadar, T, Marlowe, BE, Stillman, MJ, Galli, RL, Levy, A, Devine, JA andLieberman, HR. Morphological alterations in the hippocampus following hypobarichypoxia. Human&experimental toxicology,1996,15:312–9.
[55] Gozal, D, Daniel, JM and Dohanich, GP. Behavioral and anatomical correlates of chronicepisodic hypoxia during sleep in the rat. The Journal of neuroscience: the official journalof the Society for Neuroscience,2001,21:2442–50.
[56] Zola-Morgan, S, Squire, LR and Amaral, DG. Human amnesia and the medial temporalregion: enduring memory impairment following a bilateral lesion limited to field CA1ofthe hippocampus. The Journal of neuroscience: the official journal of the Society forNeuroscience,1986,6:2950–67.
[57] Prigatano, GP, Parsons, O, Wright, E, Levin, DC and Hawryluk, G. Neuropsychological testperformance in mildly hypoxemic patients with chronic obstructive pulmonary disease.Journal of consulting and clinical psychology,1983,51:108–16.
[58] Bédard, MA, Montplaisir, J, Richer, F, Rouleau, I and Malo, J. Obstructive sleep apneasyndrome: pathogenesis of neuropsychological deficits. Journal of clinical andexperimental neuropsychology,1991,13:950–64.
[59] Bradwell, A. R., Williams, D., Beazley, M., and Imray, C. H. E. Can acute mountainsickness be induced by exercise? In: Roach,R. C., Wagner, P. D., and Hackett, P. H.(eds.),Hypoxia: Into theNext Millennium,1999,368, Plenum/Kluwer Academic Publishi
[60] Roach, RC, Maes, D, Sandoval, D, Robergs, RA, Icenogle, M, Hinghofer-Szalkay, H, Lium,D and Loeppky, JA. Exercise exacerbates acute mountain sickness at simulated highaltitude. Journal of applied physiology (Bethesda, Md.:1985),2000,88:581–5.
[61] Saito, S, Nishihara, F, Takazawa, T, Kanai, M, Aso, C, Shiga, T and Shimada, H.Exercise-induced cerebral deoxygenation among untrained trekkers at moderate altitudes.Archives of environmental health,54:271–6.
[62] Sutton, JR, Reeves, JT, Wagner, PD, Groves, BM, Cymerman, A, Malconian, MK, Rock,PB, Young, PM, Walter, SD and Houston, CS. Operation Everest II: oxygen transportduring exercise at extreme simulated altitude. Journal of applied physiology (Bethesda,Md.:1985),1988,64:1309–21.
[63] Coote, JH, Tsang, G, Baker, A and Stone, B. Respiratory changes and structure of sleep inyoung high-altitude dwellers in the Andes of Peru. European journal of applied physiologyand occupational physiology,1993,66:249–53.
[64] Hackett, PH, Roach, RC, Harrison, GL, Schoene, RB and Mills, WJ. Respiratory stimulantsand sleep periodic breathing at high altitude. Almitrine versus acetazolamide. TheAmerican review of respiratory disease,1987,135:896–8.
[65] Matsuzawa, Y, Kobayashi, T, Fujimoto, K, Yamaguchi, S, Shinozaki, S, Kubo, K,Sekiguchi, M, Hayashi, R, Sakai, A and Ueda, G. Nocturnal periodic breathing and arterialoxygen desaturation in acute mountain sickness. Journal of Wilderness Medicine,1994,5:269–281.
[66] Schoene, RB. The brain at high altitude. Wilderness&environmental medicine,1999,10:93–6.
[67] Shukitt-Hale, B, Banderet, LE and Lieberman, HR. Relationships between symptoms,moods, performance, and acute mountain sickness at4,700meters. Aviation, space, andenvironmental medicine,1991,62:865–9.
[68] Samaja, M, Brenna, L, Allibardi, S and Cerretelli, P. Human red blood cell aging at5,050-m altitude: a role during adaptation to hypoxia. Journal of applied physiology(Bethesda, Md.:1985),1993,75:1696–701.
[69] Doughty, HA and Beardmore, C. Bleeding time at altitude. Journal of the Royal Society ofMedicine,1994,87:317–9.
[70] Roach, RC and Hackett, PH. Frontiers of hypoxia research: acute mountain sickness. TheJournal of experimental biology,2001,204:3161–70.
[71] Garrido, E, Castelló, A, Ventura, JL, Capdevila, A and Rodríguez, FA. Cortical atrophy andother brain magnetic resonance imaging (MRI) changes after extremely high-altitudeclimbs without oxygen. International journal of sports medicine,1993,14:232–4.
[72] Song, SY, Asaji, T, Tanizaki, Y, Fujimaki, T, Matsutani, M and Okeda, R. Cerebralthrombosis at altitude: its pathogenesis and the problems of prevention and treatment.Aviation, space, and environmental medicine,1986,57:71–6.
[73] Hackett, PH, Yarnell, PR, Hill, R, Reynard, K, Heit, J and McCormick, J. High-altitudecerebral edema evaluated with magnetic resonance imaging: clinical correlation andpathophysiology. JAMA: the journal of the American Medical Association,1998,280:1920–5.
[74] Garrido, E and Javierre, C. Extreme altitude transient aphasia. British journal of sportsmedicine,1996,30:364.
[75] Shlim, DR, Hackett, P, Houston, C, Steele, P, Nelson, D and Hultgren, HN. Diplopia at highaltitude. Wilderness&environmental medicine,1995,6:341; discussion341–3.
[76] Basnyat, B. Seizure and hemiparesis at high-altitude outside the setting of acute mountainsickness. Wilderness&environmental medicine,1997,8:221–2.
[77] Basnyat, B. Delirium at high altitude. High altitude medicine&biology,2002,3:69–71.
[78] Litch, JA and Bishop, RA. Transient global amnesia at high altitude. The New Englandjournal of medicine,1999,340:1444.
[79] Hornbein, T. F., and Schoene, R. B. High Altitude: An Explorationof Human Adaptation,Marcel Dekker,2001, New York.
[80] Simon, R. P. CNS response to hypoxia. In: Sutton, J. R.,Houston,C. S., and Coates, G.(eds.), Hypoxia and the Brain Proceedings ofthe Ninth International Hypoxia Symposium,Queen City Printers,1995, Burlington, VT.
[81] Fr lich, MA, Deshpande, H, Ness, T and Deutsch, G. Quantitative changes in regionalcerebral blood flow induced by cold, heat and ischemic pain: a continuous arterial spinlabeling study. Anesthesiology,2012,117:857–67.
[82] Brown, CM, Sanya, EO and Hilz, MJ. Effect of cold face stimulation on cerebral bloodflow in humans. Brain research bulletin,2003,61:81–6.
[83] Schousboe, A, Belhage, B and Frandsen, A. Role of Ca+2and other second messengers inexcitatory amino acid receptor mediated neurodegeneration: clinical perspectives. Clinicalneuroscience (New York, N.Y.),1997,4:194–8.
[84] Pinel, J. P. Tratornos cerebrovasculares [Cerebrovascular disorders]. Biopsicolog′a,2001,60–162, Petrice Hall, Madrid, Spain.
[85] Garrido, E, Segura, R, Capdevila, A, Pujol, J, Javierre, C and Ventura, JL. Are HimalayanSherpas better protected against brain damage associated with extreme altitude climbs?Clinical science (London, England:1979),1996,90:81–5.
[86] Bolmont, B and Abraini, JH. State-anxiety and low moods: evidence for a single concept.Physiology&behavior,74:421–4.
[87] Fowler, B, Elcombe, DD, Kelso, B and Porlier, G. The threshold for hypoxia effects onperceptual-motor performance. Human factors,1987,29:61–6.
[88] Kramer, AF, Coyne, JT and Strayer, DL. Cognitive function at high altitude. Human factors,1993,35:329–44.
[89] Mackintosh, JH, Thomas, DJ, Olive, JE, Chesner, IM and Knight, RJ. The effect of altitudeon tests of reaction time and alertness. Aviation, space, and environmental medicine,1988,59:246–8.
[90] West, JB. Human physiology at extreme altitudes on Mount Everest. Science,1984,223(4638):784-8.
[91] Wesensten, NJ, Crowley, J, Balkin, T, Kamimori, G, Iwanyk, E, Pearson, N, Devine, J,Belenky, G and Cymerman, A. Effects of simulated high altitude exposure on long-latencyevent-related brain potentials and performance. Aviation, space, and environmentalmedicine,1993,64:30–6.
[92] Fowler, B and Prlic, H. A comparison of visual and auditory reaction time and P300latencythresholds to acute hypoxia. Aviation, space, and environmental medicine,1995,66:645–50.
[93] Fowler, B and Lindeis, AE. The effects of hypoxia on auditory reaction time and P300latency. Aviation, space, and environmental medicine,1992,63:976–81.
[94] Fowler, B and Adams, J. Dissociation of the effects of alcohol and amphetamine on inertgas narcosis using reaction time and P300latency. Aviation, space, and environmentalmedicine,1993,64:493–9.
[95] Johnson, R., Jr. The amplitude of P300component of the eventrelatedpotential: Review andsynthesis. In: Ackles, P., Jennings,J. R., and Coles, M. G. H.(eds.), Advances inPsychophysiology,1998,3:69–137, JAI Press, London.
[96] Mahoney, CR, Castellani, J, Kramer, FM, Young, A and Lieberman, HR. Tyrosinesupplementation mitigates working memory decrements during cold exposure. Physiology&behavior,2007,92:575–82.
[97] Thomas, JR, Ahlers, ST, House, JF and Schrot, J. Repeated exposure to moderate coldimpairs matching-to-sample performance. Aviation, space, and environmental medicine,1989,60:1063–7.
[98] Van Orden, KF, Ahlers, ST, Thomas, JR, House, JF and Schrot, J. Moderate cold exposureshortens evoked potential latencies in humans. Aviation, space, and environmentalmedicine,1990,61:636–9.
[99] Watson, D. B.,Martin,R. L., McAnally,K. I., Smith, S. E., and Emonson,D. L. Effect ofnormobaric hypoxia on auditory sensitivity.Aviat. Space Environ. Med,2000,71:791–797.
[100] Fowler, B and Grant, A. Hearing thresholds under acute hypoxia and relationship toslowing in the auditory modality. Aviation, space, and environmental medicine,2000,71:946–9.
[101] Burkett, PR and Perrin, WF. Hypoxia and auditory thresholds. Aviation, space, andenvironmental medicine,1976,47:649–51.
[102] Martin, RL, Watson, DB, Smith, SE, McAnally, KI and Emonson, DL. Effect ofnormobaric hypoxia on sound localization. Aviation, space, and environmental medicine,2000,71:991–5.
[103] Fleisch, A., and Von Murant, A. Klimaphysiologische Untersuchungen in Der Schweiz, PartII [Environmental physiology research in Switzerland, Part II]. Bemo Schwabe,1948,Basel, Switzerland.
[104] Fleisch, A., and Von Murant, A. Klimaphysiologische Untersuchungenin der Schweiz, PartI [Environmental physiology researchin Switzerland, Part I].Bemo Schwabe,1994, Basel,Switzerland.
[105] Kobrick, J. Effects of hypoxia on the luminance threshold for target detection. Aviation,space, and environmental medicine,1983,54:112–5.
[106] No l-Jorand, MC, Bragard, D and Plaghki, L. Pain perception under chronic high-altitudehypoxia. The European journal of neuroscience,1996,8:2075–9.
[107] Plaghki, L, Delisle, D and Godfraind, JM. Heterotopic nociceptive conditioning stimuli andmental task modulate differently the perception and physiological correlates of short CO2laser stimuli. Pain,1994,57:181–92.
[108] Padawer, WJ and Levine, FM. Exercise-induced analgesia: fact or artifact? Pain,1992,48:131–5.
[109] No l-Jorand, MC and Burnet, H. The sensation of respiration in men experiencinghigh-altitude chronic hypoxia. Biological psychology,1996,43:1–12.
[110] Kobrick, JL and Appleton, B. Effects of extended hypoxia on visual performance andretinal vascular state. Journal of applied physiology,1971,31:357–62.
[111] McFarland, R. A., and Evans, J. N. Alterations in dark adaptations under reduced oxygentensions. Am. J. Physiol,1939,127:37–50.
[112] Kobrick, JL, Crohn, E, Shukitt, B, Houston, CS, Sutton, JR and Cymerman, A. OperationEverest II: lack of an effect of extreme altitude on visual contrast sensitivity. Aviation,space, and environmental medicine,1988,59:160–4.
[113] Cahoon, RL. Vigilance performance under hypoxia. The Journal of applied psychology,1970,54:479–83.
[114] Kobrick, JL, Zwick, H, Witt, CE and Devine, JA. Effects of extended hypoxia on nightvision. Aviation, space, and environmental medicine,1984,55:191–5.
[115] Richalet, JP, Duval-Arnould, G, Darnaud, B, Keromes, A and Rutgers, V. Modification ofcolour vision in the green/red axis in acute and chronic hypoxia explored with a portableanomaloscope. Aviation, space, and environmental medicine,1988,59:620–3.
[116] Smith, VC, Ernest, JT and Pokorny, J. Effect of hypoxia on FM100-Hue test performance.Modern problems in ophthalmology,1976,17:248–56.
[117] Vingrys, AJ and Garner, LF. The effect of a moderate level of hypoxia on human colorvision. Documenta ophthalmologica. Advances in ophthalmology,1987,66:171–85.
[118] Leid, J and Campagne, JM. Colour vision at very high altitude. Color research andapplication,2001,26Suppl1:S281–3.
[119] Bouquet, C, Gardette, B, Gortan, C, Therme, P and Abraini, JH. Color discrimination underchronic hypoxic conditions (simulated climb “Everest-Comex97”). Perceptual and motorskills,2000,90:169–79.
[120] Berry, DT, McConnell, JW, Phillips, BA, Carswell, CM, Lamb, DG and Prine, BC.Isocapnic hypoxemia and neuropsychological functioning. Journal of clinical andexperimental neuropsychology,1989,11:241–51.
[121] Bolmont, B., Thullier, F., and Abraini, J. H. Relationship between mood states andperformances in RT, psychomotor ability, and mental efficiency during31-day gradualdecompression in a hypobaric chamber from sea level to8848m equivalent altitu.Physiology and Behavior,2000,71(5):469-476
[122] Sharma, VM, Malhotra, MS and Baskaran, AS. Variations in psychomotor efficiency duringprolonged stay at high altitude. Ergonomics,1975,18:511–6.
[123] Pe a-Casanova, J., Hernandez, M. T., and Jarne, A. Técnicas neuropsicológicas
[Neuropsychological techniques]. In Buela-Casal G., and Sierra, C.(eds.), Manual deEvaluación Psicológica: Fundamentos, Técnicasy Aplicaciones,1997,421–454.
[124] Lezak, M. D. Neuropsychol Assess (3rd ed.), Oxford UniversityPress,1995, Oxford.
[125] Garner, SH, Sutton, JR, Burse, RL, McComas, AJ, Cymerman, A and Houston, CS.Operation Everest II: neuromuscular performance under conditions of extreme simulatedaltitude. Journal of applied physiology (Bethesda, Md.:1985),1990,68:1167–72.
[126] Abraini, JH, Bouquet, C, Joulia, F, Nicolas, M and Kriem, B. Cognitive performanceduring a simulated climb of Mount Everest: implications for brain function and centraladaptive processes under chronic hypoxic stress. Pfl gers Archiv: European journal ofphysiology,1998,436:553–9.
[127] Bouquet, CA, Gardette, B, Gortan, C and Abraini, JH. Psychomotor skills learning underchronic hypoxia. Neuroreport,1999,10:3093–9.
[128] Bolmont, B, Thullier, F and Abraini, JH. Relationships between mood states andperformances in reaction time, psychomotor ability, and mental efficiency during a31-daygradual decompression in a hypobaric chamber from sea level to8848m equivalentaltitude. Physiology&behavior,2000,71:469–76.
[129] Townes,B., Hornbein,T., Schoene,R., Sarnquist, F., andGrant, I. Human cerebral function atextreme altitude. In: West, J. B., andLahiri, S.(eds.), High Altitude and Man,1984,31–36,AmericanPhysiological Society, Bethesda.
[130] West, JB. Do climbs to extreme altitude cause brain damage? Lancet,1986,2:387–8.
[131] Forster, H V, Dempsey, JA, Birnbaum, ML, Reddan, WG, Thoden, J, Grover, RF andRankin, J. Effect of chronic exposure to hypoxia on ventilatory response to CO2andhypoxia. Journal of applied physiology,1971,31:586–92.
[132] Masuyama, S, Kimura, H, Sugita, T, Kuriyama, T, Tatsumi, K, Kunitomo, F, Okita, S,Tojima, H, Yuguchi, Y and Watanabe, S. Control of ventilation in extreme-altitude climbers.Journal of applied physiology (Bethesda, Md.:1985),1986,61:500–6.
[133] Clark, CF, Heaton, RK and Wiens, AN. Neuropsychological functioning after prolongedhigh altitude exposure in mountaineering. Aviation, space, and environmental medicine,1983,54:202–7.
[134] Jason, GW, Pajurkova, EM and Lee, RG. High-altitude mountaineering and brain function:neuropsychological testing of members of a Mount Everest expedition. Aviation, space, andenvironmental medicine,1989,60:170–3.
[135] Milne, D and Gray, D. Evidence bearing on the generalizability of laboratory findingsrelating to high-altitude mountaineering. Perceptual and motor skills,1983,57:172–4.
[136] McSweeny, AJ, Grant, I, Heaton, RK, Prigatano, GP and Adams, KM. Relationship ofneuropsychological status to everyday functioning in healthy and chronically ill persons.Journal of clinical and experimental neuropsychology,1985,7:281–91.
[137] Grant, I, Prigatano, GP, Heaton, RK, McSweeny, AJ, Wright, EC and Adams, KM.Progressive neuropsychologic impairment and hypoxemia. Relationship in chronicobstructive pulmonary disease. Archives of general psychiatry,1987,44:999–1006.
[138] Stuss, DT, Peterkin, I, Guzman, DA, Guzman, C and Troyer, AK. Chronic obstructivepulmonary disease: effects of hypoxia on neurological and neuropsychological measures.Journal of clinical and experimental neuropsychology,1997,19:515–24.
[139] Khoo, MC, Anholm, JD, Ko, SW, Downey, R, Powles, AC, Sutton, JR and Houston, CS.Dynamics of periodic breathing and arousal during sleep at extreme altitude. Respirationphysiology,1996,103:33–43.
[140] Bakharev, VD. Investigation of memory during adaptation to high mountain conditions.Human physiology,1981,7:409–14.
[141] Cavaletti, G, Moroni, R, Garavaglia, P and Tredici, G. Brain damage after high-altitudeclimbs without oxygen. Lancet,1987,1:101.
[142] Kennedy, RS, Dunlap, WP, Banderet, LE, Smith, MG and Houston, CS. Cognitiveperformance deficits in a simulated climb of Mount Everest: Operation Everest II. Aviation,space, and environmental medicine,1989,60:99–104.
[143] Oelz, O, Howald, H, Di Prampero, PE, Hoppeler, H, Claassen, H, Jenni, R, Bühlmann, A,Ferretti, G, Brückner, JC and Veicsteinas, A. Physiological profile of world-classhigh-altitude climbers. Journal of applied physiology (Bethesda, Md.:1985),1986,60:1734–42.
[144] Shock, N. W. The effects on learning of repeated exposuresto lowered oxygen tension ofinspired air. J. Comp. Psychol,1942,34:55–63.
[145] Nelson, TO, Dunlosky, J, White, DM, Steinberg, J, Townes, BD and Anderson, D.Cognition and metacognition at extreme altitudes on Mount Everest. Journal ofexperimental psychology. General,1990,119:367–74.
[146] Chleide, E, Bruhwyler, J and Mercier, M. Effect of chronic hypoxic treatment on theretention of fixed-interval responding. Physiology&behavior,1991,49:465–70.
[147] Ettinger, RH and Staddon, JE. Decreased feeding associated with acute hypoxia in rats.Physiology&behavior,1982,29:455–8.
[148] Koller, EA, Bischoff, M, Bührer, A, Felder, L and Schopen, M. Respiratory, circulatory andneuropsychological responses to acute hypoxia in acclimatized and non-acclimatizedsubjects. European journal of applied physiology and occupational physiology,1991,62:67–72.
[149] Kelman, GR, Crow, TJ and Bursill, AE. Effect of mild hypoxia on mental performanceassessed by a test of selective attention. Aerospace medicine,1969,40:301–3.
[150] Smeets, T, Otgaar, H, Candel, I and Wolf, OT. True or false? Memory is differentiallyaffected by stress-induced cortisol elevations and sympathetic activity at consolidation andretrieval. Psychoneuroendocrinology,2008,33:1378–86.
[151] Roozendaal, B. Stress and memory: opposing effects of glucocorticoids on memoryconsolidation and memory retrieval. Neurobiology of learning and memory,2002,78:578–95.
[152] Roozendaal, B, Hahn, EL, Nathan, S V, De Quervain, DJ-F and McGaugh, JL.Glucocorticoid effects on memory retrieval require concurrent noradrenergic activity in thehippocampus and basolateral amygdala. The Journal of neuroscience: the official journal ofthe Society for Neuroscience,2004,24:8161–9.
[153] Schwabe, L and Wolf, OT. Stress impairs the reconsolidation of autobiographical memories.Neurobiology of learning and memory,2010,94:153–7.
[154] Zheng, G, Chen, Y, Zhang, X, Cai, T, Liu, M, Zhao, F, Luo, W and Chen, J. Acute coldexposure and rewarming enhanced spatial memory and activated the MAPK cascades in therat brain. Brain research,2008,1239:171–80.
[155] Shukitt-Hale, B, Stillman, MJ, Welch, DI, Levy, A, Devine, JA and Lieberman, HR.Hypobaric hypoxia impairs spatial memory in an elevation-dependent fashion. Behavioraland neural biology,1994,62:244–52.
[156] Nelson, M. Psychological testing at high altitudes. Aviation, space, and environmentalmedicine,1982,53:122–6.
[157] M kinen, TM, Palinkas, L a, Reeves, DL, P kk nen, T, Rintam ki, H, Lepp luoto, J andHassi, J. Effect of repeated exposures to cold on cognitive performance in humans.Physiology&behavior,2006,87:166–76.
[158] Muthuraju, S, Maiti, P, Solanki, P, Sharma, AK, Singh, SB, Prasad, D and Ilavazhagan, G.Cholinesterase inhibitors ameliorate spatial learning deficits in rats following hypobarichypoxia. Experimental brain research. Experimentelle Hirnforschung. Expérimentationcérébrale,2010,203:583–92.
[159] Muthuraju, S, Maiti, P, Pati, S, Solanki, P, Sharma, AK, Singh, SB, Prasad, D andIlavazhagan, G. Role of cholinergic markers on memory function of rats exposed tohypobaric hypoxia. European journal of pharmacology,2011,672:96–105.
[160] Crow, TJ and Kelman, GR. Effect of mild acute hypoxia on human short-term memory.British journal of anaesthesia,1971,43:548–52.
[161] Bartholomew, CJ, Jensen, W, Petros, T V, Ferraro, FR, Fire, KM, Biberdorf, D, Fraley, E,Schalk, J and Blumkin, D. The effect of moderate levels of simulated altitude on sustainedcognitive performance. The International journal of aviation psychology,1999,9:351–9.
[162] Nemeth, D, Csábi, E, Janacsek, K, Várszegi, M and Mari, Z. Intact implicit probabilisticsequence learning in obstructive sleep apnea. Journal of sleep research,2012,21:396–401.
[163] Patil, PG, Apfelbaum, JL and Zacny, JP. Effects of a cold-water stressor on psychomotorand cognitive functioning in humans. Physiology&behavior,1995,58:1281–6.
[164] Schoofs, D, Wolf, OT and Smeets, T. Cold pressor stress impairs performance on workingmemory tasks requiring executive functions in healthy young men. Behavioralneuroscience,2009,123:1066–75.
[165] Evans, WO and Witt, NF. The interaction of high altitude and psychotropic drug action.Psychopharmacologia,1966,10:184–8.
[166] Stivalet, P, Leifflen, D, Poquin, D, Savourey, G, Launay, JC, Barraud, PA, Raphel, C andBittel, J. Positive expiratory pressure as a method for preventing the impairment ofattentional processes by hypoxia. Ergonomics,2000,43:474–85.
[167] Bonnon, M, No l-Jorand, MC and Therme, P. Effects of different stay durations onattentional performance during two mountain expeditions. Aviation, space, andenvironmental medicine,2000,71:678–84.
[168] Muller, MD, Muller, SM, Kim, C-H, Ryan, EJ, Gunstad, J and Glickman, EL. Mood andselective attention in the cold: the effect of interval versus continuous exercise. Europeanjournal of applied physiology,2011,111:1321–8.
[169] Audesirk, T, Cabell, L, Kern, M and Audesirk, G. Β-Estradiol Influences Differentiation ofHippocampal Neurons in Vitro Through an Estrogen Receptor-Mediated Process.Neuroscience,2003,121:927–934.
[170] Muthuraju, S, Maiti, P, Solanki, P, Sharma, AK, Amitabh, Singh, SB, Prasad, D andIlavazhagan, G. Acetylcholinesterase inhibitors enhance cognitive functions in ratsfollowing hypobaric hypoxia. Behavioural brain research,2009,203:1–14.
[171] Baitharu, I, Deep, SN, Jain, V, Barhwal, K, Malhotra, AS, Hota, SK, Prasad, D andIlavazhagan, G. Corticosterone synthesis inhibitor metyrapone ameliorates chronichypobaric hypoxia induced memory impairment in rat. Behavioural brain research,2012,228:53–65.
[172] Baitharu, I, Deep, SN, Jain, V, Prasad, D and Ilavazhagan, G. Inhibition of glucocorticoidreceptors ameliorates hypobaric hypoxia induced memory impairment in rat. Behaviouralbrain research,2013,240:76–86.
[173] Shukiqt-hale, B. Tyrosine Administration Prevents Hypoxia-Induced Decrements inLearning and Memory. Science,1996,:867–871.
[174] Xu, K, Sun, X, Erokwu, BO, Cernak, I and Lamanna, JC. A heat-shock protein co-inducertreatment improves behavioral performance in rats exposed to hypoxia. Advances inexperimental medicine and biology,2011,701:313–8.
[175] Townes,B., Hornbein,T., Schoene,R., Sarnquist, F., andGrant, I. Human cerebral function atextreme altitude. In: West, J. B., and Lahiri, S.(eds.), High Altitude and Man,1984,31–36,American Physiological Society, Bethesda.
[176] Huppert, FA. Memory impairment associated with chronic hypoxia. Thorax,1982,37:858–60.
[177] Kales, A, Caldwell, AB, Cadieux, RJ, Vela-Bueno, A, Ruch, LG and Mayes, SD. Severeobstructive sleep apnea--II: Associated psychopathology and psychosocial consequences.Journal of chronic diseases,1985,38:427–34.
[178] Kelly, DA, Claypoole, KH and Coppel, DB. Sleep apnea syndrome: symptomatology,associated features, and neurocognitive correlates. Neuropsychology review,1990,1:323–42.
[179] Salorio, CF, White, DA, Piccirillo, J, Duntley, SP and Uhles, ML. Learning, memory, andexecutive control in individuals with obstructive sleep apnea syndrome. Journal of clinicaland experimental neuropsychology,2002,24:93–100.
[180] Crow, TJ and Kelman, GR. Psychological effects of mild hypoxia. The Journal ofphysiology,1969,204:24P–25P.
[181] Shephard, RJ. Physiological Changes and Psychomotor Performance During AcuteHypoxia. J Appl Physiol,1956,9:343–351.
[182] Phillips, LW and Pace, N. Performance changes at moderately high altitude: short-termmemory measured by free recall. Psychological reports,1966,19:655–65.
[183] Cahoon, RL. Simple decision making at high altitude. Ergonomics,1972,15:157–63.
[184] Cudaback, D. D. Four-km altitude effects on performance andhealth. Publ. AstronomicalSoc. Pac,1984,96:463–477.
[185] Hayashi, Y, Kusakari, S, Sato-Hashimoto, M, Urano, E, Shigeno, M, Sekijima, T, Kotani, T,Murata, Y, Murakami, H, Matozaki, T and Ohnishi, H. Hypothermia-dependent and-independent effects of forced swim on the phosphorylation states of signaling molecules inmouse hippocampus. Biochemical and biophysical research communications,2012,428:475–81.
[186] Kanagawa, T, Fukuda, H, Tsubouchi, H, Komoto, Y, Hayashi, S, Fukui, O, Shimoya, K andMurata, Y. A decrease of cell proliferation by hypothermia in the hippocampus of theneonatal rat. Brain research,2006,1111:36–40.
[187] Stillman, MJ, Shukitt-Hale, B, Levy, a and Lieberman, HR. Spatial memory under acutecold and restraint stress. Physiology&behavior,1998,64:605–9.
[188] ADLER, HF, BURKHARDT, WL, IVY, AC and ATKINSON, AJ. Effect of various drugson psychomotor performance at ground level and at simulated altitudes of18,000feet in alow pressure chamber. The Journal of aviation medicine,1950,21:221–36.
[189] Jobe, JB, Shukitt-Hale, B, Banderet, LE and Rock, PB. Effects of dexamethasone and highterrestrial altitude on cognitive performance and affect. Aviation, space, and environmentalmedicine,1991,62:727–32.
[190] Figarola, TR and Billings, CE. Effects of meprobamate and hypoxia on psychomotorperformance. Aerospace medicine,1966,37:951–4.
[191] Pearson, RG and Neal, GL. Operator performance as a function of drug, hypoxia,individual, and task factors. Aerospace medicine,1970,41:154–8.
[192] House, JL and Joy, RJ. Performance of simulated military tasks at high altitude. Perceptualand motor skills,1968,27:471–81.
[193] Banderet, LE and Lieberman, HR. Treatment with tyrosine, a neurotransmitter precursor,reduces environmental stress in humans. Brain research bulletin,1989,22:759–62.
[194] Leaf, DE and Goldfarb, DS. Mechanisms of action of acetazolamide in the prophylaxis andtreatment of acute mountain sickness. Journal of applied physiology (Bethesda, Md.:1985),2007,102:1313–22.
[195] Swenson, ER and Teppema, LJ. Prevention of acute mountain sickness by acetazolam ide:as yet an unfinished story. Journal of applied physiology (Bethesda, Md.:1985),2007,102:1305–7.
[196] Bailey, DM and Davies, B. Acute mountain sickness; prophylactic benefits of antioxidantvitamin supplementation at high altitude. High altitude medicine&biology,2001,2:21–9.
[197] Le Bars, PL, Katz, MM, Berman, N, Itil, TM, Freedman, AM and Schatzberg, AF. Aplacebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba fordementia. North American EGb Study Group. JAMA,1997,278:1327–32.
[198] Chow, T, Browne, V and Heileson, H. Comparison of Ginkgo biloba versus acetazolamidein the prevention of acute mountain sickness. Medicine& Science in Sports&Exercise,2002,34(5):S246..
[199] Leadbetter GW, Hackett PH, Maakestad K, Tissot-Van Patot M, Olson S, Keyes L, et al.Comparison of Ginkgo biloba, acetazolamide, and placebo for prevention of acutemountain sickness. Abstracts from the13th international hypoxia symposium, Banff,Alberta.
[200] Moraga F, Flores A, Zapata J, Ramos P, Madariaga M, Serra J. Ginkgo bilobadecreasesacute mountain sickness (AMS) at3700m. Abstracts from the13thinternationalhypoxia symposium, Banff, Alberta, Canada, February19-22,2003. High AltMed Biol,2003,3:453.
[201] Gertsch, JH, Seto, TB, Mor, J and Onopa, J. Ginkgo biloba for the prevention of severeacute mountain sickness (AMS) starting one day before rapid ascent. High altitudemedicine&biology,2002,3:29–37.
[202] Winter, JC. The effects of an extract of Ginkgo biloba, EGb761, on cognitive behavior andlongevity in the rat. Physiology&behavior,1998,63:425–33.
[203] Winter, E. Effects of an extract of Ginkgo biloba on learning and memory in mice.Pharmacology, biochemistry, and behavior,1991,38:109–14.
[204] Cohen-Salmon, C, Venault, P, Martin, B, Raffalli-Sébille, MJ, Barkats, M, Clostre, F,Pardon, MC, Christen, Y and Chapouthier, G. Effects of Ginkgo biloba extract (EGb761)on learning and possible actions on aging. Journal of physiology, Paris,1997,91:291–300.
[205] Wirth, S, Stemmelin, J, Will, B, Christen YVES and Di Scala, G. Facilitative effects of EGb761on olfactory recognition in young and aged rats. Pharmacology, biochemistry, andbehavior,2000,65:321–6.
[206] Barkats, M, Venault, P, Christen, Y and Cohen-Salmon, C. Effect of long-term treatmentwith EGb761on age-dependent structural changes in the hippocampi of three inbredmouse strains. Life sciences,1995,56:213–22.
[207] Stoll, S, Scheuer, K, Pohl, O and Müller, WE. Ginkgo biloba extract (EGb761)independently improves changes in passive avoidance learning and brain membranefluidity in the aging mouse. Pharmacopsychiatry,1996,29:144–9.
[208] Subhan, Z and Hindmarch, I. The psychopharmacological effects of Ginkgo biloba extractin normal healthy volunteers. International journal of clinical pharmacology research,1984,4:89–93.
[209] Rigney, U, Kimber, S and Hindmarch, I. The effects of acute doses of standardized Ginkgobiloba extract on memory and psychomotor performance in volunteers. Phytotherapyresearch: PTR,1999,13:408–15.
[210] Mix, JA and Crews, WD. An examination of the efficacy of Ginkgo biloba extract EGb761on the neuropsychologic functioning of cognitively intact older adults. Journal ofalternative and complementary medicine (New York, N.Y.),2000,6:219–29.
[211] Braquet, P.. The ginkgolides: potent platelet-activating factor antagonists isolated fromGinkgo biloba L.: chemistry, pharmacology and clinical applications. Drugs Future,1987,12,643–699.
[212] Braquet, P, Touqui, L, Shen, TY and Vargaftig, BB. Perspectives in platelet-activatingfactor research. Pharmacological reviews,1987,39:97–145.
[213] Venable, ME, Zimmerman, GA, McIntyre, TM and Prescott, SM. Platelet-activating factor:a phospholipid autacoid with diverse actions. Journal of lipid research,1993,34:691–702.
[214] Yue, TL, Gleason, MM, Hallenbeck, J and Feuerstein, G. Characterization ofplatelet-activating factor-induced elevation of cytosolic free-calcium level in neurohybridNCB-20cells. Neuroscience,1991,41:177–85.
[215] Squinto, SP, Block, AL, Braquet, P and Bazan, NG. Platelet-activating factor stimulates afos/jun/AP-1transcriptional signaling system in human neuroblastoma cells. Journal ofneuroscience research,1989,24:558–66.
[216] Bate, C, Tayebi, M and Williams, A. Ginkgolides protect against amyloid-beta1-42-mediated synapse damage in vitro. Molecular neurodegeneration,2008,3:1.
[217] Lee, T-F, Chen, C-F and Wang, LCH. Effect of ginkgolides on beta-amyloid-suppressedacetylocholine release from rat hippocampal slices. Phytotherapy research: PTR,2004,18:556–60.
[218] Liu, W-C, Ding, W-L, Gu, H-Y, Chen, M-F and Hu, J-J. Lipopolysaccharide-inducedcerebral inflammatory damage and the therapeutic effect of platelet activating factorreceptor antagonist. Neuroscience bulletin,2007,23:271–6.
[219] Teather, LA, Afonso, VM and Wurtman, RJ. Inhibition of platelet-activating factorreceptors in hippocampal plasma membranes attenuates the inflammatory nociceptiveresponse in rats. Brain research,2006,1097:230–3.
[220] Wang, S-J and Chen, H-H. Ginkgolide B, a constituent of Ginkgo biloba, facilitatesglutamate exocytosis from rat hippocampal nerve terminals. European journal ofpharmacology,2005,514:141–9.
[221] Jackson, SJ, Varley, J, Sellers, C, Josephs, K, Codrington, L, Duke, G, Njelekela, MA,Drummond, G, Sutherland, AI, Thompson, AAR and Baillie, JK. Incidence and predictorsof acute mountain sickness among trekkers on Mount Kilimanjaro. High altitude medicine&biology,2010,11:217–22.
[222] Regard, M, Landis, T, Casey, J, Maggiorini, M, B rtsch, P and Oelz, O. Cognitive changesat high altitude in healthy climbers and in climbers developing acute mountain sickness.Aviation, space, and environmental medicine,1991,62:291–5.
[223] Baumgartner, RW, Keller, S, Regard, M and B rtsch, P. Flunarizine in prevention ofheadache, ataxia, and memory deficits during decompression to4559m. High altitudemedicine&biology,2003,4:333–9.
[224] Paul, MA and Fraser, WD. Performance during mild acute hypoxia. Aviation, space, andenvironmental medicine,1994,65:891–9.
[225] Wu, X, Li, X, Han, L, Wang, T and Wei, Y. Effects of acute moderate hypoxia on humanperformance of arithmetic. Hang tian yi xue yu yi xue gong cheng=Space medicine&medical engineering,1998,11:391–5.
[226] Bjursten, H, Ederoth, P, Sigurdsson, E, Gottfredsson, M, Syk, I, Einarsson, O andGudbjartsson, T. S100B profiles and cognitive function at high altitude. High altitudemedicine&biology,2010,11:31–8.
[227] Kane, RL, Short, P, Sipes, W and Flynn, CF. Development and validation of the spaceflightcognitive assessment tool for windows (WinSCAT). Aviation, space, and environmentalmedicine,2005,76:B183–91.
[228] Virués-Ortega, J, Buela-Casal, G, Garrido, E and Alcázar, B. Neuropsychologicalfunctioning associated with high-altitude exposure. Neuropsychology review,2004,14:197–224.
[229] Gertsch, JH, Basnyat, B, Johnson, EW, Onopa, J and Holck, PS. Randomised, double blind,placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acutemountain sickness among Himalayan trekkers: the prevention of high altitude illness trial(PHAIT). BMJ (Clinical research ed.),2004,328:797.
[230] Mashayekh, A, Pham, DL, Yousem, DM, Dizon, M, Barker, PB and Lin, DDM. Effects ofGinkgo biloba on cerebral blood flow assessed by quantitative MR perfusion imaging: apilot study. Health (San Francisco),2011,:185–191.
[231] Hopkins, SR, Schoene, RB, Henderson, WR, Spragg, RG, Martin, TR and West, JB. Intenseexercise impairs the integrity of the pulmonary blood-gas barrier in elite athletes. Americanjournal of respiratory and critical care medicine,1997,155:1090–4.
[232] Reeves JT, Wagner J, Zafren K, Honigman B, Schoene RB. Seasonal variation inbarometric pressure and temperature in Summit County: effect on altitude illness. In:Sutton JR, Houston CS, Coates G, eds. Hypoxia and molecular medicine. Burlington, Vt.:Charles S. Houston,1993,275-81.
[233] Purkayastha, SS, Sharma, RP, Ilavazhagan, G, Sridharan, K, Ranganathan, S andSelvamurthy, W. Effect of vitamin C and E in modulating peripheral vascular response tolocal cold stimulus in man at high altitude. The Japanese journal of physiology,1999,49:159–67.
[234] Askew, EW. Work at high altitude and oxidative stress: antioxidant nutrients. Toxicology,2002,180:107–19.
[235] Kappes, B, Mills, W and O’Malley, J. Psychological and psychophysiological factors inprevention and treatment of cold injuries. Alaska medicine,1993,35:131–40.
[236] Giesbrecht, GG, Arnett, JL, Vela, E and Bristow, GK. Effect of task complexity on mentalperformance during immersion hypothermia. Aviation, space, and environmental medicine,1993,64:206–11.
[237] Enander, A. Effects of moderate cold on performance of psychomotor and cognitive tasks.Ergonomics,1987,30:1431–45.
[238] Richardson, R, Guanowsky, V, Ahlers, ST and Riccio, DC. Role of body temperature in theonset of, and recovery from, hypothermia-induced anterograde amnesia. PhysiologicalPsychology,1984,125-132.
[239] Nagy, ZM, Anderson, JA and Mazzaferri, TA. Hypothermia causes adult-like retentiondeficits of prior learning in infant mice. Developmental psychobiology,1976,9:447–58.
[240] Coleshaw, SR, Van Someren, RN, Wolff, AH, Davis, HM and Keatinge, WR. Impairedmemory registration and speed of reasoning caused by low body temperature. Journal ofapplied physiology: respiratory, environmental and exercise physiology,1983,55:27–31.
[241] Baddeley, AD, Cuccaro, WJ, Egstrom, GH, Weltman, G and Willis, MA. Cognitiveefficiency of divers working in cold water. Human factors,1975,17:446–54.
[242] Thomas, JR, Ahlers, ST and Schrot, J. Cold-induced impairment of delayed matching inrats. Behavioral and neural biology,1991,55:19–30.
[243] Sun, M-K and Alkon, DL. Carbonic anhydrase gating of attention: memory therapy andenhancement. Trends in pharmacological sciences,2002,23:83–9.
[244] Staley, KJ, Soldo, BL and Proctor, WR. Ionic mechanisms of neuronal excitation byinhibitory GABAA receptors. Science (New York, N.Y.),1995,269:977–81.
[245] Sun, MK, Zhao, WQ, Nelson, TJ and Alkon, DL. Theta rhythm of hippocampal CA1neuron activity: gating by GABAergic synaptic depolarization. Journal of neurophysiology,2001,85:269–79.
[246] Liebgott, T, Miollan, M, Berchadsky, Y, Drieu, K, Culcasi, M and Pietri, S. Complementarycardioprotective effects of flavonoid metabolites and terpenoid constituents of Ginkgobiloba extract (EGb761) during ischemia and reperfusion. Basic research in cardiology,2000,95:368–77.
[247] Kecskeméti, V and Balogh, I. The role of platelet-activating factor (PAF) antagonists andnitric oxide in cardiac actions of PAF. Electrophysiological and morphological study.Journal of physiology and pharmacology: an official journal of the Polish PhysiologicalSociety,2000,51:723–35.
[248] Xu, Y and Tao, Y-X. Involvement of the NMDA receptor/nitric oxide signal pathway inplatelet-activating factor-induced neurotoxicity. Neuroreport,2004,15:263–6.
[249] Alberi, L, Liu, S, Wang, Y, Badie, R, Smith-Hicks, C, Wu, J, Pierfelice, TJ, Abazyan, B,Mattson, MP, Kuhl, D, Pletnikov, M, Worley, PF and Gaiano, N. Activity-induced Notchsignaling in neurons requires Arc/Arg3.1and is essential for synaptic plasticity inhippocampal networks. Neuron,2011,69:437–44.
[250] Prado, VF, Martins-Silva, C, De Castro, BM, Lima, RF, Barros, DM, Amaral, E, Ramsey,AJ, Sotnikova, TD, Ramirez, MR, Kim, H-G, Rossato, JI, Koenen, J, Quan, H, Cota, VR,Moraes, MFD, Gomez, M V, Guatimosim, C, Wetsel, WC, Kushmerick, C, Pereira, GS,Gainetdinov, RR, Izquierdo, I, Caron, MG and Prado, M a M. Mice deficient for thevesicular acetylcholine transporter are myasthenic and have deficits in object and socialrecognition. Neuron,2006,51:601–12.
[251] Sahay, A, Scobie, KN, Hill, AS, O’Carroll, CM, Kheirbek, M a, Burghardt, NS, Fenton, A a,Dranovsky, A and Hen, R. Increasing adult hippocampal neurogenesis is sufficient toimprove pattern separation. Nature,2011,472:466–70.
[252] Zhang, R, Xue, G, Wang, S, Zhang, L, Shi, C and Xie, X. Novel object reco gnition as afacile behavior test for evaluating drug effects in AβPP/PS1Alzheimer’s disease mousemodel. Journal of Alzheimer’s disease: JAD,2012,31:801–12.
[253] Antunes, M and Biala, G. The novel object recognition memory: neurobiology, testprocedure, and its modifications. Cognitive processing,2012,13:93–110.
[254] Chiu, GS, Chatterjee, D, Darmody, PT, Walsh, JP, Meling, DD, Johnson, RW and Freund,GG. Hypoxia/reoxygenation impairs memory formation via adenosine-dependent activationof caspase1. The Journal of neuroscience: the official journal of the Society forNeuroscience,2012,32:13945–55.
[255] Haile, M, Limson, F, Gingrich, K, Li, Y-S, Quartermain, D, Blanck, T and Bekker, A.Nimodipine prevents transient cognitive dysfunction after moderate hypoxia in adult mice.Journal of neurosurgical anesthesiology,2009,21:140–4.
[256] Richard, NA and Koehle, MS. Differences in cardio-ventilatory responses to hypobaric andnormobaric hypoxia: a review. Aviation, space, and environmental medicine,2012,83:677–84.
[257] Maiti, P, Singh, SB, Sharma, AK, Muthuraju, S, Banerjee, PK and Ilavazhagan, G.Hypobaric hypoxia induces oxidative stress in rat brain. Nano,2006,49:709–716.
[258] Udayabanu, M, Kumaran, D, Nair, RU, Srinivas, P, Bhagat, N, Aneja, R and Katyal, A.Nitric oxide associated with iNOS expression inhibits acetylcholinesterase activity andinduces memory impairment during acute hypobaric hypoxia. Brain research,2008,1230:138–49.
[259] Beatty, WW, Salmon, DP, Bernstein, N, Martone, M, Lyon, L and Butters, N. Procedurallearning in a patient with amnesia due to hypoxia. Brain and cognition,1987,6:386–402.
[260] Thompson, AJ, Jarvis, GE, Duke, RK, Johnston, GAR and Lummis, SCR. Ginkgolide Band bilobalide block the pore of the5-HT receptor at a location that overlaps the picrotoxinbinding site. Neuropharmacology,2011,60:488–95.
[261] Thompson, AJ, Duke, RK and Lummis, SCR. Binding sites for bilobalide, diltiazem,ginkgolide, and picrotoxinin at the5-HT3receptor. Molecular pharmacology,2011,80:183–90.
[262] Staubli, U and Otaky, N. Serotonin controls the magnitude of LTP induced by theta burstsvia an action on NMDA-receptor-mediated responses. Brain research,1994,643:10–6.
[263] Corradetti, R, Ballerini, L, Pugliese, AM and Pepeu, G. Serotonin blocks the long-termpotentiation induced by primed burst stimulation in the CA1region of rat hippocampalslices. Neuroscience,1992,46:511–8.
[264] St ubli, U and Xu, FB. Effects of5-HT3receptor antagonism on hippocampal theta rhythm,memory, and LTP induction in the freely moving rat. The Journal of neuroscience: theofficial journal of the Society for Neuroscience,1995,15:2445–52.
[265] Hodges, H, Sowinski, P, Sinden, JD, Netto, CA and Fletcher, A. The selective5-HT3receptor antagonist, WAY100289, enhances spatial memory in rats with ibotenate lesions ofthe forebrain cholinergic projection system. Psychopharmacology,1995,117:318–32.
[266] Carli, M, Tatarczynska, E, Cervo, L and Samanin, R. Stimulation of hippocampal5-HT1Areceptors causes amnesia and anxiolytic-like but not antidepressant-like effects in the rat.European journal of pharmacology,1993,234:215–21.
[267] Gu JH, Ge JB, Li M, Wu F, Zhang W, Qin ZH. Inhibition of NF-κB activation is associatedwith anti-inflammatory and anti-apoptotic effects of Ginkgolide B in a mouse model ofcerebral ischemia/reperfusion injury. Eur J Pharm Sci,2012,20;47(4):652-60.
[268] Bredt, DS and Nicoll, RA. AMPA receptor trafficking at excitatory synapses. Neuron,2003,40:361–79.
[269] Song, I and Huganir, RL. Regulation of AMPA receptors during synaptic plasticity. Trendsin neurosciences,2002,25:578–88.
[270] Clem, RL and Barth, A. Pathway-specific trafficking of native AMPARs by in vivoexperience. Neuron,2006,49:663–70.
[271] Rumpel, S, Le Doux, J, Zador, A and Malinow, R. Postsynaptic receptor traffickingunderlying a form of associative learning. Science (New York, N.Y.),2005,308:83–8.
[272] Anwyl, R. Metabotropic glutamate receptors: electrophysiological properties and role inplasticity. Brain research. Brain research reviews,1999,29:83–120.
[273] Manahan-Vaughan, D. Group1and2metabotropic glutamate receptors play differentialroles in hippocampal long-term depression and long-term potentiation in freely moving rats.The Journal of neuroscience: the official journal of the Society for Neuroscience,1997,17:3303–11.
[274] Abel, T and Nguyen, P V. Regulation of hippocampus-dependent memory by cyclicAMP-dependent protein kinase. Progress in brain research,2008,169:97–115.
[275] Houslay, MD. Underpinning compartmentalised cAMP signalling through targeted cAMPbreakdown. Trends in biochemical sciences,2010,35:91–100.
[276] Ye X, Marina A, Carew TJ. Local synaptic integration of mitogen-activated protein kinaseand protein kinase A signaling mediates intermediate-term synaptic facilitation in Aplysia.PNAS,2012,109(44):18162-7.
[277] Banke TG, Bowie D, Lee H, Huganir RL, Schousboe A, Traynelis SF. Control of GluR1AMPA receptor function by cAMP-dependent protein kinase. J Neurosci,2000,20(1):89-102.
[2] Imray, C, Booth, A, Wright, a. and Bradwell, a. Acute altitude illnesses. Bmj,2011,343:d4943–d4943.
[3] Bahrke, MS and Shukitt-Hale, B. Effects of altitude on mood, behaviour and cognitivefunctioning. A review. Sports medicine (Auckland, N.Z.),1993,16:97–125.
[4] Richardson, C, Hogan, AM, Bucks, RS, Baya, A, Virues-Ortega, J, Holloway, JW,Rose-Zerilli, M, Palmer, LJ, Webster, RJ, Kirkham, FJ and Baldeweg, T.Neurophysiological evidence for cognitive and brain functional adaptation in adolescentsliving at high altitude. Clinical neurophysiology: official journal of the InternationalFederation of Clinical Neurophysiology,2011,122:1726–34.
[5] Dykiert, D, Hall, D, Van Gemeren, N, Benson, R, Der, G, Starr, JM and Deary, IJ. Theeffects of high altitude on choice reaction time mean and intra-individual variability:Results of the Edinburgh Altitude Research Expedition of2008. Neuropsychology,2010,24:391–401.
[6] Mineo, PM, Cassell, E a, Roberts, ME and Schaeffer, PJ. Chronic cold acclimationincreases thermogenic capacity, non-shivering thermogenesis and muscle citrate synthaseactivity in both wild-type and brown adipose tissue deficient mice. Comparativebiochemistry and physiology. Part A, Molecular&integrative physiology,2012,161:395–400.
[7] Aggarwal, S, Negi, S, Jha, P, Singh, PK, Stobdan, T and Pasha, MAQ. EGLN1involvementin high-altitude adaptation revealed through genetic analysis of extreme constitution typesdefined in Ayurveda. PNAS,2010,107(44):18961–6.
[8] Janssen, J. Club Alpin Francais, Annuaire,1890,1882–1887.
[9] Barhwal, K, Singh, SB, Hota, SK, Jayalakshmi, K and Ilavazhagan, G. Acetyl-L-carnitineameliorates hypobaric hypoxic impairment and spatial memory deficits in rats. Europeanjournal of pharmacology,2007,570:97–107.
[10] Muthuraju, S, Maiti, P, Solanki, P, Sharma, AK, Pati, S, Singh, SB, Prasad, D andIlavazhagan, G. Possible role of cholinesterase inhibitors on memory consolidationfollowing hypobaric hypoxia of rats. The International journal of neuroscience,2011,121:279–88.
[11] Maiti, P, Singh, SB, Muthuraju, S, Veleri, S and Ilavazhagan, G. Hypobaric hypoxiadamages the hippocampal pyramidal neurons in the rat brain. Brain research,2007,1175:1–9.
[12] Karinen, HM and Tikkanen, HO. Acute mountain sickness, two cases and their treatment inthe field. International journal of occupational medicine and environmental health,2012,25:304–9.
[13] Kayser, B, Hulsebosch, R and Bosch, F. Low-Dose Acetylsalicylic Acid Analog andAcetazolamide for Prevention of Acute Mountain Sickness. High Altitude Medicine&Biology,2008,9:1,15–23.
[14] White, AJ. Cognitive impairment of acute mountain sickness and acetazolamide. Aviation,space, and environmental medicine,1984,55:598–603.
[15] Esbaugh, AJ and Tufts, BL. The structure and function of carbonic anhydrase isozymes inthe respiratory system of vertebrates. Respiratory physiology&neurobiology,2006,154:185–98.
[16] Roncin, JP, Schwartz, F and D’Arbigny, P. EGb761in control of acute mountain sicknessand vascular reactivity to cold exposure. Aviation, space, and environmental medicine,1996,67:445–52.
[17] Leadbetter, G, Keyes, LE, Maakestad, KM, Olson, S, Tissot van Patot, MC and Hackett, PH.Ginkgo biloba does-and does not-prevent acute mountain sickness. Wilderness&environmental medicine,2009,20:66–71.
[18] Gilbert, DL. The first documented report of mountain sickness: the China or HeadacheMountain story. Respiration physiology,1983,52:315–26.
[19] Plutarch. Lives, Volume VII Demosthenes and Cicero. Alexander and Caesar. HarvardUniversity Press,1919, US.
[20] McFarland, RA. Psycho-physiological studies at high altitude in the Andes. II. Sensory andmotor responses during acclimatization. Journal of Comparative Psychology,1937,23:227–258.
[21] THE INTERNAL ENVIRONMENT AND BEHAVIOR Part I. Introduction and the R le ofOxygen. American Journal of Psychiatry,1941,97.
[22] Sutton, JR, Houston, CS, Mansell, AL, McFadden, MD, Hackett, PM, Rigg, JR and Powles,AC. Effect of acetazolamide on hypoxemia during sleep at high altitude. The New Englandjournal of medicine,1979,301:1329–31.
[23] Moore, LG. Comparative human ventilatory adaptation to high altitude. Respirationphysiology,2000,121:257–76.
[24] Schoene, RB. Control of ventilation in climbers to extreme altitude. Journal of appliedphysiology: respiratory, environmental and exercise physiology,1982,53:886–90.
[25] Hackett, PH, Rennie, D, Hofmeister, SE, Grover, RF, Grover, EB and Reeves, JT. Fluidretention and relative hypoventilation in acute mountain sickness. Respiration; internationalreview of thoracic diseases,1982,43:321–9.
[26] Richalet, JP, Souberbielle, JC, Antezana, AM, Déchaux, M, Le Trong, JL, Bienvenu, A,Daniel, F, Blanchot, C and Zittoun, J. Control of erythropoiesis in humans duringprolonged exposure to the altitude of6,542m. The American journal of physiology,1994,266:R756–64.
[27] Baumgartner, RW, Spyridopoulos, I, B rtsch, P, Maggiorini, M and Oelz, O. Acutemountain sickness is not related to cerebral blood flow: a decompression chamber study.Journal of applied physiology (Bethesda, Md.:1985),1999,86:1578–82.
[28] Jensen, JB, Wright, AD, Lassen, NA, Harvey, TC, Winterborn, MH, Raichle, ME andBradwell, AR. Cerebral blood flow in acute mountain sickness. Journal of appliedphysiology (Bethesda, Md.:1985),1990,69:430–3.
[29] Morganti, A, Giussani, M, Ghio, F, Pierini, A, Savoia, MT and Cogo, A.Endothelin-releasing stimuli and calcium antagonists in normal and pathological conditions.Journal of hypertension. Supplement: official journal of the International Society ofHypertension,1994,12:S27–31.
[30] Karliner, JS, Sarnquist, FF, Graber, DJ, Peters, RM and West, JB. The electrocardiogram atextreme altitude: experience on Mt. Everest. American heart journal,1985,109:505–13.
[31] Milledge, JS. ELECTROCARDIOGRAPHIC CHANGES AT HIGH ALTITUDE. Britishheart journal,1963,25:291–8.
[32] PENALOZA, D and ECHEVARRIA, M. Electrocardiographic observations on ten subjectsat sea level and during one year of residence at high altitudes. American heart journal,1957,54:811–22.
[33] West, JB and Mathieu-Costello, O. High altitude pulmonary edema is caused by stressfailure of pulmonary capillaries. International journal of sports medicine,1992,13Suppl1:S54–8.
[34] Janssen, J. Club Alpin Francais, Annuaire,1890,1882–1887.
[35] Dunlap, K. Medical studies in aviation: IV. Psychologic observations and metho ds.1918.Aviation, space, and environmental medicine,1989,60:819–21.
[36] Shipton, E. Upon that Mountain, Hodder and Stoughton,London,1943, p.129.
[37] Ruttledge,H. Everest1933: TheUnfinished Adventure,1934,164–166, Hodder andStoughton, London.
[38] THE RESPONSE OF PSYCHONEUROTICS TO VARIATIONS IN OXYGEN TENSION.American Journal of Psychiatry,1937,93.
[39] McFarland, R. A. The internal environment and behavior. Am.J. Psychiatry,1941,97:868–877.
[40] McFarland, R. A. Psycho-physiological studies at high altitudein the Andes: III. Mental andpsycho-somatic responses duringgradual adaptation. Comp. Psychol,1937,24:147–187.
[41] Denison, DM, Ledwith, F and Poulton, EC. Complex reaction times at simulated cabinaltitudes of5,000feet and8,000feet. Aerospace medicine,1966,37:1010–3.
[42] McFarland, RA. Human factors in relation to the development of pressurized cabins.Aerospace medicine,1971,42:1303–18.
[43] Ryn, Z. Psychopathology in alpinism. Acta medica Polona,1971,12:453–67.
[44] Garrido, E, Segura, R, Capdevila, A, Aldomá, J, Rodríguez, FA, Javierra, C and Ventura, JL.New evidence from magnetic resonance imaging of brain changes after climbs at extremealtitude. European journal of applied physiology and occupational physiology,1995,70:477–81.
[45] Hornbein, TF, Townes, BD, Schoene, RB, Sutton, JR, Houston, CS and Ph, D. The cost tothe central nervous system of climbing to extremely high altitude. The New Englandjournal of medicine,1989,321:1714–9.
[46] Regard, M, Oelz, O, Brugger, P and Landis, T. Persistent cognitive impairment in climbersafter repeated exposure to extreme altitude. Neurology,1989,39:210–3.
[47] West, J. Human physiology at extreme altitudes on Mount Everest. Science,1984,223:784–788.
[48] Brierley, J. B. CerebralHypoxia (Chapter II). In: Blackwood,W.,and Corsellis, J. A.(eds.),Greenfield’s Neuropathology,1976, Arnold,London.
[49] Pichiule, P, Chávez, JC, Boero, J and Arregui, A. Chronic hypoxia induces modification ofthe N-methyl-D-aspartate receptor in rat brain. Neuroscience letters,1996,218:83–6.
[50] Reed, LJ, Marsden, P, Lasserson, D, Sheldon, N, Lewis, P, Stanhope, N, Guinan, E andKopelman, MD. FDG-PET analysis and findings in amnesia resulting from hypoxia.Memory (Hove, England),7:599–612.
[51] Adams, R. A., Victor, M., and Ropper, A. H. Trastornosmetab′olicos adquiridos del sistemanervioso [Acquired metabolicnervous system disorders]. Principios de Neurolog′a (7thed.),1999,961–967, McGraw Hill, Mexico DF.
[52] Schulze, G, Coper, H and F hndrich, C. Adaptation capacity of biogenic amines turnover tohypoxia in different brain areas of old rats. Neurochemistry international,1990,17:281–9.
[53] Shukitt-Hale, B, Stillman, MJ, Levy, A, Devine, JA and Lieberman, HR. Nimodipineprevents the in vivo decrease in hippocampal extracellular acetylcholine produced byhypobaric hypoxia. Brain research,1993,621:291–5.
[54] Shukitt-Hale, B, Kadar, T, Marlowe, BE, Stillman, MJ, Galli, RL, Levy, A, Devine, JA andLieberman, HR. Morphological alterations in the hippocampus following hypobarichypoxia. Human&experimental toxicology,1996,15:312–9.
[55] Gozal, D, Daniel, JM and Dohanich, GP. Behavioral and anatomical correlates of chronicepisodic hypoxia during sleep in the rat. The Journal of neuroscience: the official journalof the Society for Neuroscience,2001,21:2442–50.
[56] Zola-Morgan, S, Squire, LR and Amaral, DG. Human amnesia and the medial temporalregion: enduring memory impairment following a bilateral lesion limited to field CA1ofthe hippocampus. The Journal of neuroscience: the official journal of the Society forNeuroscience,1986,6:2950–67.
[57] Prigatano, GP, Parsons, O, Wright, E, Levin, DC and Hawryluk, G. Neuropsychological testperformance in mildly hypoxemic patients with chronic obstructive pulmonary disease.Journal of consulting and clinical psychology,1983,51:108–16.
[58] Bédard, MA, Montplaisir, J, Richer, F, Rouleau, I and Malo, J. Obstructive sleep apneasyndrome: pathogenesis of neuropsychological deficits. Journal of clinical andexperimental neuropsychology,1991,13:950–64.
[59] Bradwell, A. R., Williams, D., Beazley, M., and Imray, C. H. E. Can acute mountainsickness be induced by exercise? In: Roach,R. C., Wagner, P. D., and Hackett, P. H.(eds.),Hypoxia: Into theNext Millennium,1999,368, Plenum/Kluwer Academic Publishi
[60] Roach, RC, Maes, D, Sandoval, D, Robergs, RA, Icenogle, M, Hinghofer-Szalkay, H, Lium,D and Loeppky, JA. Exercise exacerbates acute mountain sickness at simulated highaltitude. Journal of applied physiology (Bethesda, Md.:1985),2000,88:581–5.
[61] Saito, S, Nishihara, F, Takazawa, T, Kanai, M, Aso, C, Shiga, T and Shimada, H.Exercise-induced cerebral deoxygenation among untrained trekkers at moderate altitudes.Archives of environmental health,54:271–6.
[62] Sutton, JR, Reeves, JT, Wagner, PD, Groves, BM, Cymerman, A, Malconian, MK, Rock,PB, Young, PM, Walter, SD and Houston, CS. Operation Everest II: oxygen transportduring exercise at extreme simulated altitude. Journal of applied physiology (Bethesda,Md.:1985),1988,64:1309–21.
[63] Coote, JH, Tsang, G, Baker, A and Stone, B. Respiratory changes and structure of sleep inyoung high-altitude dwellers in the Andes of Peru. European journal of applied physiologyand occupational physiology,1993,66:249–53.
[64] Hackett, PH, Roach, RC, Harrison, GL, Schoene, RB and Mills, WJ. Respiratory stimulantsand sleep periodic breathing at high altitude. Almitrine versus acetazolamide. TheAmerican review of respiratory disease,1987,135:896–8.
[65] Matsuzawa, Y, Kobayashi, T, Fujimoto, K, Yamaguchi, S, Shinozaki, S, Kubo, K,Sekiguchi, M, Hayashi, R, Sakai, A and Ueda, G. Nocturnal periodic breathing and arterialoxygen desaturation in acute mountain sickness. Journal of Wilderness Medicine,1994,5:269–281.
[66] Schoene, RB. The brain at high altitude. Wilderness&environmental medicine,1999,10:93–6.
[67] Shukitt-Hale, B, Banderet, LE and Lieberman, HR. Relationships between symptoms,moods, performance, and acute mountain sickness at4,700meters. Aviation, space, andenvironmental medicine,1991,62:865–9.
[68] Samaja, M, Brenna, L, Allibardi, S and Cerretelli, P. Human red blood cell aging at5,050-m altitude: a role during adaptation to hypoxia. Journal of applied physiology(Bethesda, Md.:1985),1993,75:1696–701.
[69] Doughty, HA and Beardmore, C. Bleeding time at altitude. Journal of the Royal Society ofMedicine,1994,87:317–9.
[70] Roach, RC and Hackett, PH. Frontiers of hypoxia research: acute mountain sickness. TheJournal of experimental biology,2001,204:3161–70.
[71] Garrido, E, Castelló, A, Ventura, JL, Capdevila, A and Rodríguez, FA. Cortical atrophy andother brain magnetic resonance imaging (MRI) changes after extremely high-altitudeclimbs without oxygen. International journal of sports medicine,1993,14:232–4.
[72] Song, SY, Asaji, T, Tanizaki, Y, Fujimaki, T, Matsutani, M and Okeda, R. Cerebralthrombosis at altitude: its pathogenesis and the problems of prevention and treatment.Aviation, space, and environmental medicine,1986,57:71–6.
[73] Hackett, PH, Yarnell, PR, Hill, R, Reynard, K, Heit, J and McCormick, J. High-altitudecerebral edema evaluated with magnetic resonance imaging: clinical correlation andpathophysiology. JAMA: the journal of the American Medical Association,1998,280:1920–5.
[74] Garrido, E and Javierre, C. Extreme altitude transient aphasia. British journal of sportsmedicine,1996,30:364.
[75] Shlim, DR, Hackett, P, Houston, C, Steele, P, Nelson, D and Hultgren, HN. Diplopia at highaltitude. Wilderness&environmental medicine,1995,6:341; discussion341–3.
[76] Basnyat, B. Seizure and hemiparesis at high-altitude outside the setting of acute mountainsickness. Wilderness&environmental medicine,1997,8:221–2.
[77] Basnyat, B. Delirium at high altitude. High altitude medicine&biology,2002,3:69–71.
[78] Litch, JA and Bishop, RA. Transient global amnesia at high altitude. The New Englandjournal of medicine,1999,340:1444.
[79] Hornbein, T. F., and Schoene, R. B. High Altitude: An Explorationof Human Adaptation,Marcel Dekker,2001, New York.
[80] Simon, R. P. CNS response to hypoxia. In: Sutton, J. R.,Houston,C. S., and Coates, G.(eds.), Hypoxia and the Brain Proceedings ofthe Ninth International Hypoxia Symposium,Queen City Printers,1995, Burlington, VT.
[81] Fr lich, MA, Deshpande, H, Ness, T and Deutsch, G. Quantitative changes in regionalcerebral blood flow induced by cold, heat and ischemic pain: a continuous arterial spinlabeling study. Anesthesiology,2012,117:857–67.
[82] Brown, CM, Sanya, EO and Hilz, MJ. Effect of cold face stimulation on cerebral bloodflow in humans. Brain research bulletin,2003,61:81–6.
[83] Schousboe, A, Belhage, B and Frandsen, A. Role of Ca+2and other second messengers inexcitatory amino acid receptor mediated neurodegeneration: clinical perspectives. Clinicalneuroscience (New York, N.Y.),1997,4:194–8.
[84] Pinel, J. P. Tratornos cerebrovasculares [Cerebrovascular disorders]. Biopsicolog′a,2001,60–162, Petrice Hall, Madrid, Spain.
[85] Garrido, E, Segura, R, Capdevila, A, Pujol, J, Javierre, C and Ventura, JL. Are HimalayanSherpas better protected against brain damage associated with extreme altitude climbs?Clinical science (London, England:1979),1996,90:81–5.
[86] Bolmont, B and Abraini, JH. State-anxiety and low moods: evidence for a single concept.Physiology&behavior,74:421–4.
[87] Fowler, B, Elcombe, DD, Kelso, B and Porlier, G. The threshold for hypoxia effects onperceptual-motor performance. Human factors,1987,29:61–6.
[88] Kramer, AF, Coyne, JT and Strayer, DL. Cognitive function at high altitude. Human factors,1993,35:329–44.
[89] Mackintosh, JH, Thomas, DJ, Olive, JE, Chesner, IM and Knight, RJ. The effect of altitudeon tests of reaction time and alertness. Aviation, space, and environmental medicine,1988,59:246–8.
[90] West, JB. Human physiology at extreme altitudes on Mount Everest. Science,1984,223(4638):784-8.
[91] Wesensten, NJ, Crowley, J, Balkin, T, Kamimori, G, Iwanyk, E, Pearson, N, Devine, J,Belenky, G and Cymerman, A. Effects of simulated high altitude exposure on long-latencyevent-related brain potentials and performance. Aviation, space, and environmentalmedicine,1993,64:30–6.
[92] Fowler, B and Prlic, H. A comparison of visual and auditory reaction time and P300latencythresholds to acute hypoxia. Aviation, space, and environmental medicine,1995,66:645–50.
[93] Fowler, B and Lindeis, AE. The effects of hypoxia on auditory reaction time and P300latency. Aviation, space, and environmental medicine,1992,63:976–81.
[94] Fowler, B and Adams, J. Dissociation of the effects of alcohol and amphetamine on inertgas narcosis using reaction time and P300latency. Aviation, space, and environmentalmedicine,1993,64:493–9.
[95] Johnson, R., Jr. The amplitude of P300component of the eventrelatedpotential: Review andsynthesis. In: Ackles, P., Jennings,J. R., and Coles, M. G. H.(eds.), Advances inPsychophysiology,1998,3:69–137, JAI Press, London.
[96] Mahoney, CR, Castellani, J, Kramer, FM, Young, A and Lieberman, HR. Tyrosinesupplementation mitigates working memory decrements during cold exposure. Physiology&behavior,2007,92:575–82.
[97] Thomas, JR, Ahlers, ST, House, JF and Schrot, J. Repeated exposure to moderate coldimpairs matching-to-sample performance. Aviation, space, and environmental medicine,1989,60:1063–7.
[98] Van Orden, KF, Ahlers, ST, Thomas, JR, House, JF and Schrot, J. Moderate cold exposureshortens evoked potential latencies in humans. Aviation, space, and environmentalmedicine,1990,61:636–9.
[99] Watson, D. B.,Martin,R. L., McAnally,K. I., Smith, S. E., and Emonson,D. L. Effect ofnormobaric hypoxia on auditory sensitivity.Aviat. Space Environ. Med,2000,71:791–797.
[100] Fowler, B and Grant, A. Hearing thresholds under acute hypoxia and relationship toslowing in the auditory modality. Aviation, space, and environmental medicine,2000,71:946–9.
[101] Burkett, PR and Perrin, WF. Hypoxia and auditory thresholds. Aviation, space, andenvironmental medicine,1976,47:649–51.
[102] Martin, RL, Watson, DB, Smith, SE, McAnally, KI and Emonson, DL. Effect ofnormobaric hypoxia on sound localization. Aviation, space, and environmental medicine,2000,71:991–5.
[103] Fleisch, A., and Von Murant, A. Klimaphysiologische Untersuchungen in Der Schweiz, PartII [Environmental physiology research in Switzerland, Part II]. Bemo Schwabe,1948,Basel, Switzerland.
[104] Fleisch, A., and Von Murant, A. Klimaphysiologische Untersuchungenin der Schweiz, PartI [Environmental physiology researchin Switzerland, Part I].Bemo Schwabe,1994, Basel,Switzerland.
[105] Kobrick, J. Effects of hypoxia on the luminance threshold for target detection. Aviation,space, and environmental medicine,1983,54:112–5.
[106] No l-Jorand, MC, Bragard, D and Plaghki, L. Pain perception under chronic high-altitudehypoxia. The European journal of neuroscience,1996,8:2075–9.
[107] Plaghki, L, Delisle, D and Godfraind, JM. Heterotopic nociceptive conditioning stimuli andmental task modulate differently the perception and physiological correlates of short CO2laser stimuli. Pain,1994,57:181–92.
[108] Padawer, WJ and Levine, FM. Exercise-induced analgesia: fact or artifact? Pain,1992,48:131–5.
[109] No l-Jorand, MC and Burnet, H. The sensation of respiration in men experiencinghigh-altitude chronic hypoxia. Biological psychology,1996,43:1–12.
[110] Kobrick, JL and Appleton, B. Effects of extended hypoxia on visual performance andretinal vascular state. Journal of applied physiology,1971,31:357–62.
[111] McFarland, R. A., and Evans, J. N. Alterations in dark adaptations under reduced oxygentensions. Am. J. Physiol,1939,127:37–50.
[112] Kobrick, JL, Crohn, E, Shukitt, B, Houston, CS, Sutton, JR and Cymerman, A. OperationEverest II: lack of an effect of extreme altitude on visual contrast sensitivity. Aviation,space, and environmental medicine,1988,59:160–4.
[113] Cahoon, RL. Vigilance performance under hypoxia. The Journal of applied psychology,1970,54:479–83.
[114] Kobrick, JL, Zwick, H, Witt, CE and Devine, JA. Effects of extended hypoxia on nightvision. Aviation, space, and environmental medicine,1984,55:191–5.
[115] Richalet, JP, Duval-Arnould, G, Darnaud, B, Keromes, A and Rutgers, V. Modification ofcolour vision in the green/red axis in acute and chronic hypoxia explored with a portableanomaloscope. Aviation, space, and environmental medicine,1988,59:620–3.
[116] Smith, VC, Ernest, JT and Pokorny, J. Effect of hypoxia on FM100-Hue test performance.Modern problems in ophthalmology,1976,17:248–56.
[117] Vingrys, AJ and Garner, LF. The effect of a moderate level of hypoxia on human colorvision. Documenta ophthalmologica. Advances in ophthalmology,1987,66:171–85.
[118] Leid, J and Campagne, JM. Colour vision at very high altitude. Color research andapplication,2001,26Suppl1:S281–3.
[119] Bouquet, C, Gardette, B, Gortan, C, Therme, P and Abraini, JH. Color discrimination underchronic hypoxic conditions (simulated climb “Everest-Comex97”). Perceptual and motorskills,2000,90:169–79.
[120] Berry, DT, McConnell, JW, Phillips, BA, Carswell, CM, Lamb, DG and Prine, BC.Isocapnic hypoxemia and neuropsychological functioning. Journal of clinical andexperimental neuropsychology,1989,11:241–51.
[121] Bolmont, B., Thullier, F., and Abraini, J. H. Relationship between mood states andperformances in RT, psychomotor ability, and mental efficiency during31-day gradualdecompression in a hypobaric chamber from sea level to8848m equivalent altitu.Physiology and Behavior,2000,71(5):469-476
[122] Sharma, VM, Malhotra, MS and Baskaran, AS. Variations in psychomotor efficiency duringprolonged stay at high altitude. Ergonomics,1975,18:511–6.
[123] Pe a-Casanova, J., Hernandez, M. T., and Jarne, A. Técnicas neuropsicológicas
[Neuropsychological techniques]. In Buela-Casal G., and Sierra, C.(eds.), Manual deEvaluación Psicológica: Fundamentos, Técnicasy Aplicaciones,1997,421–454.
[124] Lezak, M. D. Neuropsychol Assess (3rd ed.), Oxford UniversityPress,1995, Oxford.
[125] Garner, SH, Sutton, JR, Burse, RL, McComas, AJ, Cymerman, A and Houston, CS.Operation Everest II: neuromuscular performance under conditions of extreme simulatedaltitude. Journal of applied physiology (Bethesda, Md.:1985),1990,68:1167–72.
[126] Abraini, JH, Bouquet, C, Joulia, F, Nicolas, M and Kriem, B. Cognitive performanceduring a simulated climb of Mount Everest: implications for brain function and centraladaptive processes under chronic hypoxic stress. Pfl gers Archiv: European journal ofphysiology,1998,436:553–9.
[127] Bouquet, CA, Gardette, B, Gortan, C and Abraini, JH. Psychomotor skills learning underchronic hypoxia. Neuroreport,1999,10:3093–9.
[128] Bolmont, B, Thullier, F and Abraini, JH. Relationships between mood states andperformances in reaction time, psychomotor ability, and mental efficiency during a31-daygradual decompression in a hypobaric chamber from sea level to8848m equivalentaltitude. Physiology&behavior,2000,71:469–76.
[129] Townes,B., Hornbein,T., Schoene,R., Sarnquist, F., andGrant, I. Human cerebral function atextreme altitude. In: West, J. B., andLahiri, S.(eds.), High Altitude and Man,1984,31–36,AmericanPhysiological Society, Bethesda.
[130] West, JB. Do climbs to extreme altitude cause brain damage? Lancet,1986,2:387–8.
[131] Forster, H V, Dempsey, JA, Birnbaum, ML, Reddan, WG, Thoden, J, Grover, RF andRankin, J. Effect of chronic exposure to hypoxia on ventilatory response to CO2andhypoxia. Journal of applied physiology,1971,31:586–92.
[132] Masuyama, S, Kimura, H, Sugita, T, Kuriyama, T, Tatsumi, K, Kunitomo, F, Okita, S,Tojima, H, Yuguchi, Y and Watanabe, S. Control of ventilation in extreme-altitude climbers.Journal of applied physiology (Bethesda, Md.:1985),1986,61:500–6.
[133] Clark, CF, Heaton, RK and Wiens, AN. Neuropsychological functioning after prolongedhigh altitude exposure in mountaineering. Aviation, space, and environmental medicine,1983,54:202–7.
[134] Jason, GW, Pajurkova, EM and Lee, RG. High-altitude mountaineering and brain function:neuropsychological testing of members of a Mount Everest expedition. Aviation, space, andenvironmental medicine,1989,60:170–3.
[135] Milne, D and Gray, D. Evidence bearing on the generalizability of laboratory findingsrelating to high-altitude mountaineering. Perceptual and motor skills,1983,57:172–4.
[136] McSweeny, AJ, Grant, I, Heaton, RK, Prigatano, GP and Adams, KM. Relationship ofneuropsychological status to everyday functioning in healthy and chronically ill persons.Journal of clinical and experimental neuropsychology,1985,7:281–91.
[137] Grant, I, Prigatano, GP, Heaton, RK, McSweeny, AJ, Wright, EC and Adams, KM.Progressive neuropsychologic impairment and hypoxemia. Relationship in chronicobstructive pulmonary disease. Archives of general psychiatry,1987,44:999–1006.
[138] Stuss, DT, Peterkin, I, Guzman, DA, Guzman, C and Troyer, AK. Chronic obstructivepulmonary disease: effects of hypoxia on neurological and neuropsychological measures.Journal of clinical and experimental neuropsychology,1997,19:515–24.
[139] Khoo, MC, Anholm, JD, Ko, SW, Downey, R, Powles, AC, Sutton, JR and Houston, CS.Dynamics of periodic breathing and arousal during sleep at extreme altitude. Respirationphysiology,1996,103:33–43.
[140] Bakharev, VD. Investigation of memory during adaptation to high mountain conditions.Human physiology,1981,7:409–14.
[141] Cavaletti, G, Moroni, R, Garavaglia, P and Tredici, G. Brain damage after high-altitudeclimbs without oxygen. Lancet,1987,1:101.
[142] Kennedy, RS, Dunlap, WP, Banderet, LE, Smith, MG and Houston, CS. Cognitiveperformance deficits in a simulated climb of Mount Everest: Operation Everest II. Aviation,space, and environmental medicine,1989,60:99–104.
[143] Oelz, O, Howald, H, Di Prampero, PE, Hoppeler, H, Claassen, H, Jenni, R, Bühlmann, A,Ferretti, G, Brückner, JC and Veicsteinas, A. Physiological profile of world-classhigh-altitude climbers. Journal of applied physiology (Bethesda, Md.:1985),1986,60:1734–42.
[144] Shock, N. W. The effects on learning of repeated exposuresto lowered oxygen tension ofinspired air. J. Comp. Psychol,1942,34:55–63.
[145] Nelson, TO, Dunlosky, J, White, DM, Steinberg, J, Townes, BD and Anderson, D.Cognition and metacognition at extreme altitudes on Mount Everest. Journal ofexperimental psychology. General,1990,119:367–74.
[146] Chleide, E, Bruhwyler, J and Mercier, M. Effect of chronic hypoxic treatment on theretention of fixed-interval responding. Physiology&behavior,1991,49:465–70.
[147] Ettinger, RH and Staddon, JE. Decreased feeding associated with acute hypoxia in rats.Physiology&behavior,1982,29:455–8.
[148] Koller, EA, Bischoff, M, Bührer, A, Felder, L and Schopen, M. Respiratory, circulatory andneuropsychological responses to acute hypoxia in acclimatized and non-acclimatizedsubjects. European journal of applied physiology and occupational physiology,1991,62:67–72.
[149] Kelman, GR, Crow, TJ and Bursill, AE. Effect of mild hypoxia on mental performanceassessed by a test of selective attention. Aerospace medicine,1969,40:301–3.
[150] Smeets, T, Otgaar, H, Candel, I and Wolf, OT. True or false? Memory is differentiallyaffected by stress-induced cortisol elevations and sympathetic activity at consolidation andretrieval. Psychoneuroendocrinology,2008,33:1378–86.
[151] Roozendaal, B. Stress and memory: opposing effects of glucocorticoids on memoryconsolidation and memory retrieval. Neurobiology of learning and memory,2002,78:578–95.
[152] Roozendaal, B, Hahn, EL, Nathan, S V, De Quervain, DJ-F and McGaugh, JL.Glucocorticoid effects on memory retrieval require concurrent noradrenergic activity in thehippocampus and basolateral amygdala. The Journal of neuroscience: the official journal ofthe Society for Neuroscience,2004,24:8161–9.
[153] Schwabe, L and Wolf, OT. Stress impairs the reconsolidation of autobiographical memories.Neurobiology of learning and memory,2010,94:153–7.
[154] Zheng, G, Chen, Y, Zhang, X, Cai, T, Liu, M, Zhao, F, Luo, W and Chen, J. Acute coldexposure and rewarming enhanced spatial memory and activated the MAPK cascades in therat brain. Brain research,2008,1239:171–80.
[155] Shukitt-Hale, B, Stillman, MJ, Welch, DI, Levy, A, Devine, JA and Lieberman, HR.Hypobaric hypoxia impairs spatial memory in an elevation-dependent fashion. Behavioraland neural biology,1994,62:244–52.
[156] Nelson, M. Psychological testing at high altitudes. Aviation, space, and environmentalmedicine,1982,53:122–6.
[157] M kinen, TM, Palinkas, L a, Reeves, DL, P kk nen, T, Rintam ki, H, Lepp luoto, J andHassi, J. Effect of repeated exposures to cold on cognitive performance in humans.Physiology&behavior,2006,87:166–76.
[158] Muthuraju, S, Maiti, P, Solanki, P, Sharma, AK, Singh, SB, Prasad, D and Ilavazhagan, G.Cholinesterase inhibitors ameliorate spatial learning deficits in rats following hypobarichypoxia. Experimental brain research. Experimentelle Hirnforschung. Expérimentationcérébrale,2010,203:583–92.
[159] Muthuraju, S, Maiti, P, Pati, S, Solanki, P, Sharma, AK, Singh, SB, Prasad, D andIlavazhagan, G. Role of cholinergic markers on memory function of rats exposed tohypobaric hypoxia. European journal of pharmacology,2011,672:96–105.
[160] Crow, TJ and Kelman, GR. Effect of mild acute hypoxia on human short-term memory.British journal of anaesthesia,1971,43:548–52.
[161] Bartholomew, CJ, Jensen, W, Petros, T V, Ferraro, FR, Fire, KM, Biberdorf, D, Fraley, E,Schalk, J and Blumkin, D. The effect of moderate levels of simulated altitude on sustainedcognitive performance. The International journal of aviation psychology,1999,9:351–9.
[162] Nemeth, D, Csábi, E, Janacsek, K, Várszegi, M and Mari, Z. Intact implicit probabilisticsequence learning in obstructive sleep apnea. Journal of sleep research,2012,21:396–401.
[163] Patil, PG, Apfelbaum, JL and Zacny, JP. Effects of a cold-water stressor on psychomotorand cognitive functioning in humans. Physiology&behavior,1995,58:1281–6.
[164] Schoofs, D, Wolf, OT and Smeets, T. Cold pressor stress impairs performance on workingmemory tasks requiring executive functions in healthy young men. Behavioralneuroscience,2009,123:1066–75.
[165] Evans, WO and Witt, NF. The interaction of high altitude and psychotropic drug action.Psychopharmacologia,1966,10:184–8.
[166] Stivalet, P, Leifflen, D, Poquin, D, Savourey, G, Launay, JC, Barraud, PA, Raphel, C andBittel, J. Positive expiratory pressure as a method for preventing the impairment ofattentional processes by hypoxia. Ergonomics,2000,43:474–85.
[167] Bonnon, M, No l-Jorand, MC and Therme, P. Effects of different stay durations onattentional performance during two mountain expeditions. Aviation, space, andenvironmental medicine,2000,71:678–84.
[168] Muller, MD, Muller, SM, Kim, C-H, Ryan, EJ, Gunstad, J and Glickman, EL. Mood andselective attention in the cold: the effect of interval versus continuous exercise. Europeanjournal of applied physiology,2011,111:1321–8.
[169] Audesirk, T, Cabell, L, Kern, M and Audesirk, G. Β-Estradiol Influences Differentiation ofHippocampal Neurons in Vitro Through an Estrogen Receptor-Mediated Process.Neuroscience,2003,121:927–934.
[170] Muthuraju, S, Maiti, P, Solanki, P, Sharma, AK, Amitabh, Singh, SB, Prasad, D andIlavazhagan, G. Acetylcholinesterase inhibitors enhance cognitive functions in ratsfollowing hypobaric hypoxia. Behavioural brain research,2009,203:1–14.
[171] Baitharu, I, Deep, SN, Jain, V, Barhwal, K, Malhotra, AS, Hota, SK, Prasad, D andIlavazhagan, G. Corticosterone synthesis inhibitor metyrapone ameliorates chronichypobaric hypoxia induced memory impairment in rat. Behavioural brain research,2012,228:53–65.
[172] Baitharu, I, Deep, SN, Jain, V, Prasad, D and Ilavazhagan, G. Inhibition of glucocorticoidreceptors ameliorates hypobaric hypoxia induced memory impairment in rat. Behaviouralbrain research,2013,240:76–86.
[173] Shukiqt-hale, B. Tyrosine Administration Prevents Hypoxia-Induced Decrements inLearning and Memory. Science,1996,:867–871.
[174] Xu, K, Sun, X, Erokwu, BO, Cernak, I and Lamanna, JC. A heat-shock protein co-inducertreatment improves behavioral performance in rats exposed to hypoxia. Advances inexperimental medicine and biology,2011,701:313–8.
[175] Townes,B., Hornbein,T., Schoene,R., Sarnquist, F., andGrant, I. Human cerebral function atextreme altitude. In: West, J. B., and Lahiri, S.(eds.), High Altitude and Man,1984,31–36,American Physiological Society, Bethesda.
[176] Huppert, FA. Memory impairment associated with chronic hypoxia. Thorax,1982,37:858–60.
[177] Kales, A, Caldwell, AB, Cadieux, RJ, Vela-Bueno, A, Ruch, LG and Mayes, SD. Severeobstructive sleep apnea--II: Associated psychopathology and psychosocial consequences.Journal of chronic diseases,1985,38:427–34.
[178] Kelly, DA, Claypoole, KH and Coppel, DB. Sleep apnea syndrome: symptomatology,associated features, and neurocognitive correlates. Neuropsychology review,1990,1:323–42.
[179] Salorio, CF, White, DA, Piccirillo, J, Duntley, SP and Uhles, ML. Learning, memory, andexecutive control in individuals with obstructive sleep apnea syndrome. Journal of clinicaland experimental neuropsychology,2002,24:93–100.
[180] Crow, TJ and Kelman, GR. Psychological effects of mild hypoxia. The Journal ofphysiology,1969,204:24P–25P.
[181] Shephard, RJ. Physiological Changes and Psychomotor Performance During AcuteHypoxia. J Appl Physiol,1956,9:343–351.
[182] Phillips, LW and Pace, N. Performance changes at moderately high altitude: short-termmemory measured by free recall. Psychological reports,1966,19:655–65.
[183] Cahoon, RL. Simple decision making at high altitude. Ergonomics,1972,15:157–63.
[184] Cudaback, D. D. Four-km altitude effects on performance andhealth. Publ. AstronomicalSoc. Pac,1984,96:463–477.
[185] Hayashi, Y, Kusakari, S, Sato-Hashimoto, M, Urano, E, Shigeno, M, Sekijima, T, Kotani, T,Murata, Y, Murakami, H, Matozaki, T and Ohnishi, H. Hypothermia-dependent and-independent effects of forced swim on the phosphorylation states of signaling molecules inmouse hippocampus. Biochemical and biophysical research communications,2012,428:475–81.
[186] Kanagawa, T, Fukuda, H, Tsubouchi, H, Komoto, Y, Hayashi, S, Fukui, O, Shimoya, K andMurata, Y. A decrease of cell proliferation by hypothermia in the hippocampus of theneonatal rat. Brain research,2006,1111:36–40.
[187] Stillman, MJ, Shukitt-Hale, B, Levy, a and Lieberman, HR. Spatial memory under acutecold and restraint stress. Physiology&behavior,1998,64:605–9.
[188] ADLER, HF, BURKHARDT, WL, IVY, AC and ATKINSON, AJ. Effect of various drugson psychomotor performance at ground level and at simulated altitudes of18,000feet in alow pressure chamber. The Journal of aviation medicine,1950,21:221–36.
[189] Jobe, JB, Shukitt-Hale, B, Banderet, LE and Rock, PB. Effects of dexamethasone and highterrestrial altitude on cognitive performance and affect. Aviation, space, and environmentalmedicine,1991,62:727–32.
[190] Figarola, TR and Billings, CE. Effects of meprobamate and hypoxia on psychomotorperformance. Aerospace medicine,1966,37:951–4.
[191] Pearson, RG and Neal, GL. Operator performance as a function of drug, hypoxia,individual, and task factors. Aerospace medicine,1970,41:154–8.
[192] House, JL and Joy, RJ. Performance of simulated military tasks at high altitude. Perceptualand motor skills,1968,27:471–81.
[193] Banderet, LE and Lieberman, HR. Treatment with tyrosine, a neurotransmitter precursor,reduces environmental stress in humans. Brain research bulletin,1989,22:759–62.
[194] Leaf, DE and Goldfarb, DS. Mechanisms of action of acetazolamide in the prophylaxis andtreatment of acute mountain sickness. Journal of applied physiology (Bethesda, Md.:1985),2007,102:1313–22.
[195] Swenson, ER and Teppema, LJ. Prevention of acute mountain sickness by acetazolam ide:as yet an unfinished story. Journal of applied physiology (Bethesda, Md.:1985),2007,102:1305–7.
[196] Bailey, DM and Davies, B. Acute mountain sickness; prophylactic benefits of antioxidantvitamin supplementation at high altitude. High altitude medicine&biology,2001,2:21–9.
[197] Le Bars, PL, Katz, MM, Berman, N, Itil, TM, Freedman, AM and Schatzberg, AF. Aplacebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba fordementia. North American EGb Study Group. JAMA,1997,278:1327–32.
[198] Chow, T, Browne, V and Heileson, H. Comparison of Ginkgo biloba versus acetazolamidein the prevention of acute mountain sickness. Medicine& Science in Sports&Exercise,2002,34(5):S246..
[199] Leadbetter GW, Hackett PH, Maakestad K, Tissot-Van Patot M, Olson S, Keyes L, et al.Comparison of Ginkgo biloba, acetazolamide, and placebo for prevention of acutemountain sickness. Abstracts from the13th international hypoxia symposium, Banff,Alberta.
[200] Moraga F, Flores A, Zapata J, Ramos P, Madariaga M, Serra J. Ginkgo bilobadecreasesacute mountain sickness (AMS) at3700m. Abstracts from the13thinternationalhypoxia symposium, Banff, Alberta, Canada, February19-22,2003. High AltMed Biol,2003,3:453.
[201] Gertsch, JH, Seto, TB, Mor, J and Onopa, J. Ginkgo biloba for the prevention of severeacute mountain sickness (AMS) starting one day before rapid ascent. High altitudemedicine&biology,2002,3:29–37.
[202] Winter, JC. The effects of an extract of Ginkgo biloba, EGb761, on cognitive behavior andlongevity in the rat. Physiology&behavior,1998,63:425–33.
[203] Winter, E. Effects of an extract of Ginkgo biloba on learning and memory in mice.Pharmacology, biochemistry, and behavior,1991,38:109–14.
[204] Cohen-Salmon, C, Venault, P, Martin, B, Raffalli-Sébille, MJ, Barkats, M, Clostre, F,Pardon, MC, Christen, Y and Chapouthier, G. Effects of Ginkgo biloba extract (EGb761)on learning and possible actions on aging. Journal of physiology, Paris,1997,91:291–300.
[205] Wirth, S, Stemmelin, J, Will, B, Christen YVES and Di Scala, G. Facilitative effects of EGb761on olfactory recognition in young and aged rats. Pharmacology, biochemistry, andbehavior,2000,65:321–6.
[206] Barkats, M, Venault, P, Christen, Y and Cohen-Salmon, C. Effect of long-term treatmentwith EGb761on age-dependent structural changes in the hippocampi of three inbredmouse strains. Life sciences,1995,56:213–22.
[207] Stoll, S, Scheuer, K, Pohl, O and Müller, WE. Ginkgo biloba extract (EGb761)independently improves changes in passive avoidance learning and brain membranefluidity in the aging mouse. Pharmacopsychiatry,1996,29:144–9.
[208] Subhan, Z and Hindmarch, I. The psychopharmacological effects of Ginkgo biloba extractin normal healthy volunteers. International journal of clinical pharmacology research,1984,4:89–93.
[209] Rigney, U, Kimber, S and Hindmarch, I. The effects of acute doses of standardized Ginkgobiloba extract on memory and psychomotor performance in volunteers. Phytotherapyresearch: PTR,1999,13:408–15.
[210] Mix, JA and Crews, WD. An examination of the efficacy of Ginkgo biloba extract EGb761on the neuropsychologic functioning of cognitively intact older adults. Journal ofalternative and complementary medicine (New York, N.Y.),2000,6:219–29.
[211] Braquet, P.. The ginkgolides: potent platelet-activating factor antagonists isolated fromGinkgo biloba L.: chemistry, pharmacology and clinical applications. Drugs Future,1987,12,643–699.
[212] Braquet, P, Touqui, L, Shen, TY and Vargaftig, BB. Perspectives in platelet-activatingfactor research. Pharmacological reviews,1987,39:97–145.
[213] Venable, ME, Zimmerman, GA, McIntyre, TM and Prescott, SM. Platelet-activating factor:a phospholipid autacoid with diverse actions. Journal of lipid research,1993,34:691–702.
[214] Yue, TL, Gleason, MM, Hallenbeck, J and Feuerstein, G. Characterization ofplatelet-activating factor-induced elevation of cytosolic free-calcium level in neurohybridNCB-20cells. Neuroscience,1991,41:177–85.
[215] Squinto, SP, Block, AL, Braquet, P and Bazan, NG. Platelet-activating factor stimulates afos/jun/AP-1transcriptional signaling system in human neuroblastoma cells. Journal ofneuroscience research,1989,24:558–66.
[216] Bate, C, Tayebi, M and Williams, A. Ginkgolides protect against amyloid-beta1-42-mediated synapse damage in vitro. Molecular neurodegeneration,2008,3:1.
[217] Lee, T-F, Chen, C-F and Wang, LCH. Effect of ginkgolides on beta-amyloid-suppressedacetylocholine release from rat hippocampal slices. Phytotherapy research: PTR,2004,18:556–60.
[218] Liu, W-C, Ding, W-L, Gu, H-Y, Chen, M-F and Hu, J-J. Lipopolysaccharide-inducedcerebral inflammatory damage and the therapeutic effect of platelet activating factorreceptor antagonist. Neuroscience bulletin,2007,23:271–6.
[219] Teather, LA, Afonso, VM and Wurtman, RJ. Inhibition of platelet-activating factorreceptors in hippocampal plasma membranes attenuates the inflammatory nociceptiveresponse in rats. Brain research,2006,1097:230–3.
[220] Wang, S-J and Chen, H-H. Ginkgolide B, a constituent of Ginkgo biloba, facilitatesglutamate exocytosis from rat hippocampal nerve terminals. European journal ofpharmacology,2005,514:141–9.
[221] Jackson, SJ, Varley, J, Sellers, C, Josephs, K, Codrington, L, Duke, G, Njelekela, MA,Drummond, G, Sutherland, AI, Thompson, AAR and Baillie, JK. Incidence and predictorsof acute mountain sickness among trekkers on Mount Kilimanjaro. High altitude medicine&biology,2010,11:217–22.
[222] Regard, M, Landis, T, Casey, J, Maggiorini, M, B rtsch, P and Oelz, O. Cognitive changesat high altitude in healthy climbers and in climbers developing acute mountain sickness.Aviation, space, and environmental medicine,1991,62:291–5.
[223] Baumgartner, RW, Keller, S, Regard, M and B rtsch, P. Flunarizine in prevention ofheadache, ataxia, and memory deficits during decompression to4559m. High altitudemedicine&biology,2003,4:333–9.
[224] Paul, MA and Fraser, WD. Performance during mild acute hypoxia. Aviation, space, andenvironmental medicine,1994,65:891–9.
[225] Wu, X, Li, X, Han, L, Wang, T and Wei, Y. Effects of acute moderate hypoxia on humanperformance of arithmetic. Hang tian yi xue yu yi xue gong cheng=Space medicine&medical engineering,1998,11:391–5.
[226] Bjursten, H, Ederoth, P, Sigurdsson, E, Gottfredsson, M, Syk, I, Einarsson, O andGudbjartsson, T. S100B profiles and cognitive function at high altitude. High altitudemedicine&biology,2010,11:31–8.
[227] Kane, RL, Short, P, Sipes, W and Flynn, CF. Development and validation of the spaceflightcognitive assessment tool for windows (WinSCAT). Aviation, space, and environmentalmedicine,2005,76:B183–91.
[228] Virués-Ortega, J, Buela-Casal, G, Garrido, E and Alcázar, B. Neuropsychologicalfunctioning associated with high-altitude exposure. Neuropsychology review,2004,14:197–224.
[229] Gertsch, JH, Basnyat, B, Johnson, EW, Onopa, J and Holck, PS. Randomised, double blind,placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acutemountain sickness among Himalayan trekkers: the prevention of high altitude illness trial(PHAIT). BMJ (Clinical research ed.),2004,328:797.
[230] Mashayekh, A, Pham, DL, Yousem, DM, Dizon, M, Barker, PB and Lin, DDM. Effects ofGinkgo biloba on cerebral blood flow assessed by quantitative MR perfusion imaging: apilot study. Health (San Francisco),2011,:185–191.
[231] Hopkins, SR, Schoene, RB, Henderson, WR, Spragg, RG, Martin, TR and West, JB. Intenseexercise impairs the integrity of the pulmonary blood-gas barrier in elite athletes. Americanjournal of respiratory and critical care medicine,1997,155:1090–4.
[232] Reeves JT, Wagner J, Zafren K, Honigman B, Schoene RB. Seasonal variation inbarometric pressure and temperature in Summit County: effect on altitude illness. In:Sutton JR, Houston CS, Coates G, eds. Hypoxia and molecular medicine. Burlington, Vt.:Charles S. Houston,1993,275-81.
[233] Purkayastha, SS, Sharma, RP, Ilavazhagan, G, Sridharan, K, Ranganathan, S andSelvamurthy, W. Effect of vitamin C and E in modulating peripheral vascular response tolocal cold stimulus in man at high altitude. The Japanese journal of physiology,1999,49:159–67.
[234] Askew, EW. Work at high altitude and oxidative stress: antioxidant nutrients. Toxicology,2002,180:107–19.
[235] Kappes, B, Mills, W and O’Malley, J. Psychological and psychophysiological factors inprevention and treatment of cold injuries. Alaska medicine,1993,35:131–40.
[236] Giesbrecht, GG, Arnett, JL, Vela, E and Bristow, GK. Effect of task complexity on mentalperformance during immersion hypothermia. Aviation, space, and environmental medicine,1993,64:206–11.
[237] Enander, A. Effects of moderate cold on performance of psychomotor and cognitive tasks.Ergonomics,1987,30:1431–45.
[238] Richardson, R, Guanowsky, V, Ahlers, ST and Riccio, DC. Role of body temperature in theonset of, and recovery from, hypothermia-induced anterograde amnesia. PhysiologicalPsychology,1984,125-132.
[239] Nagy, ZM, Anderson, JA and Mazzaferri, TA. Hypothermia causes adult-like retentiondeficits of prior learning in infant mice. Developmental psychobiology,1976,9:447–58.
[240] Coleshaw, SR, Van Someren, RN, Wolff, AH, Davis, HM and Keatinge, WR. Impairedmemory registration and speed of reasoning caused by low body temperature. Journal ofapplied physiology: respiratory, environmental and exercise physiology,1983,55:27–31.
[241] Baddeley, AD, Cuccaro, WJ, Egstrom, GH, Weltman, G and Willis, MA. Cognitiveefficiency of divers working in cold water. Human factors,1975,17:446–54.
[242] Thomas, JR, Ahlers, ST and Schrot, J. Cold-induced impairment of delayed matching inrats. Behavioral and neural biology,1991,55:19–30.
[243] Sun, M-K and Alkon, DL. Carbonic anhydrase gating of attention: memory therapy andenhancement. Trends in pharmacological sciences,2002,23:83–9.
[244] Staley, KJ, Soldo, BL and Proctor, WR. Ionic mechanisms of neuronal excitation byinhibitory GABAA receptors. Science (New York, N.Y.),1995,269:977–81.
[245] Sun, MK, Zhao, WQ, Nelson, TJ and Alkon, DL. Theta rhythm of hippocampal CA1neuron activity: gating by GABAergic synaptic depolarization. Journal of neurophysiology,2001,85:269–79.
[246] Liebgott, T, Miollan, M, Berchadsky, Y, Drieu, K, Culcasi, M and Pietri, S. Complementarycardioprotective effects of flavonoid metabolites and terpenoid constituents of Ginkgobiloba extract (EGb761) during ischemia and reperfusion. Basic research in cardiology,2000,95:368–77.
[247] Kecskeméti, V and Balogh, I. The role of platelet-activating factor (PAF) antagonists andnitric oxide in cardiac actions of PAF. Electrophysiological and morphological study.Journal of physiology and pharmacology: an official journal of the Polish PhysiologicalSociety,2000,51:723–35.
[248] Xu, Y and Tao, Y-X. Involvement of the NMDA receptor/nitric oxide signal pathway inplatelet-activating factor-induced neurotoxicity. Neuroreport,2004,15:263–6.
[249] Alberi, L, Liu, S, Wang, Y, Badie, R, Smith-Hicks, C, Wu, J, Pierfelice, TJ, Abazyan, B,Mattson, MP, Kuhl, D, Pletnikov, M, Worley, PF and Gaiano, N. Activity-induced Notchsignaling in neurons requires Arc/Arg3.1and is essential for synaptic plasticity inhippocampal networks. Neuron,2011,69:437–44.
[250] Prado, VF, Martins-Silva, C, De Castro, BM, Lima, RF, Barros, DM, Amaral, E, Ramsey,AJ, Sotnikova, TD, Ramirez, MR, Kim, H-G, Rossato, JI, Koenen, J, Quan, H, Cota, VR,Moraes, MFD, Gomez, M V, Guatimosim, C, Wetsel, WC, Kushmerick, C, Pereira, GS,Gainetdinov, RR, Izquierdo, I, Caron, MG and Prado, M a M. Mice deficient for thevesicular acetylcholine transporter are myasthenic and have deficits in object and socialrecognition. Neuron,2006,51:601–12.
[251] Sahay, A, Scobie, KN, Hill, AS, O’Carroll, CM, Kheirbek, M a, Burghardt, NS, Fenton, A a,Dranovsky, A and Hen, R. Increasing adult hippocampal neurogenesis is sufficient toimprove pattern separation. Nature,2011,472:466–70.
[252] Zhang, R, Xue, G, Wang, S, Zhang, L, Shi, C and Xie, X. Novel object reco gnition as afacile behavior test for evaluating drug effects in AβPP/PS1Alzheimer’s disease mousemodel. Journal of Alzheimer’s disease: JAD,2012,31:801–12.
[253] Antunes, M and Biala, G. The novel object recognition memory: neurobiology, testprocedure, and its modifications. Cognitive processing,2012,13:93–110.
[254] Chiu, GS, Chatterjee, D, Darmody, PT, Walsh, JP, Meling, DD, Johnson, RW and Freund,GG. Hypoxia/reoxygenation impairs memory formation via adenosine-dependent activationof caspase1. The Journal of neuroscience: the official journal of the Society forNeuroscience,2012,32:13945–55.
[255] Haile, M, Limson, F, Gingrich, K, Li, Y-S, Quartermain, D, Blanck, T and Bekker, A.Nimodipine prevents transient cognitive dysfunction after moderate hypoxia in adult mice.Journal of neurosurgical anesthesiology,2009,21:140–4.
[256] Richard, NA and Koehle, MS. Differences in cardio-ventilatory responses to hypobaric andnormobaric hypoxia: a review. Aviation, space, and environmental medicine,2012,83:677–84.
[257] Maiti, P, Singh, SB, Sharma, AK, Muthuraju, S, Banerjee, PK and Ilavazhagan, G.Hypobaric hypoxia induces oxidative stress in rat brain. Nano,2006,49:709–716.
[258] Udayabanu, M, Kumaran, D, Nair, RU, Srinivas, P, Bhagat, N, Aneja, R and Katyal, A.Nitric oxide associated with iNOS expression inhibits acetylcholinesterase activity andinduces memory impairment during acute hypobaric hypoxia. Brain research,2008,1230:138–49.
[259] Beatty, WW, Salmon, DP, Bernstein, N, Martone, M, Lyon, L and Butters, N. Procedurallearning in a patient with amnesia due to hypoxia. Brain and cognition,1987,6:386–402.
[260] Thompson, AJ, Jarvis, GE, Duke, RK, Johnston, GAR and Lummis, SCR. Ginkgolide Band bilobalide block the pore of the5-HT receptor at a location that overlaps the picrotoxinbinding site. Neuropharmacology,2011,60:488–95.
[261] Thompson, AJ, Duke, RK and Lummis, SCR. Binding sites for bilobalide, diltiazem,ginkgolide, and picrotoxinin at the5-HT3receptor. Molecular pharmacology,2011,80:183–90.
[262] Staubli, U and Otaky, N. Serotonin controls the magnitude of LTP induced by theta burstsvia an action on NMDA-receptor-mediated responses. Brain research,1994,643:10–6.
[263] Corradetti, R, Ballerini, L, Pugliese, AM and Pepeu, G. Serotonin blocks the long-termpotentiation induced by primed burst stimulation in the CA1region of rat hippocampalslices. Neuroscience,1992,46:511–8.
[264] St ubli, U and Xu, FB. Effects of5-HT3receptor antagonism on hippocampal theta rhythm,memory, and LTP induction in the freely moving rat. The Journal of neuroscience: theofficial journal of the Society for Neuroscience,1995,15:2445–52.
[265] Hodges, H, Sowinski, P, Sinden, JD, Netto, CA and Fletcher, A. The selective5-HT3receptor antagonist, WAY100289, enhances spatial memory in rats with ibotenate lesions ofthe forebrain cholinergic projection system. Psychopharmacology,1995,117:318–32.
[266] Carli, M, Tatarczynska, E, Cervo, L and Samanin, R. Stimulation of hippocampal5-HT1Areceptors causes amnesia and anxiolytic-like but not antidepressant-like effects in the rat.European journal of pharmacology,1993,234:215–21.
[267] Gu JH, Ge JB, Li M, Wu F, Zhang W, Qin ZH. Inhibition of NF-κB activation is associatedwith anti-inflammatory and anti-apoptotic effects of Ginkgolide B in a mouse model ofcerebral ischemia/reperfusion injury. Eur J Pharm Sci,2012,20;47(4):652-60.
[268] Bredt, DS and Nicoll, RA. AMPA receptor trafficking at excitatory synapses. Neuron,2003,40:361–79.
[269] Song, I and Huganir, RL. Regulation of AMPA receptors during synaptic plasticity. Trendsin neurosciences,2002,25:578–88.
[270] Clem, RL and Barth, A. Pathway-specific trafficking of native AMPARs by in vivoexperience. Neuron,2006,49:663–70.
[271] Rumpel, S, Le Doux, J, Zador, A and Malinow, R. Postsynaptic receptor traffickingunderlying a form of associative learning. Science (New York, N.Y.),2005,308:83–8.
[272] Anwyl, R. Metabotropic glutamate receptors: electrophysiological properties and role inplasticity. Brain research. Brain research reviews,1999,29:83–120.
[273] Manahan-Vaughan, D. Group1and2metabotropic glutamate receptors play differentialroles in hippocampal long-term depression and long-term potentiation in freely moving rats.The Journal of neuroscience: the official journal of the Society for Neuroscience,1997,17:3303–11.
[274] Abel, T and Nguyen, P V. Regulation of hippocampus-dependent memory by cyclicAMP-dependent protein kinase. Progress in brain research,2008,169:97–115.
[275] Houslay, MD. Underpinning compartmentalised cAMP signalling through targeted cAMPbreakdown. Trends in biochemical sciences,2010,35:91–100.
[276] Ye X, Marina A, Carew TJ. Local synaptic integration of mitogen-activated protein kinaseand protein kinase A signaling mediates intermediate-term synaptic facilitation in Aplysia.PNAS,2012,109(44):18162-7.
[277] Banke TG, Bowie D, Lee H, Huganir RL, Schousboe A, Traynelis SF. Control of GluR1AMPA receptor function by cAMP-dependent protein kinase. J Neurosci,2000,20(1):89-102.
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