Synapses are key structures involved in transmitting information in the nervous system, and their functions rely on the regulation of various lipids. Lipids play important roles in synapse formation, neurotransmitter release, and signal transmission, and dysregulation of lipid metabolism is closely associated with various neurodegenerative diseases. The complex roles of lipids in synaptic function and neurological diseases have recently garnered increasing attention, but their specific mechanisms remain to be fully understood. This review aims to explore how lipids regulate synaptic activity in the central nervous system, focusing on their roles in synapse formation, neurotransmitter release, and signal transmission. Additionally, it discusses the mechanisms by which glial cells modulate synaptic function through lipid regulation. This review shows that within the central nervous system, lipids are essential components of the cell membrane bilayer, playing critical roles in synaptic structure and function. They regulate presynaptic vesicular trafficking, postsynaptic signaling pathways, and glial-neuronal interactions. Cholesterol maintains membrane fluidity and promotes the formation of lipid rafts. Glycerophospholipids contribute to the structural integrity of synaptic membranes and are involved in the release of synaptic vesicles. Sphingolipids interact with synaptic receptors through various mechanisms to regulate their activity and are also involved in cellular processes such as inflammation and apoptosis. Fatty acids are vital for energy metabolism and the synthesis of signaling molecules. Abnormalities in lipid metabolism may lead to impairments in synaptic function, affecting information transmission between neurons and the overall health of the nervous system. Therapeutic strategies targeting lipid metabolism, particularly through cholesterol modulation, show promise for treating these conditions. In neurodegenerative diseases such as Alzheimer's disease, Parkinson disease, and amyotrophic lateral sclerosis, dysregulation of lipid metabolism is closely linked to synaptic dysfunction. Therefore, lipids are not only key molecules in neural regeneration and synaptic repair but may also contribute to neurodegenerative pathology when metabolic dysregulation occurs. Further research is needed to elucidate the specific mechanisms linking lipid metabolism to synaptic dysfunction and to develop targeted lipid therapies for neurological diseases.

Abstract Blood-brain barrier (BBB) impairment, which causes leakage of harmful peripheral substances into the brain, is an early indicator of Alzheimer’s disease (AD). Microglia are known to regulate BBB integrity, but the underlying mechanisms of this process remain unclear. We here analyzed BBB permeability and structural integrity in mice. Loss of TREM2 function was found to impair the structural integrity of the BBB; TREM2-deficient microglia showed CCL2 upregulation via activation of the NFκB pathway. The CCL2-CCR2 axis reduced the expression of endothelial tight junction proteins, including claudin-5, occludin, and ZO-1. BBB impairment led to increased leakage of amyloid β (Aβ) and β2-microglobulin (β2M) from peripheral tissues into the brain parenchyma, accelerating the formation of Aβ plaques and subsequent cognitive decline. Importantly, pharmacological blocking of CCR2 restored the BBB integrity, prevented peripheral Aβ deposition in the brain, and improved cognitive function in Trem2-knockout mice. Collectively, these results suggested that loss of TREM2 function induced BBB impairment and accelerated AD progression. Our study thus establishes TREM2 as a critical target for future studies of treatments to prevent and mitigate the effects of AD.

Background:The neuropeptide galanin has been shown to exhibit anticonvulsant effects in animal models. However, only a few studies have attempted to identify the galanin receptor subtype (s) involved in this effect. In the present study, the expression of galanin and that of its receptors in a rat model of temporal lobe epilepsy was studied to reveal the epileptogenesis-related alterations.Methods:Pilocarpine-inducted status epilepticus (SE) rat model was used for temporal lobe epilepsy. Galanin and galanin receptor mRNA was detected by Real-time polymerase chain reaction in dorsal hippocampus of rats at three different time points following SE: at the acute phase (24h), latent period (7 days), and chronic epileptic period (8 weeks). Using immunohistochemistry, galanin positive fibers and bodies were also observed.Results:In the acute seizure phase, a significant up-regulation of the galanin mRNA was observed in the hippocampus. Meanwhile, galanin-positive cells appeared, while galanin-positive fibers disappeared in the hilus of the dentate gyrus, stratum radiatum of CA1, and stratum lucidum of CA3, indicating an increase in galanin synthesis and release during the acute seizure phase. The gene expression analysis also indicated a significant increase in the transcription of galanin receptors GalR1 and GalR3 24h after SE. The increased levels of GalR1 mRNA were also observed in the latent and chronic epileptic periods.Conclusion:In general, these data suggest that adaptive changes occur in the galanin system during epileptogenesis that may affect its antiepileptic effects. Furthermore, these changes should be taken into account when attempting to pharmacologically modulate this system.

The role of microglia in the pathogenesis of neurodegenerative diseases

[目的]明确m6A去甲基化酶ALKBH5对含S1PR3基因3'-非编码区(3'-UTR)双荧光素酶报告基因的调控作用.[方法]以大鼠前额叶皮层脑区cDNA为模板,利用聚合酶链式反应(PCR)扩增S1PR3基因3'-UTR中含有m6A修饰位点的目的片段.利用重叠延伸PCR方法将三个靶序列GGACT、GGACT、AGACT中的第三位A突变为C,并将野生型S1PR3-3'-UTR片段和突变型S1PR3-mut-3'-UTR片段分别正向插入到pmiR-RB-Report?vector载体中.将pcDNA3.1-ALKBH5或空载体pcDNA3.1与野生型和突变型双荧光素酶报告载体分别共转染PC12细胞,并检测荧光素酶活性.[结果]成功构建了包含S1PR3基因3'-UTR野生型双荧光素酶报告载体pmiR-S1PR3-3'-UTR和突变型双荧光素酶报告载体pmiR-S1PR3-mut-3'-UTR.荧光素酶活性分析表明与空载体pcDNA3.1组相比,ALKBH5可显著降低野生型及突变型C1和C2报告载体荧光素酶的活性(P＜0.05),而对突变型C3没有影响(P＞0.05).[结论]初步证明S1PR3基因3'-UTR区是去甲基化酶ALKBH5的作用靶点,ALKBH5通过识别S1PR3基因3'-UTR区C3处的m6A修饰位点而降低pmiR-S1PR3-3'-UTR荧光素酶的活性.

Objective To elucidate the impact of prenatal stress(PS)on evoked expression of c-Fos in select emotion-related brain areas.Methods An experimental model of maternal exposure to chronic restraint stress in rats was employed as PS model.Subsequently,we assessed c-Fos and NeuN staining by immunofluorescence staining method in various brain regions of PS offspring rats,including the medial prefrontal cortex(mPFC),basolateral amygdala(BLA),ventral hippocampus(VH),and ventrolateral periaqueductal gray(vlPAG).Results Our findings revealed a significant decrease in the density and proportion of c-Fos positive neurons in the mPFC and BLA regions of PS-exposed offspring compared to control offspring.The density of c-Fos positive neurons in the VH region reduced in PS-exposed offspring,while no change was observed in the vlPAG region.Conclusion Our results indicated that PS induced a decreased density of stress-sensitive neurons in mPFC,BLA and VH brain regions,suggesting a potential underlying mechanism for the observed behavioral changes.

目的 利用孕期束缚应激诱导产后抑郁(PPD)大鼠模型,探索产后抑郁对子宫组织形态学特点、氧化应激指标、炎性因子及雌激素受体α(ERα)等的影响.方法 选择 2～3 月龄雌、雄性 SD大鼠合笼,怀孕雌鼠随机分为对照组和 PPD组,每组各 6 只.PPD组通过孕期束缚应激诱导构建PPD模型.两组大鼠在产后 4～6 d,通过糖水偏好和强迫游泳实验检测抑郁样行为,采集血液检测血浆雌激素(E2)水平,通过 HE染色观察子宫内膜形态,采用 ELISA 法检测子宫组织氧化应激指标[超氧化物歧化酶(SOD)、丙二醛(MDA)]及炎性因子白介素-1β(IL-1β)水平,实时荧光定量PCR法检测IL-1β及ERαmRNA表达水平,蛋白免疫印迹方法(Western blotting)检测ERα蛋白表达水平.结果 与对照组比较,PPD组大鼠糖水消耗率显著降低、强迫游泳不动时间显著延长(P均<0.01).与对照组比较,PPD组大鼠血浆 E2 水平显著降低(P<0.01),子宫指数显著降低(P<0.01),内膜萎缩变薄,细胞缩小,间质部分纤维组织增生.与对照组比较,PPD 组子宫组织中 MDA 含量显著增加、SOD活性显著降低(P均<0.01),炎性因子 IL-1β表达量显著增加(P<0.05),ERαmRNA及蛋白表达水平均显著升高(P<0.01).结论 孕期束缚应激可成功建立PPD大鼠模型;PPD可导致大鼠子宫发生相应的病理改变,如形态学变化、氧化应激水平及炎性因子、ERα表达增加等;但这些变化的具体机制尚需进一步探讨.

目的 利用RNA干扰技术建立多巴胺D2受体(D2R)低表达的高催乳素大鼠垂体瘤MMQ细胞模型.方法 设计3对可沉默D2R基因表达的小干扰RNA(siRNA)序列,转染MMQ细胞,建立包括siRNA1组、siRNA2组、siRNA3组、阴性对照(siNT)组和空白对照(CTRL)组的5组细胞模型,采用Western blot法检测各组MMQ细胞D2R蛋白表达.选择干扰高表达细胞株,加入溴隐亭1μmol/L进行干扰,采用酶联免疫吸附测定(ELISA)法、Western blot法及实时定量聚合酶链反应(qRT-PCR)法分别观察干扰后MMQ细胞催乳素的分泌、催乳素蛋白相对表达量及催乳素mRNA水平.结果 5组D2R蛋白相对表达量比较,差异有统计学意义(F=19.936,P<0.01);其中siRNA1组、siRNA3组D2R蛋白相对表达量[(0.23±0.12)、(0.57±0.24)]与siNT组(0.81±0.24)、CTRL组(0.94±0.21)比较,差异均有统计学意义(均P<0.01);siRNA1组、siRNA3组对MMQ细胞的D2R蛋白表达抑制率分别为74％和35％.干扰后,siRNA组、CTRL组、siNT组MMQ细胞催乳素分泌、催乳素蛋白相对表达量、催乳素mRNA水平比较,差异均有统计学意义(F=10.898、7.485、7.898,均P<0.05);siRNA组催乳素分泌高于siNT组、CTRL组[(2.91±0.12)ng/ml比(2.14±0.15)、(2.09±0.44)ng/ml];siRNA组催乳素蛋白相对表达量高于siNT组、CTRL组[(0.99±0.67)比(0.85±0.13)、(0.82±0.12)];siRNA组催乳素mRNA水平高于siNT组、CTRL组[(1.00±0.07)比(0.69±0.09)、(0.73±0.14)],差异均有统计学意义(均P<0.05).结论 基于RNA干扰技术构建的D2R低表达的高催乳素MMQ细胞模型为目标药物治疗高催乳素血症的靶点研究提供了可靠的细胞模型.

目的 探讨根皮素(phloretin,PHL)对脂多糖(lipopolysaccharide,LPS)导致的BV2小胶质细胞的氧化应激损伤的抑制作用及可能的分子机制.方法 利用LPS建立BV2小胶质细胞的氧化应激损伤模型,对该模型予以不同浓度的PHL预处理.利用MTS方法检测细胞活力.ELISA法检测氧化应激相关产物一氧化氮(nitric oxide,NO)、丙二醛(malondialdehyde,MDA)、谷胱甘肽(glutathione,GSH)含量及超氧化物歧化酶(superoxide dismutase,SOD)的活性.双荧光素酶活性检验方法检测抗氧化响应元件荧光素酶报告基因质粒(antioxidant reaction element luciferase reporter plasmid,ARE-LUC)报告基因转录活性.Western blotting法检测磷酸化核因子-E2相关因子2(nuclear factor E2-related factor 2,Nrf2)和血红蛋白加氧酶-1(heme oxygenase-1,HO-1)蛋白表达.结果 与对照组相比,LPS处理后的BV2小胶质细胞活力显著降低,氧化应激产物NO和MDA水平明显升高,GSH含量和SOD活性明显下降,但Nrf2磷酸化水平、ARE-LUC报告基因转录活性和HO-1蛋白表达略有增高.与模型组比较,高剂量PHL(20μmol/L)预处理明显改善了LPS导致的BV2小胶质细胞活力下降,降低NO和MDA的含量,增高GSH的含量和SOD的活性,且进一步增加了Nrf2的磷酸化水平,上调ARE-LUC的转录活性和HO-1蛋白的表达.结论 PHL可以显著抑制LPS导致的BV2小胶质细胞的氧化应激损伤,Nrf2/ARE通路可能是根皮素发挥抑制BV2小胶质细胞氧化应激损伤作用的途径之一.

[目的]探究rno-miR-129-5p对含有大鼠大麻素Ⅰ型受体(CB1R)基因3'-非编码区(UTR)双荧光素酶报告载体的调控作用.[方法]以大鼠前额叶皮层脑区和海马脑区cDNA为模板,利用聚合酶链式反应(PCR)扩增出含有rno-miR-129-5p与CBIR基因3'-UTR结合位点的目的片段.利用重叠延伸的方法将两个靶序列CAAAAA分别突变为 CAGGCC,并将 CB1R 3'-UTR 和 CB1R-mut 3'-UTR 插入到 pmiR-RB-Report?vector 载体中.将rno-miR-129-5p mimic或其Negative control(NC)与野生型和突变型双荧光素酶报告载体共转染至PC12细胞后,检测其荧光素酶活性.[结果]成功构建了包含CB1R基因3'-UTR野生型双荧光素酶报告载体pmiR-CB1R 3'-UTR和突变型双荧光素酶报告载体pmiR-CB1R-mut 3'-UTR.荧光素酶活性检测发现rno-miR-129-5p mimic可以下调野生型报告载体的活性(P＜0.05),而对突变型没有影响.[结论]初步证明CB1R基因3'-UTR是rno-miR-129-5p的作用靶点.

Traditional antidepressants largely interfere with monoaminergic transport or degradation systems, taking several weeks to have their therapeutic actions. Moreover, a large proportion of depressed patients are resistant to these therapies. Several atypical antidepressants have been developed which interact with G protein coupled receptors (GPCRs) instead, as direct targeting of receptors may achieve more efficacious and faster antidepressant actions. The focus of this review is to provide an update on how distinct GPCRs mediate antidepressant actions and discuss recent insights into how GPCRs regulate the pathophysiology of Major Depressive Disorder (MDD). We also discuss the therapeutic potential of novel GPCR targets, which are appealing due to their ligand selectivity, expression pattern, or pharmacological profiles. Finally, we highlight recent advances in understanding GPCR pharmacology and structure, and how they may provide new avenues for drug development.

目的:探讨SD大鼠乳鼠皮层神经元细胞原代培养方法,并鉴定其培养效果,以期建立一种生物学功能良好的体外细胞实验模型.方法:取出生24h的SD大鼠乳鼠,分离出大脑皮层,在胰酶消化之前先进行离心,然后将胰酶消化后多次离心得到的细胞悬液接种于L-多聚赖氨酸包被的培养皿和共聚焦皿中,以加B27的Neurobasal-A培养基进行神经元细胞的原代培养,倒置显微镜下观察培养细胞的生长状态;通过免疫荧光组化的方法采用神经元标记物MAP-2进行神经元纯度的鉴定;在导入Fluo4-AM的原代神经元细胞,观察电刺激后胞内钙离子信号的变化,以验证神经元细胞的生理状态.结果:采用此方法培养的神经元细胞紧密贴壁、分散均匀、状态良好,神经元细胞周围突起相互连接形成网络;经MAP-2免疫荧光组化技术鉴定神经元的纯度达到95％以上;胞内钙离子信号的变化提示所培养的神经元具有良好的生物学功能.结论:该方法能获得纯度较高并且生物学功能良好的原代培养的SD大鼠乳鼠皮层神经元细胞.

光遗传学在发现之初,就受到了广泛关注.这项突破性技术的诞生,有助于我们精准地探究大脑的神经环路和功能.光遗传学也因此荣获了许多科学奖项.本文就光遗传学的发展过程和工作原理进行了简要的介绍.

[This corrects the article DOI: 10.3389/fpsyt.2021.763032.].

Objective: Rapid eye movement sleep deprivation (REM-SD) can cause a decline in learning and memory and lead to changes in behavior. Therefore, REM sleep plays a key role in processes that govern learning and memory. However, the mechanism underlying REM-SD-induced learning and memory impairment is unclear and the underlying molecular signaling still needs to be identified. In the present study, we investigated the role of the cPKCγ-Ng signaling pathway in REM-SD-induced learning and memory impairment. Method: Sixty male rats were divided into Control, REM-SD, REM-SD+cPKCγ activator PMA, REM-SD+cPKCγ inhibitor H-7, and sleep revival (SR) groups. The Morris water maze was used to assess spatial learning and memory. Western blot analysis was used to detect cPKCγ total protein expression and membrane translocation levels, and Ng total protein expression and phosphorylation levels. Results: The REM-SD group performed worse on the Morris water maze test than the control group. Western blot analysis showed that cPKCγ membrane translocation and Ng phosphorylation levels were significantly lower in the REM-SD group. SR following REM-SD restored learning and memory ability, cPKCγ transmembrane translocation, and Ng phosphorylation levels, but not to levels observed before REM-SD. PMA and H-7 significantly improved/disrupted task ability as well as cPKCγ transmembrane translocation and Ng phosphorylation levels in REM-SD rats. Conclusion: The REM-SD induced learning and memory impairment in rats and may be associated with the cPKCγ-Ng signaling pathway. Specifically, activation of the cPKCγ-Ng signaling pathway may protect against REM-SD.

目的 观察神经肽Y(NPY)受体及炎性因子在急性束缚应激(RES)大鼠前额叶内侧皮层(mPFC)和下丘脑中的表达,探讨NPY受体Y5R在急性RES大鼠mPFC中可能的作用机制.方法 将SD雄性大鼠随机分为对照组(CTL组)和模型组(RES组).采用专业大鼠固定器束缚RES组大鼠2 h制备急性RES模型,CTL组不进行处理.造模结束后处死大鼠,实时定量PCR检测各组大鼠mPFC及下丘脑NPY受体及炎性因子mRNA表达情况;蛋白质印迹检测NPY受体Y5 R及炎性因子IL-1β的蛋白表达情况;免疫荧光染色检测NPY受体Y5 R及小胶质细胞标志物Iba-1的分布和定位.结果 与CTL组相比,RES组大鼠mPFC NPY受体Y5R的mRNA和蛋白水平均显著降低(P<0.05或P<0.01);炎性因子mRNA水平显著升高(P<0.05),蛋白水平差异无统计学意义(P>0.05).RES组大鼠下丘脑NPY受体Y5R及炎性因子mRNA和蛋白水平与CTL组相比差异均无统计学意义(P>0.05).免疫荧光染色检测结果显示NPY受体Y5R及小胶质细胞标志物Iba-1不存在共定位.结论 NPY受体Y5 R参与了急性束缚应激大鼠mPFC的病理过程,但其作用机制与小胶质细胞神经炎性反应无相关性.

Palmar hyperhidrosis (PH) refers to excessive sweating that affects patients’ quality of life, resulting in social and work impairment and emotional distress. Thoracic sympathectomy (TS) is the best surgery option for palmar hyperhidrosis; however, there was no agreement for the choice of optimal surgery level. The aim of this study was to systematically compare postoperative effect between thoracoscopic T3 and T4 thoracic sympathectomy for palmar hyperhidrosis and to help clinical decision. Studies comparing T3 versus T4 thoracic sympathectomy for palmar hyperhidrosis were searched overall the database and a meta-analysis was performed. After searching, 12 articles were selected and a total of 1192 patients with palmar hyperhidrosis, of whom 567 patients underwent T3 thoracic sympathectomy and 625 patients underwent T4 thoracic sympathectomy. After analysis, we found that T4 thoracic sympathectomy had fewer side effects than T3 thoracic sympathectomy, so T4 may be the optimal level for thoracic sympathectomy in palmar hyperhidrosis patients.

Unilateral auditory deprivation results in lateralization changes in the central auditory system, interfering with the integration of binaural information and thereby leading to a decrease in binaural auditory functions such as sound localization. Principal neurons of the lateral superior olive (LSO) are responsible for computing the interaural intensity differences that are critical for sound localization in the horizontal plane. To investigate changes caused by unilateral auditory deprivation, electrophysiological activity was recorded from LSO principal neurons in control rats and rats with unilateral cochlear ablation. At one week after unilateral cochlear ablation, the excitability of LSO principal neurons on the side ipsilateral to the ablation (the ablated side) was greater than that on the side contralateral to the ablation (the intact side); however, the input resistance increased on both sides. Furthermore, by analysing the miniature inhibitory postsynaptic currents and miniature excitatory postsynaptic currents, we found that unilateral auditory deprivation weakened the inhibitory driving force on the intact side, whereas it strengthened the excitatory driving force on the ablated side. In summary, asymmetric changes in the electrophysiological activity of LSO principal neurons were found on both sides at postnatal day 19, one week after unilateral cochlear ablation.