运动改善抑郁症认知功能障碍的机制研究进展☆
钟绮琳*钟舒明*赖顺凯*贾艳滨*○☆
【摘要】抑郁症患者认知功能障碍症状恢复困难，严重制约患者的全面功能康复，而现有抗抑郁药物治疗对认知功能改善作用有限。运动作为抑郁症重要的非药物疗法具有潜在的改善认知功能作用，但其具体作用机制仍不明确。本文梳理和总结运动干预改善抑郁症认知功能障碍的生物学机制，发现运动可改善相关脑区功能，经脑源性神经营养因子、血管内皮细胞生长因子、犬尿氨酸代谢通路、神经炎症、脂联素等多种途径促进中枢神经系统神经可塑性，以及治疗躯体症状，最终改善认知功能。
【关键词】抑郁症运动干预认知功能脑功能生物学机制神经可塑性脑源性神经营养因子神经炎症脂联素
【中图分类号】R749.4 【文献标识码】A
Rearch progress on the mechanisms of exerci improving cognitive dysfunction in major depressive disor⁃der. ZHONG Qilin, ZHONG Shuming, LAI Shunkai, JIA Yanbin. First Affiliated Hospital of Jinan University, Guangzhou 510630,China.Tel*************.
【Abstract】The difficulty in the recovery of cognitive symptoms verely restricts the functional rehabilitation of patients with major depressive disorder, while the cognitive improvement of existing ant
idepressant therapy is limited. Exerci, as an important non-drug therapy for major depressive disorder in recent years, has a potential cognitive improvement effect. However, the specific mechanism of exerci is still unclear. This review summarizes the biological mechanisms by which exerci intervention improves cognitive dysfunction in major depressive disorder and finds that exerci can improve the function of related brain areas, promote neuronal plasticity in many ways, and treat physical symptoms, thus improving cognitive performance.
【Key words】Major depressive disorder Exerci Cognitive dysfunction Brain function Biological mechanism Neuronal Plasticity Brain-derived neurotrophic factor Neuroinflammation Adiponectin
认知功能障碍症状在抑郁症的病程中持续存在，部分认知维度表现出素质性特征，部分维度则为状态性或瘢痕性的特征[1]。认知功能障碍症状恢复困难是制约抑郁症患者全面功能恢复的重要原因，而抗抑郁药物治疗对认知功能改善作用有限[2]。运动疗法是近年抗抑郁治疗的重要非药物干预手段之一，安全性高，且具有良好的抗抑郁效果[3-4]。运动疗法具有潜在的改善认知功能作用[5]。目前运动改善抑郁症认知功能障碍的具体机制仍不明确，本文梳理和总结运动干预改善抑郁症认知功能损伤的相关研究并加以综述，深入分析探讨其可能的神经生物学机制，为未来运动疗法的深入研究提供思路。
1 抑郁症患者认知功能障碍相关的脑部改变
海马和前额叶等与认知功能相关脑区的皮质体积减少是抑郁症患者的脑结构特征[6-7]。神经网络异常在抑郁症认知功能障碍的发病中起重要作用。自传体记忆网络（auto‐biographic memory network，AMN）和认知控制网络（cognitive control network，CCN）是抑郁症相关的核心神经认知网络。
AMN的关键节点包括眶内前额叶皮质、延髓前扣带回皮质、顶区前扣带回皮质、楔前叶和压后皮质，CCN则主要包括背外侧前额叶和背侧前扣带回皮质。抑郁症患者AMN过度活跃且存在过度连接，CCN激活则受到抑制[8]。CCN内部以
doi: 10.3969/j.issn.1002-0152.2022.11.011
☆2022年国家自然面上项目（编号：82271564）；广州市科技计划
项目（编号：202201020047）
*暨南大学附属第一医院精神医学科（广州 510630）
通信作者（E-mail：*********************）
·综述·
及CCN和AMN区域之间更大的正连通性与抑郁症患者更好的情景记忆表现相关，而AMN内更强的连通性与抑郁症患者更差的情景记忆和工作记忆表现相关[9]。磁共振氢质子波谱研究显示，抑郁症患者的工作记忆损伤与患者右侧前额叶皮质N-乙酰天冬氨酸/肌酸的比值下降有关[10]，而执行功能损伤则与患者左侧杏仁核N-乙酰天冬氨酸/肌酸的比值下降相关[11]，提示抑郁症患者的认知功能障碍亦受脑生化代谢水平影响。此外，还有研究发现抑郁症患者的脑部微血管功能与言语记忆、执行功能、工作记忆等认知表现相关[12]。
2 运动改善相关脑区功能
目前研究主要支持有氧运动对抑郁症患者认知功能障碍具有改善作用。动物实验研究发现，有氧运动可促进慢性应激抑郁模型大鼠海马齿状回区的神经发生[13]。持续4周的跑步机锻炼使慢性不可预测应激抑郁模型大鼠的海马齿状回和CA1区毛细血管总长度和总体积增加[14]。肌肉健康可能通过影响脑体积和白质信号改善抑郁症患者的认知功能[15]。临床研究发现，运动后抑郁症患者的左侧背外侧前额叶皮质激活当即得到增强[16]。为保证运动干预的效果，需进行每周至少3次、中等强度、持续至少9周、有监督的有氧运动[17]。以上证据表明，运动可促抑郁症认知功能的相关脑区发生积极改变。虽然不同形式的运动可能存在不同的影响机制，但现有研究多采用有氧运动来探索运动改善抑郁症认知功能障碍的机制，缺乏对不同运动形式的机制研究。
3 运动改善神经可塑性
3.1 脑源性神经营养因子（brain-derived neurotrophic fac⁃tor，BDNF）抑郁症患者的血清BDNF水平升高与记忆和执行功能改善有关[18-19]。近期研究发现，每周定期锻炼有助于减轻抑郁症状和减少BDNF Val66Met等位基因携带对认知功能的有害影响[20]，这提示运动的疗效可能与BDNF基因多态性相关。因此，BDNF的作用是运动改善抑郁症认知功能障碍的重要机制。运动可通过诱导脑部BDNF表达，促进脑神经可塑性过程，起到抗抑郁和改善认知功能的效果。
运动可通过促进组织蛋白酶B分泌增强脑中BDNF表达。运动使肌肉分泌的肌细胞因子组织蛋白酶B可进入血脑屏障，促进脑中BDNF分泌，从而促进神经发生和突触可塑性，改善记忆和学习功能[21-22]。
运动还可通过激活过氧化物酶体增殖物激活受体γ辅激活因子1α（peroxisome proliferator-activated receptor gamma coactivator-1alpha，PGC-1α）/含Ⅲ型纤连蛋白域蛋白5（fibronectin type III domain-containing protein 5，FNDC5）/鸢尾素（irisin）通路促进BDNF表达。运动可诱导神经元PGC-1α基因表达上调，进而促使FNDC5分泌，提高鸢尾素水平，令中枢神经系统BDNF表达增加[23]。运动代谢产物乳酸可同样经PGC-1α/FNDC5/irisin通路促BDNF分泌，改善突触可塑性，提高认知功能[24]。
另外，运动亦可通过影响酮体β-羟基丁酸和内源性大麻素促进BDNF表达[25-26]。
junior
3.2 血管内皮细胞生长因子（vascular endothelial cell growth factor，VEGF）运动使VEGF分泌增加，可促进脑部血管新生，改善血管功能障碍，增强脑部血流灌注，从而增强脑功能[27]。BDNF和VEGF的作用相辅相成[28]，可能在改善认知功能时具有协同作用。
3.3 犬尿氨酸代谢通路运动可通过上调PGC-1α表达使犬尿氨酸转氨酶的肌肉表达增加，导致犬尿氨酸和犬尿酸之间平衡发生有益的变化，可因此改善5-羟色胺失衡[29]。运动对犬尿氨酸通路的激活减少了慢性应激所致的神经炎症损伤，促进脑神经可塑性发生改变，可由此改善认知功能[30]。
3.4 神经炎症运动干预上调PGC-1α表达，还能够降低炎性细胞因子的脑内表达，减轻神经炎症，从而改善认知功能[31-32]。本课题组最新研究发现，非编码RNA可调节免疫因子和神经营养因子，改善神经炎症和神经可塑性[33]。非编码RNA有可能参与运动干预的作用机制，是一个有价值的研究方向。
3.5 脂联素运动可促进脂肪细胞分泌脂联素，激活下游信号通路，增加神经发生、改善树突可塑性，逆转抑郁小鼠的认知功能障碍[12]。这一发现提示脂联素在运动治疗和抑郁症认知功能障碍中起重要作用，脂肪细胞因子可能具备极大研究潜力。
目前研究中关于运动干预改善抑郁症认知功能的不同途径，主要通过神经系统可塑性改变来提高认知功能，提示中枢神经系统可塑性是运动干预的核心作用机制。
4 运动通过治疗躯体症状改善认知功能
抑郁症的部分躯体症状与认知功能存在联系。睡眠紊乱是抑郁症患者常见的症状，且造成更严重的认知功能损害[34]，慢性失眠患者前额叶皮质存在与认知功能损害相关的脑代谢物改变[35]。运动可通过调节睡眠紊乱而部分改善
不言而喻翻译老年抑郁症患者认知功能[36]。不良的心血管功能也是抑郁症患者认知功能障碍的危险因素之一，有氧运动提高抑郁症患者的心肺健康，改善血管功能，可能因此改善认知功能障碍[37]。因此，运动可通过治疗睡眠紊乱和心肺功能等躯体症状来改善认知功能障碍，但其中的作用机制尚不明确，这一研究领域仍存在许多空白。
5 总结与展望
综上所述，运动可改善抑郁症认知功能障碍相关脑区的功能活动。同时，运动可通过对BDNF、VEGF、犬尿氨酸代谢通路、神经炎症和脂联素的影响促进神经可塑性，从而改善抑郁症的认知功能。未来可开展更多临床研究，从神经影像学、生物学、表观遗传学等多个角度深入探讨运动改善抑郁症患者认知功能障碍的机制。不同运动强度、运动频率、运动时长对抑郁症患者认知功能的作用也亟待更多研究证据，以支持临床应用中更有针对性地开出有效运动处方。
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