Background Invasive vagus nerve stimulation therapy has been approved for the adjunctive treatment of treatment-resistant depression,which may contribute to the anti-inflammatory properties of vagus nerve stimulation(VNS),whereas the efficacy of non-invasive transcutaneous cervical vagus nerve stimulation(tcVNS)in treating major depressive disorder(MDD)and its impact on plasma inflammatory factors remain unclear.Objective To observe the effect of escitaloprom combined with tcVNS on the status of depression,anxiety and sleep quality as well as the plasma levels of interleukin-6(IL-6)and interleukin-10(IL-10)in MDD patients,in order to provide references for the recovery and treatment of MDD patients.Methods From August 21,2019 to April 17,2024,45 patients who met the diagnostic criteria for MDD in the Diagnostic and Statistical Manual of Mental Disorders,fifth edition(DSM-5)were recruited from the psychosomatic outpatient clinic of the First Affiliated Hospital of Air Force Military Medical University.Subjects were divided into study group(n=23)and control group(n=22)using random number table method.All patients were treated with escitalopram.On this basis,study group added a 30-minute tcVNS therapy once a day for 4 weeks.While control group was given corresponding sham stimulation,and the duration of each stimulation lasted 30 seconds.Before and after 4 weeks of treatment,Hamilton Depression Scale-17 item(HAMD-17)was used to assess depressive symptoms,and HAMD-17 anxiety/somatization subfactor and insomnia subfactor were used to assess patients' anxiety/somatization symptoms and sleep quality.Levels of plasma IL-6 and IL-10 were measured by enzyme-linked immunosorbent assay(ELISA).Results The generalized estimating equation model yielded a significant time effect for HAMD-17 total score,anxiety/somatization subfactor score and insomnia subfactor score in both groups(Wald χ2=315.226,495.481,82.420,P<0.01).After 4 weeks of treatment,HAMD-17 total score and anxiety/somatization subfactor score of study group were lower than those of control group,with statistically significant differences(Wald χ2=4.967,32.543,P<0.05 or 0.01),while no statistically significant difference was found in the insomnia subfactor score between two groups(Wald χ2=0.819,P=0.366).Significant time effects were reported on plasma IL-6 and IL-10 levels in both groups(Wald χ2=21.792,5.242,P<0.05 or 0.01).Compared with baseline data,a reduction in plasma IL-6 levels was detected in both groups(Wald χ2=22.015,6.803,P<0.01),and an increase in plasma IL-10 levels was reported in study group(Wald χ2=5.118,P=0.024)after 4 weeks of treatment.Conclusion Escitalopram combined with tcVNS therapy is effective in improving depressive symptoms,anxiety/somatization symptoms and sleep quality in patients with MDD.Additionally,it helps reduce plasma IL-6 levels and increase IL-10 levels.

BACKGROUND:Intestinal dysbacteriosis is frequently implicated in generalized anxiety disorder (GAD). However, the molecular mechanisms and functional changes of the gut-brain axis in GAD remain largely unexplored. METHODS:We investigated anxiety-like behaviors, gut microbiota changes, brain region-specific endocannabinoid (eCB) system alterations, including the expression of cannabinoid type 1 (CB1R), monoacylglycerol lipase (MAGL), and fatty acid amide hydrolase (FAAH) in the hippocampus (Hip), prefrontal cortex (PFC), and amygdala (Amy), as well as plasma medium- and long-chain fatty acids (MLCFAs) in a mouse model of chronic restraint stress (CRS) and antibiotic-treated mice receiving fecal microbiota transplantation from GAD patients (FMT-GAD). Additionally, we assessed the impact of FMT-GAD on anxiety-like behavior in systemic CB1R/FAAH/MAGL knockout mice. RESULTS:CRS induced anxiety-like behaviors, suppressed eCB signaling in the brain, and altered the gut microbiota and plasma MLCFA composition in mice. FMT-GAD-treated mice exhibited anxiety-like behaviors, increased FAAH expression in the Hip and Amy, and MAGL expression in the Hip, while reducing CB1R expression in the Hip. FMT-GAD was associated with decreased plasma polyunsaturated fatty acids (PUFAs) and reduced microbiome function for fatty acid biosynthesis. Notably, FMT-GAD intensified anxiety-like behaviors in CB1R-KO mice but failed to induce anxiety-like behaviors in MAGL-KO and FAAH-KO mice. CONCLUSIONS:This study demonstrates that the interplay between the gut microbiota and the eCB system modulates GAD-related anxiety-like behaviors.

OBJECTIVE:This study investigated the role of endocannabinoid (eCB) signaling in anxiety-like behaviors associated with a PTSD mouse model (SPS&S), focusing on oxidative stress and inflammation. METHODS:We examined expression of eCB-related proteins (Cannabinoid receptor type 1, CB1 Receptor; NAPE-specific phospholipase D, NAPE-PLD; Fatty acid amide hydrolase, FAAH; and Monoacylglycerol lipase, MAGL) and inflammatory markers (IL-1β, caspase-1) in the mPFC, hippocampus, and amygdala of SPS&S-exposed mice. Plasma oxidative stress markers (MDA, SOD, ROS) and cytokines (IL-1β, IL-6, TNF-α, COX-2) were measured by ELISA. The CB1 receptor agonist WIN 55,212-2 or vehicle was administered systemically, then anxiety-like behaviors and conditioned fear were assessed. RESULTS:SPS&S exposure induced significant anxiety-like behaviors and increased freezing in fear tests. It decreased CB1 receptor and NAPE-PLD expression while increasing FAAH and MAGL levels in all examined brain regions, alongside elevated IL-1β and caspase-1. Plasma oxidative stress and inflammatory cytokines were also elevated. WIN 55,212-2 administration mitigated anxiety-like behaviors but not conditioned fear responses. Crucially, it normalized the elevated plasma oxidative stress and inflammatory cytokine levels. CONCLUSION:SPS&S disrupts eCB signaling and increases neuroinflammation and peripheral oxidative stress/inflammation. Activation of CB1 receptor alleviates PTSD-associated anxiety-like behaviors and normalizes peripheral oxidative/inflammatory biomarkers, highlighting the critical involvement of eCB-related oxidative stress and inflammatory pathways. Targeting the eCB system represents a potential therapeutic strategy for anxiety symptoms in PTSD.

BACKGROUND:The mechanisms underlying esketamine's therapeutic effects remain elusive. The study aimed to explore the impact of single esketamine treatment on LPS-induced adolescent depressive-like behaviors and the role of Nrf2 regulated neuroinflammatory response in esketamine-produced rapid antidepressant efficacy. METHODS:Adolescent male C57BL/6J mice were randomly assigned to three groups: control, LPS, and LPS + esketamine (15 mg/kg, i.p.). Depressive-like behaviors were evaluated via the OFT, NFST, and TST. Protein expression of Nrf2 and inflammatory cytokines, including TNF-α, IL-1β, and iNOS in the hippocampus and mPFC, were measured by western blot. Moreover, the Nrf2 inhibitor, ML385, was also applied in the current study. The depressive-like behaviors and the protein expression of Nrf2, TNF-α, IL-1β, and iNOS in mPFC and hippocampus were also measured. Additionally, the plasma's pro-inflammatory cytokines and anti-inflammatory cytokines were assessed using ELISA methods with or without ML385. RESULTS:A single administration of esketamine treatment alleviated the LPS-induced depressive-like behaviors. Esketamine increased the expression of Nrf2 and reduced the expression of the inflammatory cytokines, including TNF-α, IL-1β, and iNOS, in the mPFC and hippocampus. Notably, pharmacological inhibition of Nrf2 via ML385 administration abrogated the antidepressive-like behaviors and anti-inflammatory effects induced by esketamine. In the periphery, esketamine mitigated the LPS-induced elevation of pro-inflammatory cytokines, and the reduction of anti-inflammatory cytokines, and this effect was reversed by Nrf2 inhibition. CONCLUSION:Esketamine treatment exerts rapid antidepressant effects and attenuates neuroinflammation in LPS-induced adolescent depressive-like behaviors, potentially through the activation of Nrf2-mediated anti-inflammatory signaling.

Mounting evidence has identified the rapid and sustained antidepressive and anxiolytic-like effects of esketamine. However, the underlying mechanism of this no-monoamine target rapid-onset antidepressant is still underexplored. Immune-inflammatory pathways and cell-mediated immune activation, mainly including inflammatory cytokines in plasma, play a pivotal role in the pathogenesis of major depressive disorder and are also a potential therapeutic target for MDD. The current study was designed to clarify the role of esketamine on the expression of plasma cytokines in a depressive-like model introduced by chronic variable stress (CVS). In this study, a 21-day consecutive CVS protocol was applied to produce depressive- and anxiety-like behaviors. After the single dose or 7-day repeated administration of esketamine or fluoxetine, the depressive- and anxiety-like behaviors and the expression of inflammatory cytokines in plasma were examined. Both a single dose of esketamine and 7-days repeated fluoxetine administration elicited anti-depressive and anxiolytic effects in mice exposed to CVS. Additionally, CVS produced significant changes in the plasma inflammatory factors, notably increasing the expression of IL-1β, IL-6, IL-8, IL-17A, TNFα, IL-4, IL-9, IL-24, IL-37, IFN-β, and CXCL12, while reducing IL-10 and IL-33. With the administration of esketamine and fluoxetine, CVS-produced inflammatory disturbances were partially normalized. Together, our findings provide a novel insight that acute esketamine treatment could rescue CVS-produced depressive-like and anxiety-like behaviors in mice by normalizing the expression of inflammatory cytokines; this effect was similar to the repeated administration of fluoxetine. These results contributed to the understating of rapid anti-depressant effects elicited by esketamine.

Brain glycogen, which is distinct from muscle glycogen and liver glycogen, has become a crucial node linking metabolism, epigenetics, and autophagy. Recent studies have suggested that brain glycogen governs multiple neurobehavioral processes, such as memory formation and consolidation. However, the changes in brain glycogen levels in mental diseases and the associations of these changes with the disease prognosis are unknown. Here, we review the psychological functions of brain glycogen and the different characteristics of astrocytic glycogen and neuronal glycogen. In addition, we summarize the alterations in brain glycogen levels in depression, schizophrenia and sleep disorders, highlighting that brain glycogen functions as an important metabolite responsible for the development of mental diseases. In summary, brain glycogen is a key to understanding the pathology of mental diseases and deserves more attention in future research.

抑郁症是危害人类健康的主要精神疾病之一.现有的单胺类假说并不能完全解释抑郁症的发病机制,以此为靶点的抗抑郁药物起效速度慢、部分患者缺乏疗效.线粒体是存在于真核细胞中的多功能细胞器,在能量产生、细胞凋亡、氧化应激、神经发生等过程中发挥关键作用.近年来,大量的证据表明线粒体功能障碍和抑郁症发病机制关系密切.在本文中,我们对线粒体能量代谢障碍与抑郁症关系的研究进展进行综述,包括线粒体DNA损伤、线粒体和炎症及神经发生之间的关联、线粒体靶向治疗抑郁症的潜能等,并总结了现有抗抑郁治疗与线粒体功能调控相关的进展,从而为深入理解抑郁症发病机制以及筛选靶向线粒体的新型治疗策略提供参考.

INTRODUCTION:Repetitive transcranial magnetic stimulation (rTMS) is a clinically useful therapy for depression. However, the effects of rTMS on the metabolism of fatty acids (FAs) and the composition of gut microbiota in depression are not well established.METHODS:Mice received rTMS (15 Hz, 1.26 T) for seven consecutive days after exposure to chronic unpredictable mild stress (CUMS). The subsequent depressive-like behaviors, the composition of gut microbiota of stool samples, as well as medium- and long-chain fatty acids (MLCFAs) in the plasma, prefrontal cortex (PFC), and hippocampus (HPC) were evaluated.RESULTS:CUMS induced remarkable changes in gut microbiotas and fatty acids, specifically in community diversity of gut microbiotas and PUFAs in the brain. 15 Hz rTMS treatment alleviates depressive-like behaviors and partially normalized CUMS induced alterations of microbiotas and MLCFAs, especially the abundance of Cyanobacteria, Actinobacteriota, and levels of polyunsaturated fatty acids (PUFAs) in the hippocampus and PFC.CONCLUSION:These findings revealed that the modulation of gut microbiotas and PUFAs metabolism might partly contribute to the antidepressant effect of rTMS.

目的 观察抑郁症患者肠道菌群移植对小鼠行为及海马内源性大麻素(eCB)的影响.方法 将健康受试者和抑郁症患者的肠道菌群移植给"伪无菌"小鼠,通过糖水偏好实验、旷场实验以及悬尾实验评估其抑郁样行为,并检测海马eCB相关分子的表达水平.①模型小鼠的制备:通过灌胃的方法使用"鸡尾酒"抗生素清除小鼠原有的肠道菌群,连续灌胃14 d,制备"伪无菌"小鼠模型;最后一次抗生素灌胃结束48 h后,将小鼠随机分为对照组(n=6)和抑郁组(n=10),每周一、三、五分别对各组小鼠进行粪菌移植,持续3周,制备"人源化"小鼠模型;②行为学测试:粪菌移植结束24 h后进行糖水偏好实验、旷场实验和悬尾实验以评估小鼠的抑郁样行为;③行为学测试结束24 h后处死动物,通过Western blotting法检测小鼠海马组织eCB相关分子的表达情况.结果 ①与对照组比较,抑郁组抑郁样行为表现显著,具体表现为旷场实验中抑郁组小鼠进入中心区次数、中心区运动距离、运动总距离、中心区停留时间比均显著降低(P＜0.01),糖水偏好率显著下降(P＜0.05),悬尾不动时间显著增长(P＜0.01).②Western blotting结果显示,与对照组比较,抑郁组CB1R、NAPE-PLD、DAGLα蛋白表达均显著下调,差异具有统计学意义(P＜0.05).③海马NAPE-PLD和DAGLα的表达水平与小鼠进入中心区次数、中心区运动距离、中心区停留时间比和糖水偏好率均呈正相关(均P＜0.05),而且DAGLα、NAPE-PLD表达水平与悬尾不动时间均呈负相关(均P＜0.05).结论 抑郁症患者肠道菌群可能通过调节海马eCB相关分子诱导小鼠产生抑郁样行为.

青少年抑郁症是指发生在未成年时期,以显著而持续的情绪低落、快感缺失为主要表现的一类精神疾病.青少年抑郁症严重损害患者社会认知功能,并增加自杀风险.目前青少年抑郁症的发病机制仍不清楚,且缺乏针对青少年抑郁症的可靠治疗药物.青少年抑郁症临床特点包括了更严重的社交回避、高发的非自杀性自伤行为和自杀意念等,而上述症状与奖赏环路功能异常密切相关.因此,奖赏环路功能异常可能是青少年抑郁的重要发病机制.本文将回顾青少年奖赏环路特征发育及其功能异常在青少年抑郁症中的作用机制最新进展,从而为未来青少年抑郁症发病机制研究及筛选有效的青少年抑郁症治疗措施提供理论根据.

Objective To investigate the effect of venlafaxine on the depression-like behavior, and the expression of CNPase, MBP and Nrg1 Ⅲ-ErbB2 expression in prefrontal cortex（PFC） of cuprizone（CPZ） treated mice. Methods A total of 32 C57BL/6 male mice aged 8-weeks were randomly divided into control group, venlafaxine（Ven） group, model（CPZ） group and CPZ+Ven group. Mice in CPZ and CPZ+Ven groups were fed with diet containing 0.2% CPZ for 5 weeks to establish CPZ model. Ven and CPZ+Ven groups received 20 mg/（kg·d） venlafaxine by gavage for 5 weeks. Control group and CPZ group were gavaged with 200 μl saline every day during the same time period. Open field experiment, sugar-water preference experiment and tail suspension experiment were carried out after 5-week intervention, and then 5 mice in each group were killed immediately. PFC was collected in liquid nitrogen. The protein levels of CNPase and MBP in PFC were detected by Western blot, and the level of Nrg1 Ⅲ-ErbB2 mRNA was detected by RT-PCR. The remaining mice（n=3） were perfused and fixed with 4% PFA,and then the morphological changes of oligodendrocytes were observed by immunofluorescence staining for CNPase. Results The total distance traveled in open field and distance of central movement of CPZ group were shorter than those of the control group [（12.50±4.73） m vs（25.63±5.64） m,（5.92±1.98） % vs（11.78±4.17） %]. The immobility time of suspended tail test was longer than that of the control group [（153.75±26.4） s vs（71.62±20.95） s]. Sugar preference index was lower than that of the control group [（79.16±6.53） % vs（92.67±2.97） %]. The protein expression levels of CNPase and MBP in PFC were lower than those of the control group [（0.56±0.08） vs（0.85±0.13）,（0.37±0.05） vs（1.01±0.08）]. The mRNA levels of Nrg1Ⅲ and ErbB2 were lower than those of the control group [（0.38±0.27） vs（1.06±0.16）,（0.42±0.41） vs（1.01±0.01）]. The differences of all the above were statistically significant（P ＜ 0.05）. The total distance traveled in open field and distance of central movement of CPZ+Ven group were longer than those of the CPZ group [（22.64±6.59） m vs（12.50±4.73） m,（10.6±2.85） % vs（5.92±1.98） %]. The immobility time of suspended tail test was longer than that of the CPZ group [（109.25±35.69） s vs（153.75±26.4） s].Sugar preference index was lower than that of the CPZ group [（91.63±2.98） % vs（79.16±6.53） %]. The protein expression levels of CNPase and MBP in PFC were lower than those of the CPZ group [（0.84±0.09） vs（0.56±0.08）,（0.71±0.13） vs（0.37±0.05）]. The mRNA levels of Nrg1Ⅲ and ErbB2 were lower than those of the CPZ group [（0.70±0.33） vs（0.38±0.27）,（0.80±0.25） vs（0.42±0.41）]. The differences of all the above were statistically significant（P ＜ 0.05）. CNPase immunofluorescence staining showed that there were fewer CNPase oligodendrocytes in the PFC of mice in the CPZ group than in the control group and the CPZ+Ven group.Conclusions Venlafaxine can up-regulate the levels of CNPase and MBP protein and the mRNA levels of Nrg1Ⅲ and ErbB2 in the PFC of CPZ mice,increase the number of oligodendrocytes,and alleviate depressionlike behaviors.

目的 观察青年和老年小鼠吸入异氟醚后对学习记忆、海马线粒体、突触以及神经元树突形态的影响.方法 青年(6月龄)及老年(18月龄)雄性C57BL/6小鼠各20只,随机分为4组(n=10):青年组、青年吸醚组、老年组和老年吸醚组.青年组和老年组均吸入1 000 mL/L O2 2 h,青年吸醚组和老年吸醚组均吸入15 mL/L异氟醚气体2h;通过新奇物体识别测试观察小鼠的行为表现,评估其学习记忆能力;使用透射电镜技术观察小鼠海马线粒体和突触的区域分布及超微结构;利用高尔基染色观察海马神经元树突形态变化.结果 ①与青年组相比,老年组对新物体的探索率降低(P＜0.05),树突棘数量减少(P＜0.01),线粒体面积增大(P＜0.05),线粒体密度降低(P＜0.01),突触数量减少且结构模糊.②与青年组相比,青年吸醚组对新物体的探索率减少(P＜0.05),树突长度变短(P＜0.05),树突分支数量减少(P＜0.01),线粒体面积增大(P＜0.01),突触结构被破坏;与老年组相比,老年吸醚组的新物体探索率降低(P＜0.01),树突长度、分支和树突棘数量均发生显著性下调(均P＜0.05),线粒体面积增大、密度降低(P＜0.05),突触结构受损严重.③与青年吸醚组相比,老年吸醚组的新物体探索率降低(P＜0.01),树突长度减小(P＜0.05),树突棘减少(P＜0.01),线粒体面积增大(P＜0.05),密度降低(P＜0.01),突触小泡受损严重,突触数量较少.结论 异氟醚会造成小鼠学习记忆功能下降,表现为海马神经元树突形态改变、线粒体和突触受损,并且这种损伤对老年小鼠更为严重.

BACKGROUND:Neural oscillations play a role in the antidepressant effects of repetitive transcranial magnetic stimulation (rTMS). However, the effects of high-frequency rTMS on the neural oscillations of the medial prefrontal cortex (mPFC) and hippocampus (HPC) and its molecular mechanism have not been fully clarified.METHODS:The depressive-like behaviours, local field potentials (LFPs) of the ventral HPC (vHPC)-mPFC, and alternations of endocannabinoid system (ECS) in the HPC and mPFC were observed after rTMS treatment. Meanwhile, depressive-like behaviours and LFPs were also observed after cannabinoid type-1 receptor (CB1R) antagonist AM281 or monoacylglycerol lipase inhibitor JZL184 injection. Moreover, the antidepressant effect of rTMS was further assessed in glutamatergic-CB1R and gamma-amino butyric acid (GABA)-ergic -CB1R knockout mice.RESULTS:Alternations of endocannabinoids and energy value and synchronisation of mPFC-vHPC, especially the decrease of theta oscillation induced by CUMS, were alleviated by rTMS. JZL184 has similar effects to rTMS and AM281 blocked the effects of rTMS. GABAergic-CB1R deletion inhibited CUMS-induced depressive-like behaviours whereas Glutaminergic-CB1R deletion dampened the antidepressant effects of rTMS.LIMITATIONS:The immediate effect of rTMS on field-potential regulation was not observed. Moreover, the role of region-specific regulation of the ECS in the antidepressant effect of rTMS was unclear and the effects of cell-specific CB1R knockout on neuronal oscillations of the mPFC and vHPC should be further investigated.CONCLUSION:Endocannabinoid system mediated the antidepressant effects and was involved in the regulation of LFP in the vHPC-mPFC of high-frequency rTMS.

Objective To investigate the impact of electroacupuncture on behavior and the gut microbiome in chronic unpredictable mild stress（CUMS） mouse model. Methods A total of 40 male C57BL/6mice were randomly distributed into control group, electroacupuncture group, CUMS group and treatment group（CUMS + electroacupuncture）, with 10 mice in each group. CUMS group and CUMS + electroacupuncture group accepted CUMS modeling. After the completion of modeling, mice in the control group and CUMS group were given sham stimulation for 7 days, and mice in the electroacupuncture group and CUMS + electroacupuncture group were given 2/15 Hz, 1.0 mA electroacupuncture stimulation for 7 days. 24 hours after the last intervention, feces were collected and stored at-80℃. Sugar preference test, open field test and forced swimming test were conducted on mice. 16S rDNA sequencing was performed on the feces of four groups of mice. α diversity, β diversity analysis and Linear Discriminant analysis Effect Size（LEfSe） were carried out by Operational Taxonomic Units（OTU） information. Spearman correlation analysis of the correlation between the behavioral indicators of mice and the enrichment levels of different bacterial populations. Results The time of exploring the open field center area of CUMS group mice was shorter than that of the control group [（22.058±4.148） s vs（37.864±4.407） s], the sugar preference rate was lower than that of the control group [（53.427±14.550）%vs（76.514±15.701）%], and the forced swimming immobility time was longer than that of the control group [（82.599±32.369） s vs（47.606±15.344） s], the difference was statistically significant（P＜0.01）. The time of exploring the open field center area of CUMS + electroacupuncture group mice was longer than that of the CUMS group [（30.604±6.060） s vs（22.058±4.148） s], the sugar preference rate was higher than that of the CUMS group [（72.731±13.933）% vs（53.427±14.550）%], and the forced swimming immobility time was shorter than that of the CUMS group [（53.633±17.933） s vs（82.599±32.369） s], the difference was statistically significant（P ＜ 0.05）. The number of OTU, ACE index and Chao index of intestinal flora in CUMS group were lower than those in the control group, and the difference was statistically significant（P ＜ 0.05）, but there was no statistical significance in the difference between CUMS + electroacupuncture group and CUMS group（P＞0.05）.Ruminococcaceae＿UCG-002, Lachnoclostridium and Rikenella ceae＿RC9＿gut＿group were abundant in the CUMS group, which were positively correlated with depressive-like behavior（P＜0.05）. Phylum Actinobacteria and genus Rikenella, Dubosiella, Ileibacterium, Bifidobacterium and Allobaculum were enriched in the electroacupuncture group and CUMS + electroacupuncture groups, all of which were negatively correlated with depressive-like behaviors. Conclusions Electroacupuncture treatment can ameliorate depressive-like behavior and regulate the composition of gut microbiota in CUMS-treated mice.

目的:探讨氟西汀对慢性不可预见应激(Chronic Unpredictable Mild Stress,CUS)模型大鼠海马内磷脂酰乙醇胺(phosphatidylethanolamine,PE)组成的影响.方法:(1)将24只SD大鼠随机分为对照组(Sham)、模型组(CUS)和氟西汀组(Flx).CUS组和Flx组均接受CUS造模,并且在造模后接受生理盐水(1 mL/kg)或氟西汀(10 mg/kg)腹腔注射,连续14天;Sham不进行CUS造模,但是每天接受腹腔注射生理盐水.随后处死大鼠,取海马进行脂质组学分析,比较各处理组海马总的PE和PE小分子相对丰度、不同碳链长度和含不同不饱和键PE的相对丰度差异.结果:(1)与CUS组相比,Sham组PE相对丰度明显减低,而Flx组明显增高(P＜0.05);(2)与Sham组相比,CUS组9个PE小分子相对丰度发生变化,PE(34∶1e)、PE(36∶1p)、PE(36∶2)、PE(36∶2p)、PE(36∶4)、PE(38∶2)、PE(38∶4)和 PE(40:7)共8个上调(P＜0.05或0.01),PE(34∶0p)下调(P＜0.05),CUS 组碳链长度为36的PE丰度上升(P＜0.05),碳链长度为38的PE丰度下降(P＜0.01),CUS组含0个不饱和键、4个不饱和键的PE丰度下调(P＜0.01,P＜0.05),而1个不饱和键的PE丰度上升(P＜0.05);(3)与CUS组相比,Flx组6个PE分子相对丰度减少,包括PE(34∶1e)、PE(36∶2)、PE(36∶4)、PE(38∶1p)、PE(38∶6e)和 PE(40∶5p)(P＜0.05或0.01),Flx 组碳链长度为34的 PE 丰度下降(P＜0.05),碳链长度为36的PE水平升高(P＜0.05),Flx组含1个不饱和键的PE丰度下调(P＜0.05),差异具有统计学意义.结论:氟西汀可以调节CUS模型大鼠海马的PE水平.

目的 观察重复经颅磁刺激(rTMS)对慢性不可预见应激(CUS)模型大鼠海马鞘磷脂(SM)和神经酰胺(Cer)水平的影响.方法 将24只SD大鼠随机分为对照组(Sham组)、模型组(CUS组)和rTMS干预组(CUS+rTMS组),每组8只.CUS组和CUS+rTMS组大鼠均接受CUS造模(28 d),造模结束后,CUS+rTMS组每日接受rTMS(5 Hz,1.26 Tesla)干预;Sham组和CUS组在每日同一时间段接受假rTMS干预,连续7 d.通过糖水偏好实验和强迫游泳实验检测各组大鼠的抑郁样行为,在行为学检测结束后,处死大鼠,分离海马组织,通过高效液相色谱-质谱联用技术检测海马SM和Cer水平及组成小分子差异.采用SPSS 19.0软件分析各组大鼠海马中SM和Cer相对含量与行为学的相关性.结果 ①CUS模型可诱导大鼠抑郁样行为,显著降低海马SM水平但显著提高Cer相对丰度;rTMS干预能够改善CUS所致大鼠的抑郁样行为,并部分改善CUS大鼠海马SM和Cer水平的变化.②与Sham组相比,CUS组7个SM和1个Cer小分子相对丰度降低,13个Cer小分子相对丰度升高(P＜0.05,P＜0.01);③与CUS组相比,CUS+rTMS组3个SM和1个Cer小分子相对丰度升高,11个Cer小分子相对丰度降低(P＜0.01);与Sham组相比,CUS+rTMS组2个Cer小分子相对丰度降低,1个SM和1个Cer小分子相对丰度升高(P＜0.05,P＜0.01);④各组海马中的SM相对含量与强迫游泳不动时间呈负相关,与糖水偏好率呈显著正相关(P＜0.05);Cer相对含量与强迫游泳不动时间呈显著正相关(P＜0.01),与糖水偏好率呈显著负相关性(P＜0.01).结论 通过调节大鼠海马中SM和Cer相对含量和组成变化,rTMS可以改善CUS模型大鼠抑郁样行为,并且SM和Cer相对含量与抑郁样行为密切相关.

The neuroprotective effect of electroacupuncture (EA) treatment has been well studied; growing evidence suggests that changes in lipid composition may be involved in the pathogenesis of post-traumatic stress disorder (PTSD) and may be a target for treatment. However, the influence of early EA intervention on brain lipid composition in patients with PTSD has never been investigated. Using a modified single prolonged stress (mSPS) model in mice, we assessed the anti-PTSD-like effects of early intervention using EA and evaluated changes in lipid composition in the hippocampus and prefrontal cortex (PFC) using a mass spectrometry-based lipidomic approach. mSPS induced changes in lipid composition in the hippocampus, notably in the content of sphingolipids, glycerolipids, and fatty acyls. These lipid changes were more robust than those observed in the PFC. Early intervention with EA after mSPS ameliorated PTSD-like behaviors and partly normalized mSPS-induced lipid changes, notably in the hippocampus. Cumulatively, our data suggest that EA may reverse mSPS-induced PTSD-like behaviors due to region-specific regulation of the brain lipidome, providing new insights into the therapeutic mechanism of EA.

Objective:To investigate the effects of fluoxetine (Flx) on lipidomics of hippocampal tissue in chronic unpredictable stress (CUS) model rats.Methods:A total of 30 Sprague-Dawley rats were randomly divided into Sham group, CUS group and CUS+ Flx group, with 10 rats in each group. Rats in the CUS group and CUS+ Flx group were received one or two random stimuli every day for 28 days, and then they were received intraperitoneal injection of normal saline(1 ml/kg) and fluoxetine(10 mg/kg) respectively once a day for 14 days. Rats in the Sham group were maintained in their home cages for 28 days, and then received intraperitoneal injection of saline (1 ml/kg) once a day for 14 days. The sugar water preference experiment was carried out 24 hours after the last injection, and then the rats were killed to separate the rat hippocampus. The levels of lipid composition in hippocampus were detected by high performance liquid chromatography-mass spectrometry. The relative content of lipid was analyzed by Simca-p 14.1 and LipidSearch software version 4.1. SPSS 19.0 was used for statistical analysis. One-way ANOVA or Kruskal-Wallis test was used for comparison among groups, and Bonferroni test was used for post-hoc test. Pearson correlation or Spearman correlation was used to analyze the correlation between behavioral indexes and lipid molecular level in hippocampus.Results:There was significant difference in sugar preference test among the three groups ( F=12.830, P<0.001). The percentage of sucrose intake of rats in CUS group ((43.57±12.38)%) was significantly lower than those in Sham group ((67.09±11.81)%) and CUS+ Flx group ((62.74±8.58)%) (both P<0.05). Ninety five differential lipid molecules were screened among the three groups by lipidomic analysis, mainly distributed in glycerophospholipids and sphingolipids. Among them, levels of PE (34∶1e)+ H( r=-0.477), PE(18∶1p/20∶1)+ H( r=-0.433), PE(18∶1/18∶1)+ Na( r=-0.603), PE(36∶2p)-H( r=-0.382), PE(16∶0/20∶4)-H( r=-0.464), PE(18∶0/18.2)-H( r=-0.482), PE(16∶0e/22∶6)-H( r=-0.514), PE(18∶1/20∶4)-H( r=-0.511) and CerG1 (d18∶2/24∶0+ O)+ H( r=-0.490) were negatively correlated with sucrose preference rate (all P<0.05), whereas levels of PE (42∶6p)+ Na( r=0.379), PE(34∶0p)-H( r=0.397) and SM (d22∶1/16.0)+ HCOO( r=0.388) were positively correlated with sucrose preference rate (all P<0.05). Conclusion:Flx improves the depressive-like behavior of CUS model rats, which may be related to the regulation of hippocampal glycerophospholipid and sphingolipid metabolism.

Objective:To investigate the effect of repetitive transcranial magnetic stimulation (rTMS) on the hippocampal lipidome in a rat model of chronic unpredictable stress(CUS).Methods:Twenty-four SD rats were randomly assigned to the following 3 groups ( n=8 for each group): sham group, CUS group and CUS+ rTMS group. The sham group received only sham stimulation and rats in the CUS and CUS+ rTMS group were subjected to CUS stimulation. Then, rats received 5 Hz rTMS (5 Hz, 1.26 Tesla) or sham rTMS for 7 days. After the last stimulation, all rats underwent sucrose preference test, open filed test and forced swimming test so as to observe the effect of rTMS on depressive behavior. Then, rats were sacrificed, and the levels of lipid composition in hippocampus were determined by high performance liquid chromatography mass spectrometry and analyzed by lipid search software version 4.1 and SIMCA-P 14.1.The software of SPSS 19.0 was used for statistical analysis. Univariate analysis of variance was used for comparison among groups, and Tukey test was used for multiple comparison. Results:(1)There were significant differences in open field test, sugar preference test and forced swimming test among the three groups( F=6.853-7.466, all P<0.05). In the open field experiment, the exploring time and percentage of movement distance in central area of rats in CUS group((50.72±6.38)s, (11.41±1.55)%) was significantly less than that of sham group ((86.06±7.31)s, (18.60±1.21)%) and CUS+ rTMS group((79.87±7.87)s, (16.74±1.27)%)(all P<0.05). The results of sucrose preference test showed that the percentage of sucrose intake of rats in CUS group ((37.63±6.06)%) was significantly lower than that in sham group ((68.30±6.39)%) and CUS+ rTMS group ((62.68±5.50)%)(both P<0.05) . In forced swimming test, the immobility time of rats in CUS group ((137.60±13.36)s) was significantly longer than that of sham group ((80.57±10.36)s)) and CUS+ rTMS group ((86.14±11.49)s) (both P<0.05). (2)The levels of lipid composition in hippocampus were significantly different in the three groups( F=3.826-15.440, all P<0.05). The contents of phosphatidylethanolamine (PE) ((20 850±956.56)×10 7, (24 133.33±1 242.04)×10 7), phosphatidylinositol (PI) ((788.78±136.11)×10 7, (953.65±131.26)×10 7), lysophosphatidylcholine (LPC) ((340.29±35.66)×10 7, (275.32±35.78)×10 7), creatine phosphate (CerP) ((239.65±18.14)×10 7, (293.82±38.28)×10 7), sphingosine (So) ((22.96±4.04)×10 7, (15.36±3.87)×10 7), diglyceride (DG) ((3.35±0.85)×10 7, (4.57±1.02)×10 7) and monoglyceride (MG) ((6.71±0.82)×10 7, (7.94±0.91)×10 7)in hippocampus of rats in CUS group were significantly higher than those of sham group(all P<0.05), while the phosphatidic acid(PA) ((424.52±33.38)×10 7, (509.22±42.09)×10 7) and acyl carnitine(AcCa) ((2.68±0.33)×10 7, (3.39±0.33)×10 7) decreased(both P<0.05). Compared with CUS group, the contents of PE(21 816.67±928.26)×10 7, PI(83.16±91.52)×10 7, LPC(323.59±33.91)×10 7, CerP(236.39±32.02)×10 7, So(23.35±4.46)×10 7, DG(3.16±0.85)×10 7 and MG(7.03±0.26)×10 7 in the hippocampus of CuS+ rTMS group decreased, while the contents of PA(421.55±44.28)×10 7 and ACCA(2.56±0.32)×10 7 in the hippocampus of CUS+ rTMS group increased (all P<0.05). Conclusion:The levels of glycerophospholipids, glyceroglycerides, sphingolipids, fatty acids and other lipids in the hippocampus of CUS model rats are abnormal. And the 5 Hz rTMS intervention can ameliorate the depression like behavior and the disturbances of lipid in hippocampus of CUS model rats.

目的 观察帕罗西汀对慢性不可预见应激(CUS)模型大鼠前额叶皮质(PFC)中鞘磷脂(SM)和神经酰胺(Cer)水平的影响.方法 按照随机数字表法将21只SD大鼠随机分为对照组(Sham组)、模型组(CUS组)和帕罗西汀组(Par组),每组7只.CUS组和Par组均接受CUS造模,并且在造模后每天腹腔注射生理盐水(1 ml/kg)或帕罗西汀(10 mg/kg),连续7 d;Sham组在同一时间段每天腹腔注射生理盐水.随后处死大鼠,取PFC进行质谱分析,比较各处理组SM和Cer以及其组成小分子相对丰度的差异.结果 CUS组的SM相对丰度倍数为(0.73±0.16),显著低于Sham组的(1.02±0.08)和Par组的(0.89±0.05)(均P<0.05);CUS组的Cer相对丰度倍数为(1.35±0.18),显著高于Sham组的(1.05±0.10)和Par组的(1.14±0.11)(均P<0.05);Sham组和Par组的SM和Cer相对丰度比较,差异均无统计学意义(P>0.05).与Sham组相比,CUS组的5个SM和2个Cer小分子相对丰度降低,1个SM和5个Cer小分子相对丰度升高(均P<0.05);与Par组相比,CUS组的2个SM小分子相对丰度降低,8个Cer小分子相对丰度升高(均P<0.05);Sham组的1个SM和2个Cer小分子相对丰度降低,1个SM和6个Cer小分子相对丰度升高(均P<0.05).结论 CUS模型大鼠前额叶皮质的SM水平降低而Cer水平升高,帕罗西汀干预可以改善这一现象.