Major depressive disorder (MDD) is a leading cause of disability worldwide, and current antidepressants are limited by delayed onset and incomplete efficacy. Esketamine produces antidepressant effects more rapidly than conventional treatments, but its underlying mechanisms remain unclear. We examined whether cannabinoid type 1 receptor (CB1R) signaling is associated with hippocampal mitochondrial biogenesis-related changes following esketamine treatment in a chronic variable stress (CVS) mouse model.Mice underwent 21 days of CVS and received a single intraperitoneal injection of esketamine (15 mg/kg) 24 h before behavioral testing. Hippocampal CB1R, nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), and total cytochrome C expression were assessed by Western blotting. Additional groups received the CB1R antagonists AM251 or SR141716A before esketamine administration.CVS induced depressive-like behavioral changes in the forced swim, tail suspension, and novelty-suppressed feeding tests. These effects were accompanied by reduced hippocampal CB1R, NRF1, and TFAM expression and altered total cytochrome c expression. Esketamine reversed the behavioral abnormalities and normalized these molecular changes. Pretreatment with either CB1R antagonist prevented both the behavioral and molecular effects of esketamine.These findings indicate that the antidepressant-like effects of esketamine observed 24 h after administration are associated with CB1R-dependent changes in hippocampal mitochondrial biogenesis-related protein expression. Further studies using direct mitochondrial functional assays and loss-of-function approaches are needed to establish causality.

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.

Major depressive disorder (MDD) is a highly prevalent mental disorder with devastating consequences that often first manifest during adolescence. Anhedonia has emerged as one of the most promising symptoms of adolescent MDD, which means a longer time to remission， fewer depression-free days, and also increased risk of suicide ideas or actions. Research has shown that at least two-thirds of depressed adolescents have significant sleep-onset or sleep-maintenance problems. However, the association between sleep disorder and anhedonia, and the potential mediators are less understood. This is a cross-sectional study that includes 200 adolescents suffered from MDD between the ages of 12–17. We use Spearman’s test to explore the relationship among main variables. To evaluate the mediating effects of stress, we applied regression models and used bootstrap method to validate the significance of effects. Significant correlation exists among sleep disorder, stress, and anhedonia (P<0.05).The direct effect of sleep disorder on anhedonia was 0.214 (95

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.

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.

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.

IntroductionThis study aimed to identify the effect of electroacupuncture (EA) treatment on post-stroke depression (PSD) and explore whether cannabinoid receptor 1 (CB1R)-mediated mitochondrial biogenesis accounts for the treatment effect of EA.MethodsThe PSD mouse model was induced by a consecutive 14-day chronic unpredictable stress operation after 7 days of recovery from the bilateral common carotid artery occlusion surgery. Either EA treatment or sham stimulation was performed for 14 consecutive days from Day 7 after the BCCAO operation. Subjects’ PSD-like behaviors were tested via open field test, sucrose preference test, novelty suppressed feeding test, tail suspension test, and forced swim test, and subjects’ cognitive function was examined using Y-maze and novelty object recognition test. In addition, the levels of CB1R, mitochondrial biogenesis-related proteins (nuclear transcription factor 1, NRF1; mitochondrial transcription factor A, TFAM), proteins related to mitochondrial function (Cytochrome C, Cyto C; AIF, COX IV), and mitochondrial DNA were measured. To elucidate the role of CB1R in EA treatment, CB1R antagonists AM251 and CB1R-shRNA were given to mice before EA treatment. Likewise, subjects’ depressive-like behaviors, cognitive function, mitochondrial function, and mitochondrial biogenesis were examined after the PSD procedure.ResultsIt has been showed that EA successfully ameliorated depressive-like behaviors, improved cognitive dysfunctions, and upregulated CB1R, NRF1 and TFAM expressions. However, the supplementation of AM251 and CB1R-shRNA blocked the antidepressant-like effects generated by EA, and EA failed to improve cognitive dysfunction, upregulate CB1R protein expression, and increase mitochondrial function and biogenesis.ConclusionAltogether, these results indicated that EA ameliorated PSD-like behaviors in mice, improved cognitive dysfunctions after PSD, and promoted mitochondrial biogenesis by activating CB1R, a novel mechanism underlying EA’s antidepressant-like effects in treating PSD.

目的 观察PD-1/PD-L1在慢性束缚应激(CRS)诱导的焦虑样模型小鼠海马中的表达水平变化以及炎症反应和氧化应激通路相关指标的改变.方法 将24只C57BL/6雄性小鼠随机分为正常组和模型组.模型组每日用束缚管束缚应激2 h,连续14d;正常组不做处理.在CRS期间每隔3 d记录小鼠的体质量变化;通过旷场和高架十字迷宫行为学实验评估两组小鼠的焦虑样行为;行为学结束后,分离出海马组织,利用Western blotting技术检测两组小鼠海马的炎症和氧化应激相关蛋白的表达水平.结果 ①CRS能诱导小鼠焦虑样行为,并会减轻小鼠的体质量.②与正常组相比较,模型组小鼠海马中的IL-1β和NF-κB表达上调,IL-1Ra表达下调(P＜0.01);而PD-1/PD-L1表达水平显著性下降(P＜0.01).③模型组Nrf2、Keap1和HO-1较正常组相比,均显著性下降(P＜0.05,P＜0.01).结论 CRS可以引起小鼠的焦虑样行为,抑制海马PD-1/PD-L1的表达水平并调节海马炎症和抗氧化通路的表达水平.

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.

Introduction: Compelling evidence indicates that a single sub-anesthetic dose of (S)-ketamine elicits rapid and robust antidepressant effects. However, the underlying mechanisms behind the antidepressant effects of (S)-ketamine remain unclear. Methods: Here, using a chronic variable stress (CVS) model in mice, we analyzed changes inthe lipid compositions of the hippocampus and prefrontal cortex (PFC) with a mass spectrometry-based lipidomic approach. Results: Similar to previous research outcomes, the current study also showed that (S)-ketamine reversed depressive-like behaviors in mice produced by CVS procedures. Moreover, CVS induced changes inthe lipid compositions of the hippocampus and PFC, notably in the contents of sphingolipids, glycerolipids, and fatty acyls. With the administration of (S)-ketamine, CVS-induced lipid disturbances were partially normalized, particularly in the hippocampus. Conclusion: Altogether, our results indicated that (S)-ketamine could rescue CVS-induced depressive-like behaviors in mice through region-specific modulation of the brain lipidome, contributing to the understanding of (S)-ketamine's antidepressant effects.

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.