世居和移居高原人群移居/返回平原后脑结构和功能脱适应研究

Every year, a large number of people in the world travel to and fro between high-altitude (HA) and lowland. People who have adapted HA environment will suffer from deadaptation to HA when they descend to lowland. The brain modifications of Tibetans and Han immigrants on Qinghai-Tibet Plateau have been revealed in our previous studies. In the present study, we further observe the acute responses and recover levels of brains during the initial stage and during the later period, respectively, in HA Tibetans and Han immigrants when they descend to lowland. Magnetic Resonance Imaging and (MRI) and electroencephalogram (EEG) are used firstly to observe the brain structures (cortex thickness and volume, water diffusion of white matter fiber, iron deposition, blood flow, and vascular structure) and brain functions (resting-state and task-activated neuronal activities). Secondly, correlation of the changed brain structures and functions with the level of deadaptation, plasma cortisol, hematological measurements, and cardiovascular and pulmonary functions, as well as correlation of brain responses during the initial stage with recover during the later period are analyzed. Finally, behavioral tests are used to estimate the significance of the changes of brain structures and functions. In the other aspect, mice models simulating HA immigrants and gene-knockout mice models simulating HA natives are used for the mechanism studies of white matter on tissue, cell, and molecular levels. Our study will clarify the law of brain de-adaptation responses in different HA populations, and thus establish the predictive index of brain de-adaptation responses. The results of our study may be helpful to the valid prediction, prevention, and cure of body de-adaptation.

全世界每年都有大量人群往返于高原和平原。当适应了高原环境的人群进入平原后，机体将面临高原脱适应反应的威胁。我们前期研究显示高原世居藏族和移居汉族人群的脑发生了重塑。本项目进一步观察这两类人群进入平原后脑脱适应初期急性反应和后期恢复程度。针对人群的研究运用磁共振成像和脑电记录，首先观察脑结构（皮层厚度和体积、白质纤维水分子弥散、铁沉积、血流和血管结构）和脑功能（静息和任务刺激状态）的变化；其次分析脱适应症状程度、血浆皮质醇、血液和心肺功能分别与脑测量值的相关性以及脑脱适应急性反应程度与后期恢复水平的关联。最后行为测试用来判断脑结构和功能改变的意义。另一方面，建立模拟高原移居人群小鼠模型及通过基因突变模拟高原世居人群小鼠模型来分析脑白质改变的组织、细胞和分子机制。本项目将揭示脑高原脱适应反应规律并建立其反应程度和恢复的预测指标，其结果对防治脱适应带来的健康问题具有重要理论指导意义。

我们前期研究显示高原世居藏族和移居汉族人群的脑发生了重塑。本项目目的在于观察这两类人群进入平原后脑脱适应初期急性反应和后期的恢复程度。对青藏高原戍边士兵从平原进入高原7天和30天以及返回平原7天后的脑电研究显示，脑电受影响部位主要在脑后枕部。急性低氧暴露仅降低θ功率，而慢性适应增加了α和β功率但降低了δ功率，返回平原后，α功率下降，β功率保持增加。结果表明缺氧降低了低频波的功率，而复氧则增加高频波的功率。对高原支教30天的大学生研究显示，返回平原7天和3个月后脑视觉皮层和运动皮层神经细胞的低频振幅（ALFF）、区域同质性（ReHo）和体素镜像同伦连接性（VMHC）都显著增加，但功能连接却降低。因此，缺氧/复氧增加了视觉皮层和运动皮层内部神经元之间的功能连接，但减小了这两个脑区之间的连接程度。针对135名高原藏族的研究则是分析了EGLN1、EPAS1和PPARA基因的高原适应性遗传变异与高原土著人的脑网络关系。特定核苷酸多态性（SNPs）选择性地调节脑结构和功能网络。研究结果为高原缺氧下的基因型-表型相互作用提供了新的线索。本项目建立高原低压低氧动物模型研究脑改变的细胞分子机制。首先观察了成年小鼠脑白质的损伤和修复。小鼠缺氧15天后胼胝体和内囊的各向异性分数降低，平均弥散增加。白质损伤是由于少突胶质细胞前体细胞（OPCs）分化受阻导致的髓磷脂形成障碍。白质损伤可在复氧后2个月基本恢复。该结果提示缺氧脑白质损伤能够可逆恢复。另一项对脂多糖诱导肺纤维化的缺氧大鼠研究显示，大鼠的脑灰质体积广泛减小，脑损伤与低氧诱导的炎症反应有关。本项目也利用抗HIF-1α-NMs-cy5.5纳米复合材料进行低氧小鼠体内、外成像研究，显示缺氧诱导因子（HIF-1α）在肝脏表达最高，其次是肾脏和大脑。肝脏、肾脏和大脑显示出不同的代谢产物，但谷氨酸的变化相同。总之，肝脏、肾脏和大脑是机体对急性缺氧有强烈反应的三个主要器官，肝脏表现出最高的缺氧敏感性。代谢紊乱似乎是生理功能变化的基础。