太空飞行诱发宇航员抑郁症状的潜在生物学机制

Potential biological mechanisms underlying spaceflight-induced depression symptoms in astronauts

摘要

长期太空飞行中的多种极端环境因素(如宇宙辐射、微重力、社交隔离及睡眠节律紊乱等)显著增加宇航员抑郁症状的发生风险，对其心理健康和任务安全构成直接威胁。然而，该现象背后的生物学机制复杂且尚未完全阐明。太空飞行诱发宇航员抑郁症状的潜在生物学机制涉及多个方面，包括脑结构与功能的改变、神经递质及神经营养因子失调、氧化应激、神经炎症、神经内分泌系统紊乱及肠道微生物失调等。这些改变可能共同构成太空飞行诱发宇航员抑郁症状的潜在生物学基础。太空飞行及其相关应激源可能通过以下途径增加抑郁症状的发生风险：干扰海马体神经可塑性、抑制多巴胺和5-羟色胺系统功能、降低神经营养因子表达、引发氧化应激与炎症反应、激活丘脑-垂体-肾上腺轴及扰乱肠道微生物群。未来研究需整合脑机接口等前沿技术，开发个体化监测与干预策略，以实现抑郁症状的实时监测与有效预防，保障宇航员的心理健康和任务安全。

Abstract

Long-term spaceflight exposes astronauts to multiple extreme environmental factors, such as cosmic radiation, microgravity, social isolation, and circadian rhythm disruption, that markedly increase the risk of depressive symptoms, posing a direct threat to mental health and mission safety. However, the underlying biological mechanisms remain complex and incompletely understood. The potential mechanisms of spaceflight-induced depressive symptoms involve multiple domains, including alterations in brain structure and function, dysregulation of neurotransmitters and neurotrophic factors, oxidative stress, neuroinflammation, neuroendocrine system imbalance, and gut microbiota disturbances. Collectively, these changes may constitute the biological foundation of depressive in astronauts during spaceflight. Space-related stressors may increase the risk of depressive symptoms through several pathways: impairing hippocampal neuroplasticity, suppressing dopaminergic and serotonergic system function, reducing neurotrophic factor expression, triggering oxidative stress and inflammatory responses, activating the hypothalamic-pituitary-adrenal axis, and disrupting gut microbiota homeostasis. Future research should integrate advanced technologies such as brain-computer interfaces to develop individualized monitoring and intervention strategies, enabling real-time detection and effective prevention of depressive symptoms to safeguard astronauts’ psychological well-being and mission safety.

关键词

太空飞行 / 抑郁症状 / 脑功能 / 神经递质 / 氧化应激 / 炎症 / 肠道微生物 / 宇航员

Key words

spaceflight / depressive symptoms / brain function / neurotransmitters / oxidative stress / inflammation / intestinal microbiota / astronauts

随着航天技术的快速发展，人类在轨驻留时间已从数天延长至数月，未来火星探索任务甚至需要长达2年的太空飞行。宇航员在太空环境中长期暴露于多种应激源，包括宇宙辐射、微重力、社交隔离、密闭环境及睡眠节律紊乱等^[1]。这些因素不仅导致多系统生理功能紊乱，还显著增加抑郁和焦虑等心理健康问题的风险^[1-2]。美国国家航空航天局的统计数据^[3]显示，34.8%的男性宇航员和43.2%的女性宇航员在太空飞行期间曾出现抑郁症状。作为太空飞行中最常见的心理健康问题之一，抑郁症状不仅影响宇航员的任务执行效率，还可能直接威胁航天任务的安全性。然而，太空飞行诱发抑郁的生物学机制尚未完全阐明。本文总结太空飞行引发抑郁症状的潜在生物学机制，以期为探索宇航员抑郁症状的早期生物标志物提供理论依据。

1 脑结构与功能改变

长期太空飞行对宇航员的大脑结构与功能具有显著影响^[4-11]。影像学研究^[4]显示：长期太空飞行后，宇航员大脑出现中央沟变窄、脑组织向上移位及顶部脑脊液空间减少等结构性改变。此外，研究^[5-6]还发现脑室周围白质高信号增多和脑室体积扩大的现象，这些变化在短期任务中未见。长期太空飞行导致小脑白质体积增加^[7]，且这一改变可能长期存在^[6-7]。同时，腹侧额叶、颞叶、枕叶的灰质体积及丘脑体积均显著减小^[8-9]。功能磁共振成像(functional magnetic resonance imaging，fMRI)研究表明：宇航员返回地球9 d后，默认模式网络的功能连接显著下降^[10]；返回地球8个月后，丘脑的全局连通性仍持续减弱^[11]。值得注意的是，丘脑及默认模式网络的异常改变与抑郁症的发生密切相关^[12-13]，提示长期太空飞行可能通过诱导脑结构与功能的长期重塑，增加宇航员的抑郁症状发生风险。

太空飞行中的多种慢性应激源(如微重力、宇宙辐射、社交隔离和昼夜节律紊乱等)可能会干扰神经可塑性，从而增加抑郁症状的发生风险^[2]。海马体作为学习、记忆和情绪调控的核心脑区，对这些应激因素高度敏感。动物实验表明：微重力显著改变大鼠海马CA1区神经元结构，导致神经元胞体面积与周长减小、突触间隙变窄^[14]，并削弱CA3区与CA1区间的突触可塑性^[15]。长期南极探险带来的极端社会隔离和单调环境可导致探险者海马体齿状回(dentate gyrus，DG)体积显著缩小^[16]。社区老年人低社交频率与海马体及杏仁核等情绪调控脑区的体积缩小显著相关^[17]。宇宙辐射同样加剧海马体神经生物学异常，具体表现为：1)树突棘数量、密度，树突长度及分支复杂度显著降低^[18]；2)小鼠齿状回未成熟神经元数量减少^[19]；3)小鼠海马CA1区与鼻周皮层的功能连接减弱，这与抑郁样行为增加高度相关^[20]。此外，太空任务中常见的睡眠剥夺不仅通过削弱海马体与额叶、顶叶的功能连接导致记忆障碍^[21]，还通过抑制海马体内蛋白质合成及神经发生进一步加剧神经可塑性异常^[22]。海马体结构与突触可塑性的异常变化与情绪调控密切相关^[2]，可能是太空飞行诱发抑郁症状的生物学基础。

2 脑神经递质和神经营养因子的变化

长期太空飞行显著影响大脑神经递质和神经营养因子的水平。具体而言，5-羟色胺(5-hydroxytryptamine，5-HT)和多巴胺(dopamine，DA)等神经递质，以及脑多巴胺能神经营养因子(cerebral dopamine neurotrophic factor，CDNF)和胶质细胞源性神经营养因子(glial cell line-derived neurotrophic factor，GDNF)均受到显著影响^[2]。这些分子在抑郁症的病理机制中发挥关键作用^[23-25]。

2.1 5-HT系统

大脑5-HT系统功能障碍与抑郁症发病机制密切相关^[24]。俄罗斯“Bion-M1”生物卫星为期1个月的太空飞行实验^[26]表明，太空飞行对小鼠纹状体、额叶皮层和下丘脑的5-HT系统产生影响。具体表现为：纹状体中5-HT代谢关键酶单胺氧化酶A(monoamine oxidase A，MAO-A)基因及中脑中缝核中单胺氧化酶B(monoamine oxidase B，MAO-B)基因的表达水平显著下调；同时，额叶皮质中MAO-A基因和下丘脑中5-HT_2A受体基因的表达也显著降低。额叶皮层在情绪调节中起重要作用，而下丘脑中5-HT_2A受体通过调控室旁核中促肾上腺皮质激素释放激素(corticotrophin-releasing hormone，CRH)的分泌^[27]，进而影响皮质酮(啮齿动物中的主要糖皮质激素)等肾上腺皮质激素的释放。短期(5~7 d)和长期(>14 d)太空飞行均显著提高了小鼠血浆皮质酮水平^[28]，表明太空飞行可能通过下丘脑5-HT_2A受体调控皮质酮分泌。啮齿动物中皮质酮的过度释放与抑郁样行为密切相关^[29]。这一机制为研究太空飞行诱发抑郁症状的生物学基础提供了重要线索。然而，太空飞行并未显著改变中缝核中5-HT系统关键调控因子的基因表达，包括色氨酸羟化酶2(tryptophan hydroxylase 2，TPH2)、5-HT转运体和5-HT_1A受体。鉴于中缝核是5-HT神经元胞体的主要集中区域，上述结果提示太空飞行对5-HT系统的整体影响可能较为局限^[26]，更可能通过特定脑区或特定通路的选择性调控发挥作用。

2.2 DA系统

动物实验^[26]表明，长期太空飞行显著抑制DA合成与代谢通路中关键酶的基因表达。例如，小鼠黑质中编码DA生物合成关键酶——酪氨酸羟化酶(tyrosine hydroxylase，TH)的基因表达水平显著降低^[26]。同时，纹状体中DA代谢酶——儿茶酚-O-甲基转移酶(catechol-O-methyltransferase，COMT)及纹状体和下丘脑中多巴胺D1受体的基因表达也显著下降^[26]。此外，单次低剂量碳核辐照可迅速抑制大鼠前额叶皮层、下丘脑及纹状体的DA周转过程^[30]。研究进一步显示：下丘脑在应激诱导的抑郁症病理机制中发挥重要作用^[31]；而奖赏与厌恶加工的受损与抑郁症核心症状之一——快感缺失密切相关^[32]。奖赏加工涉及多个脑区的协同调控，包括腹侧被盖区、伏隔核、前额叶皮层、纹状体及黑质等^[32]。这些发现提示，长期太空飞行及其相关应激因素可能通过干扰DA系统功能诱发抑郁样行为^[33]。然而，目前仍缺乏太空飞行对腹侧被盖区和伏隔核等奖赏通路关键脑区中DA水平及基因表达影响的研究。未来研究应重点探讨这些脑区的DA系统在长期太空飞行中的动态变化，并揭示其与抑郁情绪的潜在关联机制。

2.3 神经营养因子

神经营养因子是调控突触可塑性、神经元存活及分化的关键因子^[23]。长期太空飞行显著影响GDNF和CDNF的基因表达。俄罗斯“Bion-M1”生物卫星实验^[34]显示：小鼠纹状体和下丘脑中GDNF基因表达显著下调，而额叶皮层和中脑中缝核中表达显著上调；同时，黑质中CDNF基因表达降低，但中缝核中的表达升高。值得注意的是，这些变化在正常重力条件下的航天舱模拟环境中并未出现，提示微重力可能是主要诱导因素。GDNF和CDNF在维持DA能神经元存活及功能中发挥重要作用^[35]，且均被证实可改善抑郁样行为^[36]。研究^[37]发现GDNF可从纹状体逆向运输至黑质DA神经元胞体，表明其在黑质-纹状体通路中可能作为DA神经元的目标衍生营养因子发挥作用。因此，太空飞行诱导的GDNF和CDNF基因表达下调可能加剧DA系统损伤，并导致抑郁症状的发生。此外，太空飞行对GDNF和CDNF基因表达的影响表现出明显的脑区特异性和协同应答特征：在黑质-纹状体DA系统中，纹状体GDNF和黑质CDNF的表达同步下调，而在中缝核(5-HT系统核心区域)，二者表达则同步上调^[34]。这一现象的分子机制仍需进一步深入研究。

相比之下，微重力对神经生长因子(nerve growth factor，NGF)和脑源性神经营养因子(brain-derived neurotrophic factor，BDNF)的水平及基因表达无显著影响。经历91 d太空飞行的小鼠返回地球后，其大脑皮质、海马及小脑中的BDNF和NGF蛋白质水平未见明显变化^[38]。此外，“Bion-M1”任务后，小鼠额叶皮层、视觉皮质、海马、纹状体、下丘脑、中脑和黑质中BDNF、TrkB(BDNF受体)和p75神经营养因子受体的基因表达均未发生显著改变^[39]。这些结果表明BDNF信号通路对太空飞行中的微重力等应激源具有较强耐受性，提示在长期太空任务的应激环境下，BDNF在调控神经发生和情绪相关功能方面的表达稳定性可能高于GDNF和CDNF。

3 氧化应激

氧化应激是机体内氧化物质与抗氧化物质失衡，导致活性氧(reactive oxygen species，ROS)和活性氮(reactive nitrogen species，RNS)过度积聚，进而引发细胞损伤的病理状态^[40]。航天飞行中的微重力、空间辐射和低氧环境可显著促进细胞内ROS和RNS的生成^[40]。短期(5~13 d)太空飞行后，宇航员外周血单核细胞中抗氧化酶基因[如超氧化物歧化酶1(superoxide dismutase 1，SOD1)和谷胱甘肽过氧化物酶1(glutathione peroxidase 1，GPX1)]表达显著上调，同时DNA/RNA氧化损伤标志物8-羟基-2’-脱氧鸟苷(8-hydroxy-2’-deoxyguanosine，8-OHdG)水平显著升高^[41]。一项针对59名宇航员的研究^[42]进一步表明：太空飞行显著降低机体抗氧化能力，导致尿液中氧化应激标志物(如8-OHdG和前列腺素F2α)水平明显升高。动物实验证实：航天相关应激因素(如辐射暴露^[43]、模拟微重力^[44]、社交隔离^[45]或睡眠剥夺^[46])均可诱发啮齿动物脑组织中氧化应激标志物显著升高，导致中枢神经系统氧化损伤。此外，抑郁症患者常伴随氧化应激水平升高和抗氧化防御能力下降^[47]。因此，太空飞行可能通过诱导氧化应激，促进抑郁症状的发生与发展。

4 神经炎症

太空飞行可导致宇航员外周免疫系统功能紊乱，具体表现为：白细胞总数及单核细胞、粒细胞、B细胞与T细胞数量增加，而自然杀伤(natural killer，NK)细胞比例下降且功能受损^[48-49]。同时，促炎性细胞因子[如白细胞介素(interleukin，IL)-6、肿瘤坏死因子-α(tumor necrosis factor-alpha，TNF-α)、C反应蛋白(C-reactive protein，CRP)]与抗炎因子(如IL-10)水平均显著升高^[50]。在长达340 d的太空任务后，宇航员与地面双生子对照相比，其外周血中促炎性ω-6脂肪酸代谢物(如花生四烯酸)及炎症标志物(CRP、IL-1受体拮抗剂、单核细胞趋化蛋白-1)水平显著升高，而抗炎性ω-3脂肪酸代谢物(如二十碳五烯酸)水平显著降低^[51]。除外周免疫系统改变外，太空飞行还导致小鼠中枢神经系统免疫稳态失衡：一方面抑制脑组织先天免疫防御功能，另一方面激活特定促炎性细胞因子信号通路^[52]。小鼠海马体出现星形胶质细胞增生及血脑屏障完整性破坏^[53]。激活的星形胶质细胞可分泌促炎性细胞因子，可能加剧神经炎症反应，从而对中枢神经系统功能构成潜在威胁^[54]。

地面模拟研究证实太空环境对神经免疫系统的负面影响。在微重力条件下，人体外周血单核细胞的炎症反应增强，T细胞和NK细胞功能受损^[55]，同时促炎性细胞因子水平升高^[56]。在模型小鼠中，微重力暴露导致海马区IL-1β和IL-10等炎症因子水平上升，而隔离环境则上调海马中IL-6等11种细胞因子的表达^[57]。此外，辐射暴露可诱导小鼠脑组织促炎性细胞因子基因表达增加^{[40, 58]}，并引发前额叶皮层星形胶质细胞和小胶质细胞异常激活，进而触发神经炎症级联反应^[58-59]。临床和动物研究^[60]表明神经炎症是抑郁症发病机制的关键环节。抑郁症患者外周血炎症标志物水平升高，关键脑区(如前额叶皮层和海马体)存在显著神经炎症，表现为小胶质细胞激活及IL-1β、IL-6、TNF-α等促炎性细胞因子水平升高^[60]。综上所述，太空飞行相关应激源可能通过诱导神经炎症和免疫系统失调，在太空环境诱发的抑郁症状中发挥重要作用，为深入探究其生物学机制提供了重要线索。

5 神经内分泌紊乱

太空飞行期间航天员唾液皮质醇的昼夜节律发生显著改变，其模式与地面慢性应激状态(如早期创伤)相似，提示太空飞行可能诱发宇航员类似慢性应激的神经内分泌紊乱^[61]。与短期太空飞行相比，长期太空飞行的宇航员在着陆时血浆和尿液皮质醇峰值更高，表明长时间太空飞行对下丘脑-垂体-肾上腺(hypothalamic-pituitary-adrenal，HPA)轴的激活程度更强^[62-63]。动物实验^[28]进一步显示：长期(>14 d)和短期(5~7 d)太空飞行后，大鼠的血浆皮质酮水平均显著升高，而血浆儿茶酚胺水平仅在长期飞行后显著增加。

在太空环境中，舱内设备的持续噪声构成慢性应激源，长期暴露可能持续激活HPA轴，进而引发抑郁等负面心理状态^[64]。模拟实验^[65]表明：微重力和辐射暴露均可导致HPA轴下游功能亢进，表现为促肾上腺皮质激素(adrenocorticotropic hormone，ACTH)和皮质酮水平显著升高；然而，辐射虽能增强对促肾上腺皮质激素释放激素(corticotropin-releasing hormone，CRH)的抑制作用，却加重T细胞功能抑制，从而破坏机体在微重力环境下的适应性代偿平衡^[65]。此外，航天员普遍面临的睡眠不足问题可能进一步激活HPA轴，导致皮质醇水平升高，从而增加抑郁症状的风险^[66]。而HPA轴过度激活与抑郁症的病理机制密切相关^[67]。综上所述，太空飞行诱发的抑郁症状可能与神经内分泌网络紊乱密切相关。

6 肠道微生物失调

太空飞行显著改变了宇航员肠道微生物群的物种组成。飞行期间，宇航员肠道中厚壁菌门(Firmicutes)与拟杆菌门(Bacteroidetes)的比值显著升高，但飞行结束后可逐渐恢复至基线水平^[51]。中国15 d和35 d的航天任务数据^[68]显示：宇航员粪便样本中潜在益生菌如乳酸杆菌属(Lactobacillus)和双歧杆菌属(Bifidobacterium)的丰度减少，而拟杆菌属(Bacteroides)的丰度显著增加。在国际空间站执行6~12个月的长期太空任务期间，宇航员肠道中17个菌属的丰度均发生了显著变化。其中，瘤胃球菌属(Ruminococcus)、粪球菌属(Coprococcus)、多尔氏菌属(Dorea)和假丁酸弧菌属(Pseudobutyrivibrio)的丰度下降，而粪杆菌属(Faecalibacterium)和毛螺菌属(Lachnospira)的丰度升高^[69]。约11个菌属的改变在陆地研究^{[1, 70]}中已被证实与抑郁症等心理健康问题显著相关，可能是抑郁症状的重要预测因子。这些肠道微生物群的变化与短链脂肪酸产量减少及促炎性细胞因子(如IL-8和TNF-α)的水平升高密切相关，提示微生物群失调可能与免疫功能紊乱存在关联^{[50, 69]}。

在模拟微重力环境下，小鼠肠道菌群中潜在益生菌[如普拉梭菌(Faecalibacterium prausnitzii)和直肠真杆菌(Roseburia inulinivorans)]的丰度下降，而拟杆菌属的丰度上升^[71-72]。微重力还显著降低了抗炎菌属[如粪杆菌属和毛螺菌科(Lachnospiraceae)]的丰度^[73]。质子照射实验^[74]显示：小鼠肠道中瘤胃球菌科(Ruminococcaceae)和毛螺菌科的丰度降低，拟杆菌属的丰度增加，同时氨基酸代谢和炎症相关代谢通路受到影响。太空飞行导致的肠道微生物群变化可能通过以下机制影响抑郁情绪的发生：1)减少短链脂肪酸的产生；2)调控谷氨酸、色氨酸等氨基酸代谢通路，从而影响γ-氨基丁酸(gamma-aminobutyric acid，GABA)和5-HT等神经递质的合成；3)诱发免疫功能紊乱及炎症反应^{[70, 75]}。这些发现揭示了太空飞行中肠道微生物群失调与抑郁症状潜在关联的复杂机制，为航天医学和心理健康干预提供了重要研究方向。

7 结语与展望

长期太空飞行对宇航员心理健康的影响备受关注。其诱发抑郁症状的潜在生物学机制涉及多个方面，包括脑结构与功能的改变、神经递质及神经营养因子失调、氧化应激、神经炎症、神经内分泌系统紊乱及肠道微生物失调等。太空飞行及其相关应激源可能通过以下途径增加抑郁症状的发生风险：干扰海马体神经可塑性、抑制DA和5-HT系统功能、降低神经营养因子表达、引发氧化应激与炎症反应、激活HPA轴及扰乱肠道微生物群。然而，这些机制推测主要基于现有抑郁症的理论假说，目前尚缺乏针对伴有抑郁症状宇航员的直接机制研究。此外，当前研究面临诸多局限性，如真实太空飞行数据的样本量有限、地面模拟实验与实际太空环境的差异较大，以及多因素交互作用的机制尚未完全阐明。

未来研究应着重探讨太空飞行诱发抑郁症状的确切生物学机制，特别是肠道微生物群与脑-肠轴在太空环境中的相互作用。同时，需系统研究太空飞行对宇航员大脑神经可塑性的动态影响，并明确宇航员返回地球后神经可塑性的恢复机制。此外，应加强跨学科合作，建立多模态、个体化的心理健康监测与干预体系。具体而言，可运用人工智能技术整合神经影像学数据(如fMRI、脑电图等)和血液生物标志物(如神经营养因子、炎症因子、皮质醇、肠道微生物代谢产物等)，构建动态预测模型，实现宇航员抑郁风险的早期识别与分级管理。同时，应重点开发创新干预策略，包括基于虚拟现实的社交隔离适应训练、靶向抗氧化的神经保护疗法、优化舱内环境设计(如光谱调控系统)、益生菌干预以调节肠道微生物群，以及经颅磁刺激、经颅交流电刺激等非侵入性神经调控技术。这些措施将有效降低宇航员在长期太空任务中抑郁的发生风险，为其心理健康和任务执行能力提供保障。

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基金资助

湖南省卫生健康委员会卫生科研课题(W20241001┫。This work was supported by the Health Research Project of Health Commission of Hunan Province)

湖南省卫生健康委员会卫生科研课题(China ┣W20241001)

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