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Journal of Central South University Medical Sciences logoLink to Journal of Central South University Medical Sciences
. 2023 Oct 28;48(10):1518–1528. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2023.230082

从突触可塑性出发探讨抑郁症和失眠的共病双向机制

Bidirectional mechanism of comorbidity of depression and insomnia based on synaptic plasticity

MENG Fanhao 1,2, WANG Long 2,✉
Editor: 田 朴
PMCID: PMC10929903  PMID: 38432881

Abstract

Insomnia is one of the most common accompanying symptoms of depression, with both sharing highly overlapping molecular pathways. The same pathological changes can trigger comorbidity of insomnia and depression, which further forms a vicious cycle with the involvement of more mechanisms and disease progression. Thus, understanding the potential interaction mechanisms between insomnia and depression is critical for clinical diagnosis and treatment. Comorbidity genetic factors, the hypothalamic-pituitary-adrenal axis, along with circadian rhythms of cortisol and the brain reward mechanism, are important ways in contributing to the comorbidity occurrence and development. However, owing to lack of pertinent investigational data, intricate molecular mechanisms necessitate further elaboration. Synaptic plasticity is a solid foundation for neural homeostasis. Pathological alterations of depression and insomnia may perturb the production and release of neurotransmitter, dendritic spine remodeling and elimination, which converges and reflects in aberrant synaptic dynamics. Hence, the introduction of synaptic plasticity research route and the construction of a comprehensive model of depression and insomnia comorbidity can provide new ideas for clinical depression insomnia comorbidity treatment plans.

Keywords: depression, insomnia, synaptic plasticity, gene, immune inflammation, hypothalamic-pituitary-adrenal, brain reward mechanism

抑郁症是一种常见的具有慢性倾向的精神障碍，以情绪和认知能力低下、缺乏精力和存在自杀意念为特征，影响着全球超过4%的人口[1]，终生患病率约为16%[2]。睡眠问题常被认为是抑郁症的伴随症状，失眠为最常见的睡眠障碍，被定义为抑郁症的核心诊断标准之一，大约有三分之二的抑郁症患者患有符合失眠诊断标准的睡眠障碍[3]。虽然抑郁症和失眠共病率较高，但它们之间的确切关系仍不清楚。本综述旨在总结抑郁症和失眠共病发生及影响的双向机制，构建综合模型，并引入突触活动关系路径，以期进一步解释共病的因果关系，为共病治疗方案提供新思路，为制备相关药物提供新靶点。

1. 抑郁症和失眠的双向机制及突触活动的 桥梁作用

研究[4]认为失眠和抑郁症存在双向关系。一方面，抑郁症患者经常出现失眠的新生理变化[5]；另一方面，睡眠质量差是抑郁症的诱发因素之一，与单独患有抑郁症的患者相比，共病患者有更高的自杀风险、更严重的社会功能障碍、更高的治疗难度及更大的复发风险[6]。认清抑郁症和失眠的关系对临床诊疗十分重要，睡眠障碍能预测抑郁症的发生风险，改善睡眠也能改善患者抑郁症状[7]。目前，抗抑郁药物和催眠药被广泛用于治疗并发抑郁症和睡眠症状的患者[8]。然而，此类药物不良反应多，有的甚至会使失眠症状加重。因此，共病患者若缺乏个体化的医疗计划很可能导致疾病进展及恶化。现有研究大多集中在解释抑郁症和失眠的密切联系，关于详细的分子生物学途径的探究较少。

突触可塑性是指突触的结构及功能在特定条件下具有可变性，结构可变性主要体现在突触形态、大小及数量等方面。功能可塑性体现在突触活动引起的突触效能的增加或降低，长时程增强(long-term potentiation，LTP)和长时程抑制(long-term depression，LTD)是其核心机制。突触活动在认知、情感和行为功能的产生及调节中具有重要作用，因此可被认为是抑郁症情绪、情感的分子体现[9-10]。而突触活动及其神经功能网络也是维持睡眠稳态的重要一环，突触可塑性异常可导致失眠症状并进一步影响行为认知功能[11]。多种机制诱发的抑郁症或失眠症状都会损害突触可塑性并促进、加重共病状态[12]，详细的分子机制缺乏相关证据，但通过突触可塑性可能可以解释二者因果关系及其潜在的交互模式。

2. 分子途径及系统

2.1. 基因

失眠和抑郁症二者早已被证明具有独立遗传性，全基因组关联研究(genome wide association study，GWAS)更是明确了抑郁症[13-14]和失眠障碍[15-16]的遗传变异。近年来，越来越多的研究聚焦在抑郁症与失眠共病基因及因果关系上。最近，GWAS揭示了包括抑郁症和失眠在内的几种精神疾病的遗传背景，共鉴定出719个共有基因[17]。而相关的孟德尔随机化及连锁不平衡回归分析研究[18]证实了二者存在显著遗传相关性，且遗传倾向也是相互因果的，这从基因角度证明了抑郁症和失眠之间的共病容易形成恶性循环的观点。这些研究不仅有利于提高基因表型的风险评估水平，也可推动靶向基因治疗药物的开发及应用。

失眠和抑郁症的变异基因在小脑和额叶皮层的神经元中高度表达，共病基因对分子通路具有深刻影响，但完整生物学特征有待进一步阐明。研究[19]发现垂体中抑郁症和失眠的重叠基因表达丰富，这可能影响下丘脑-垂体-肾上腺(hypothalamic-pituitary-adrenal，HPA)轴介导的压力应激效应从而影响共病；一些与调节昼夜节律的转录-翻译有关的时钟基因可能与抑郁症及其伴发的失眠症状有关[20]；再者，脑源性神经营养因子(brain derived neurotrophic factor，BDNF)的Val66Met基因型则可通过改变皮层和血液中BDNF表达来改变抑郁、焦虑和失眠的易感性[21]。

抑郁症和失眠的重叠基因也富集于大脑及突触结构内，影响轴突生长及突触可塑性。一项关于青少年的研究[22]表明：伴睡眠症状的抑郁症与血液白细胞中DNA甲基化的独特表观遗传模式相关。LTD与LTP都是学习记忆巩固必不可少的机制，该研究发现与睡眠和抑郁相关的LTD途径的基因包括ERK12，PLA2G16，IG1FR和PLA2R1。ERK12影响LTP的形成[23]，PLA2G16介导ERK12通路[24]，IGF1R是一种蛋白质编码基因，在中枢神经发育、成熟及突触可塑性中起至关重要的作用[25]。另外一项研究[26]在探索抑郁症与失眠基因所形成的多结节网络时发现，许多次级基因中心都聚集在神经型一氧化氮合酶上，脑内的一氧化氮合酶产生的神经介质一氧化氮，在神经过程中有重要参与，影响各种精神疾病，包括抑郁症[27]。

2.2. HPA轴及皮质醇昼夜节律

HPA轴是协调神经系统和内分泌系统的重要机制，也是神经中枢应激反应的关键。下丘脑室旁核分泌肾上腺皮质激素释放激素(corticotropin releasing hormone，CRH)，CRH再通过结合反应促进促肾上腺皮质激素(adreno cortico tropic hormone，ACTH)分泌，最终刺激肾上腺皮质分泌皮质醇(cortisol，CRO)。CRO又称应激激素，可以在压力状态下维持机体生理功能的平衡与稳定，同时CRO作为HPA轴与人体内分泌之间的重要介质，其变化也是抑郁症和睡眠障碍之间的主要生理标志。

CRO与抑郁及睡眠密切相关，体现在CRO的高反应性及对应激反应恢复的迟钝上。研究[28-29]数据表明：在相同压力源情况下，相对于健康对照者，失眠、抑郁患者都具有较高的CRO水平及更强的CRO反应性。长期暴露于高CRO状态会导致细胞凋亡、抑制神经发生从而降低神经元密度，导致突触显著重塑[30-31]。再者，CRO可以通过快速作用的非基因组和缓慢作用的基因组对神经元活动产生影响[32]，其中急性的CRO暴露通过增加突触前谷氨酸释放和增强α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体(α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor，AMPAR)和N-甲基-D-天冬氨酸受体(N-methyl-D-aspartic acid receptor，NMDAR)向突触后膜的运输来增强谷氨酸传递，它们激活丝裂原蛋白激酶(extracellular regulated protein kinases，ERK)和钙/钙调蛋白激酶II(Ca/calmodulin-dependent protein kinases，CaMKII)信号通路，从而调节谷氨酸和其他神经递质的释放与学习、记忆等行为的转录依赖性机制产生关联[33-34]。慢性CRO暴露则通过抑制眶额叶皮层中的BDNF转录[35]减少海马体中的酪氨酸激酶受体B(tyrosine kinase receptor B，TrkB)和ERK信号转导[36]等多种复杂交错的信号机制产生作用。BDNF介导与睡眠期间记忆处理相关的可塑性变化，失眠和抑郁都能表现出海马BDNF下调、额叶皮质BDNF表达中断、血清BDNF表达水平降低和昼夜改变受损的重要特征。因此，有研究[37]认为慢性睡眠剥夺可能作为额外应激通过下调BDNF相关分子途径改变突触可塑性导致抑郁，但也有研究[38]认为其不存在相关性。HPA轴、睡眠、抑郁之间三者的关系虽然明确，但对涉及应激机制的因果效应研究仍较少，近5年CRO昼夜节律的研究数据较为丰富，有助于为关系阐述提供新线索。

昼夜节律是由视交叉上核(suprachiasmatic nucleus，SCN)中的分子时钟控制的24 h节律，其调控HPA轴在内的多种生理机制，也调节CRO的昼夜模式[39]。急性或慢性应激造成睡眠障碍和昼夜节律性破坏，可以直接影响稳态调节系统，如敲除SCN中核心昼夜节律基因Bmal1会显著增加小鼠焦虑抑郁样行为[40]，急性SCN光遗传学实验表明在黑暗期早期的SCN刺激也与焦虑样抑郁行为呈正相关。因此，SCN介导的生物节律在抑郁症中可能发挥核心作用。CRO受SCN调控具有特定的昼夜分泌波动曲线。CRO水平通常在醒来后30~45 min达到波峰，也称为皮质醇觉醒反应(cortisol awakening response，CAR)，之后随着一天的时间流逝而降低。CRO分泌和认知之间存在因果关系，健康的CRO昼夜节律促进学习依赖性突触的形成和维持，异常的CRO节律会造成认知缺陷、抑郁症、记忆损害等[41-42]。有研究[43]通过多日多次采样对比证实：CAR与运动皮层诱发突触可塑性的能力之间存在显著相关性，再者CRO节律失常(特别是CAR)会影响不同大脑区域中基因表达的时间程序，昼夜节律与神经调节之间的不匹配可能导致相应区域脑功能障碍[44]。因此CRO节律不仅仅是压力的生物标志物，而且在介导慢性应激至认知功能障碍途径中发挥作用[45]。

睡眠-觉醒周期是重要的日常生理节律，受SCN及其介导CRO波动的影响，SCN依照外部环境线索或时间标志设定时间。夜间光源刺激可通过视网膜-下丘脑束刺激突触前细胞释放谷氨酸以结合来自SCN的突触后神经元中的NMDAR，进而激活γ-氨基丁酸(γ-aminobutyric acid，GABA)能神经元，影响睡眠障碍[46-47]。而夜间暴露于光源或者频繁倒时差的人，也被证明更容易出现抑郁和自杀行为[48-49]。这些慢性应激造成并加剧了睡眠-觉醒周期紊乱，改变SCN昼夜节律，破坏CRO分泌曲线导致抑郁[50]。BDNF及其介导的信号传导的节律调节可能在SCN起搏器对光敏感性的昼夜节律调节中发挥重要作用，夜间暴露于光亮可以造成生物钟后移的效应被称为光致相移，而BDNF可能参与了光致相移诱发的神经变性[51-52]。睡眠和昼夜节律改变可能会损害BDNF的产生，同时减少神经营养支持，导致神经元萎缩，海马神经发生减少和神经胶质细胞丢失[53]。有回顾性调查[54-55]显示持续失眠参与者的CRO分泌模式与无睡眠障碍者显著不同，认为CRO分泌与失眠之间的关联可能与昼夜节律失调、昼夜节律与睡眠对24 h CRO分泌的交互作用有关。

其他机制也会介导HPA轴对失眠、抑郁的影响，如慢性应激和皮质醇抗性状态可削弱HPA轴的抗炎和稳态机制，促进炎症反应激活，破坏大脑奖赏环路造成正向感觉收获缺失[56]。昼夜节律失常与HPA轴功能障碍也可能通过改变肠道微生物群的结构和多样性对睡眠和抑郁状态造成影响。这些失调的共同终点是神经发生减少和突触可塑性的损害[57]。

2.3. 免疫炎症

免疫过程是免疫细胞识别细胞损伤、协助组织修复，维持机体稳态的一种调节过程。这种免疫调节与抑郁症之间存在交互关系[58]，即抑郁症患者血清中特异性促炎因子及受体表达水平上升，持续性的免疫反应也可能同时导致抑郁的发生[59]。研究[60]表明促炎因子与抑郁症的症状严重程度相关，并参与患者认知功能损害的神经生物学机制。细胞因子在突触功能的生成与维持中起重要作用，如促炎细胞因子白细胞介素6(interleukin-6，IL-6)与突触的形成关系密切[61]；促炎细胞因子也可通过诱导ERK信号途径降低突触通讯中重要神经递质的生物利用度[62]。而BDNF是在调节免疫细胞活化和神经存活中发挥重要作用的关键分子，其通过激活BDNF/TrKB途径可减少神经炎症，促进神经元重塑和新突触的形成[63]。

睡眠和免疫可能也存在这种双向交互机制，良好的睡眠可以改善免疫防御，睡眠不足则反过来引发机体炎症反应，如失眠患者的转录控制核因子-κB(nuclear transcription factor-κB，NF-κB)在睡眠不足的情况下被激活，导致炎症因子水平升高[64]。此外，人体内的炎症情况对维持正常睡眠起关键作用，来自免疫细胞的传入信号诱导睡眠，激活细胞因子，这一过程可能进一步作用于抑郁症状中。因此，失眠所引发的炎症指标上升也可看作早期诊断的预警信号，其代表着抑郁症复发或进展的可能性及自杀概率上升的风险[65]。

炎症对突触可塑性具有深远的影响，有研究[66]猜想炎症因子介导的小胶质细胞增生可能是其主要生物途径。小胶质细胞是中枢神经系统内固有的免疫效应细胞，其不同的表型具有不同的功能。静息状态下，小胶质细胞调节突触修剪促进突触功能稳定，主要由PI3K/BDNF信号介导[67]。活化的小胶质细胞则迁移到炎症部位并分泌细胞因子、趋化因子等蛋白质。小胶质细胞释放的促炎和抗炎标志物存在特殊的平衡，一旦平衡倾斜，突触可塑性便会受到影响[68]。促炎细胞因子肿瘤坏死因子α(tumor necrosis factor-α，TNF-α)是炎症的重要介质，主要通过小胶质细胞表达，虽然确切的分子机制尚未得到阐述，但不同的TNF-α浓度可能会影响小胶质细胞分泌平衡，而在调节突触可塑性方面产生差异[69]。低浓度的TNF-α促进突触可塑性，而炎症条件下常见的高浓度TNF-α则会损害LTP，诱导突触传递和可塑性的失调。再者，小胶质细胞抗炎因子IL-10能够有效抑制细菌脂多糖(lipopolysaccharides，LPS)诱导的炎症因子增加，对炎症状态下异常的突触可塑性具有恢复作用[70]。

小胶质细胞功能障碍与抑郁症认知缺陷密切相关。习得性无助(learned helplessness，LH)实验是常见抑郁造模法之一，一项实验[71]表明LH模型小鼠具有较低的树突棘密度和小胶质细胞活化增加。同时大脑中的促炎细胞因子与神经炎症和抑郁症认知障碍的进展呈正相关[72]。另有实验[73]证明小胶质细胞中抗炎因子IL-10表达的减少会诱发神经炎症，其水平与认知功能和突触可塑性损害呈负相关。而慢性睡眠障碍或睡眠剥夺也可能引发小胶质细胞功能的变化，进而导致大脑中小胶质细胞活化异常[74]。动物实验[75]证明即使没有神经炎症的迹象，慢性睡眠限制和剥夺也可能促进小胶质细胞的激活。可见睡眠剥夺不仅会引起海马体中炎症细胞因子水平升高，还会诱发神经胶质增生加剧突触损害和神经变性[76]。

综上，抑郁和失眠引发炎症反应和小胶质细胞功能异常所造成的突触可塑性损害，在共病的产生和发展中都可能起到桥接作用，因此可推测，睡眠障碍可能通过失调的炎症系统诱发神经炎症和神经保护缺陷，异常活化小胶质细胞损伤突触可塑性导致情绪障碍。

2.4. 大脑奖赏机制

大脑奖赏机制由中脑边缘奖赏环路组成，是主管“努力动机”与“奖赏反馈”的一种复杂情感反馈机制。人类为奖励分配价值并努力获得奖励，通过奖励刺激感到满足，当对这些奖赏表现出兴趣减弱时，就可称为“快感缺乏症”。其主要包含参与决策过程的前额叶皮层(prefrontal cortex，PFC)如眶额叶皮层(orbitofrontal cortex，OFC)、内侧前额叶皮层(medial prefrontal cortex，mPFC)和前扣带皮层(anterior cingulate cortex，ACC)；主要负责奖励刺激的伏隔核(nucleus accumben，NAc)；从腹侧被盖区(ventral tegmental area，VTA)投射到皮质下纹状体区域的多巴胺(dopamine，DA)能神经元[77-78]；其他脑区如在环路中发挥重要作用的外侧下丘脑(lateral hypothalamus，LH)、外侧缰核(lateral habenula，LHb)和背侧纹状体(dorsal striatum，DS)[79-80]。

抑郁症相关的奖赏环路研究近年来不断增加，促进了对神经病理机制的理解。从VTA到NAc的DA神经元投射是抑郁的重要病理改变，而一项研究[81]显示VTA至NAc的GABA能神经元投射同样关键，其选择性抑制NAc核区的胆碱能中间神经元(cholinergic interneurons，CINs)参与厌恶学习。抑郁症患者快感缺乏与大脑奖赏环路结构和功能改变也密切相关，如快感缺乏的抑郁症患者脑内ACC和OFC的灰质有丢失[82]、脑内奖赏环路的激活下调[83]等。抑郁症患者还存在严重的社交障碍，基于全脑Fos分析、体内钙成像和全细胞记录，相关研究[85]确定了一群应激/威胁反应性侧隔神经紧张素(lateral septum neurotensin neurons，NTLS)神经元，证明抑郁症模型中的社交回避来源于社交奖赏功能受损[84]。亦有研究[86-87]认为失眠与奖赏机制相关，失眠和抑郁的交互作用也能使大脑结构功能(包括奖赏环路)发生改变(如右侧OFC体积减少)，并提出环路结构中的OFC可能是失眠、抑郁共病神经病理学改变的核心区域的猜想。但由于缺乏对照实验和其他相关数据，猜想有待进一步论证。

有研究[88-89]回顾抑郁症患者治疗前后奖赏模式行为及神经影像学的变化发现，奖赏机制具有可塑性，可能受睡眠障碍的影响。但这种影响较为复杂，不仅与睡眠障碍的类型有关，也与具体奖赏功能的不同方面相关，如失眠能降低追求奖励的努力从而损害奖励学习过程。研究[90]证实睡眠障碍和奖赏系统功能障碍之间的剂量/反应关系，并依据这种特性建立了抑郁、失眠、奖赏机制的综合模型，强调睡眠障碍可以造成奖赏机制内部模块间对立，最终导致抑郁发生。后续有研究[91]在此基础上，通过线性混合模型分析，论证奖赏学习功能障碍是联系失眠和抑郁的潜在中介，进一步丰富了抑郁、失眠及奖赏环路的关系。

奖赏机制功能障碍所伴随的突触可塑性异常可能是这种关系的基础。DA能系统受奖赏机制激活，其功能障碍影响着大脑结构、神经元的发育及功能[92]。一方面，DA可以通过D1类受体(D1、D5)和D2类受体(D2、D3、D4)在刺激-回报学习过程中发挥作用，因为D1类受体与D2类受体作用相反，可分别导致环磷酸腺苷(cyclic adenosine monophosphate，cAMP)水平升高和降低，因此DA可从促进和抑制2个方向调节突触可塑性[93]。另一方面，DA通过奖赏回路组织还可以诱导LTP和LTD的神经元群体的神经回路的突触强度[94]。此外，慢性应激通过破坏HPA轴稳态，诱导糖皮质激素增加，可影响奖赏环路组织的突触可塑性，改变mPFC中谷氨酸信号转导相关基因的表达，降低大鼠mPFC中神经元的尖棘密度和长度，增加大鼠的应激脆弱性和无助感[95-96]。慢性压力也被证明可以改变VTA区的DA神经元可塑性，BDNF及其相关的分子途径在这过程中发挥重要作用[97]。最后，LHb不仅代表厌恶行为、抑郁症状和应对策略的核心神经元底物，还参与认知过程以及奖赏机制的编码，其核内兴奋性传递的突触适应是应对负面体验行为的基础[98-99]。研究[100]显示：遭遇不可预测应激的小鼠犯错误更多，脑切片中LHb神经元的AMPA/NMDA减少，这说明应激诱导LHb编码的正性和负性刺激偏向导致病理状态，同时LHb的突触可塑性影响着奖赏过程中的认知表现。

3. 抑郁症和失眠的综合模型

综上所有试验研究的结果和观点，笔者总结出以下结论：1)睡眠障碍与抑郁症的分子生物通路高度重叠；2)抑郁症所导致的病理学改变可能导致睡眠障碍的发作及加剧；3)睡眠稳态能维持抑郁相关机制运行稳定，对改善抑郁症状阻止复发至关重要；4)不管激活何种交互机制，其都可能通过影响神经递质的产生和释放、膜兴奋性、树突棘消除等机制而汇聚成分散的突触活动。基于上述所得结论及大量依据单一机制构建的失眠、抑郁症双向关系模型，可以构建一个抑郁症和失眠共病发生及影响的综合模型(图1)。人体系统结构的破坏及功能改变(基因、HPA、奖赏机制、免疫炎症、神经功能)演变为抑郁症或者失眠，单一疾病的患病状态可以通过两者高度相似的病理基础演变为二者共病，并随着病程进展、病理改变加剧及更多的机制参与演变为难治性抑郁症及顽固性失眠。同时病理机制的改变也会降低压力的耐受性，加重共病的易感性。再者，无论哪种病理机制的初始变化都会影响神经元功能，并体现在突触可塑性的异常上(图2)。

图1.

图1

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抑郁和失眠共病发生及影响双向机制模型

Figure 1 Bidirectional mechanism model for depression-insomnia comorbidity

A: Regulatory mechanism of HPA axis and SCN towards CRO secretion rhythm. B: Inflammatory factors induce the abnormal excitation of microglial cell and facilitate the neuroinflammation through activating NF-κB. C: Dopaminergic neurons within the reward circuit, projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and the medial prefrontal cortex (mPFC), and it adjusts the function of synaptic modulation bidirectionally via D1 and D2 receptor. D: DNA methylation affecting synaptic function. SCN: Suprachiasmatic nucleus; CRH: Corticotropin releasing hormone; ACTH: Adreno cortico tropic hormone; CRO: Cortisol; NF-κB: Nuclear transcription factor-κB; IL-6: Interleukin-6; IL-10: Interleukin-10; TNF-α: Tumor necrosis factor-α; BDNF: Brain derived neurotrophic factor; TrkB: Tyrosine kinase receptor B; VTA: Ventral tegmental area; NAc: Nucleus accumben; mPFC: Medial prefrontal cortex; LTP: Long-term potentiation; LTD: Long-term depression.

图2.

图2

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共病机制对突触可塑性的影响

Figure 2 Comorbidity mechanism affecting synaptic plasticity

SCN: Suprachiasmatic nucleus; HPA: Hypothalamic-pituitary-adrenal; CRO: Cortisol; BDNF: Brain derived neurotrophic factor; NF-κB: Nuclear transcription factor-κB; TrkB: Tyrosine kinase receptor B; CAMK: Ca/calmodulin-dependent protein kinases; P13K: Phosphatidylinositol-3-hydroxykinase; ERK: Extracellular regulated protein kinases; CREB: Cyclic-AMP response binding protein; NMDAR: N-methyl-D-aspartic acid receptor; AMAPR: α-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor; LTP: Long-term potentiation; LTD: Long-term depression.

4. 结 语

失眠和抑郁症具有高度重叠的分子生物通路(基因、免疫炎症、HPA、奖赏机制、神经功能等)，抑郁症或失眠可以通过相似的病理学改变引发共病，随着病程进展可能形成恶性循环。抑郁症患者伴发失眠会增加治疗难度、提高自杀风险，同时更容易转变为难治性抑郁症。失眠则可以作为抑郁症复发及疾病进展的预警。了解失眠、抑郁二者潜在交互机制对于临床诊疗十分重要，相关的研究仍然存在大量空白。突触可塑性在共病机制中具有桥梁作用，单一疾病可以通过多种机制影响神经发育成熟，减少营养支持，损害突触结构和功能，进而影响共病。基于突触可塑性的共病发生及影响双向模型提示突触可塑性可能是了解失眠、抑郁因果关系的重要途径，也将成为发掘共病详细分子路径相关研究的重点和方向。

基金资助

国家自然科学基金(81303044)；黑龙江省自然科学基金(LH2022H082)；黑龙江省博士后科研启动金项目(LBH-Q19185)；黑龙江省中医药管理局项目(ZHY2020-120)；黑龙江中医药大学研究生创新科研项目(2020yjscx016)。

This work was supported by the National Natural Science Foundation (81303044), the Natural Science Foundation of Heilongjiang Province (LH2022H082), the Postdoctoral Scientific Research Developmental Fund of Heilongjiang Province (LBH-Q19185), the Heilongjiang Provincial Administration of Traditional Chinese Medicine Project (ZHY2020-120), and the Graduate Research and Innovation Project in Heilongjiang University of Chinese Medicine (2020yjscx016), China.

利益冲突声明

作者声称无任何利益冲突。

作者贡献

孟繁昊 论文构想和撰写；王珑 论文指导和校正。所有作者阅读并同意最终的文本。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/2023101518.pdf

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