Exploration is a fundamental innate behavior essential for securing survival-necessary resources, but it also increases risks. However, the neural mechanisms encoding exploration decisions remain unknown. Here, we show that social companionship motivates both innate-driven and experience-dependent explorations in mice. Dopaminergic neurons in the ventral tegmental area (VTADA neurons) determine exploration decisions by encoding risky vigilance (via phasic firing) and exploration motivation (via tonic firing). Two subpopulations of VTADA neurons co-innervate the same population of basolateral amygdala neurons via direct and indirect pathways. Tonic firing-biased DA-D2R transmission in the medial prefrontal cortex (indirect pathway) mediates exploratory behaviors, which are reinforced by social interactions, while phasic firing-biased DA-D1R transmission in the direct pathway mediates avoidant behaviors. The dynamic balance between these two competing DA pathways coordinately encodes exploration decisions. These findings establish the VTADA neuron as a central hub and the circuit integration of biased DA transmission as a central mechanism encoding exploration decisions.

Synaptotagmins (Syts) are the primary Ca2+-sensors for synaptic vesicle exocytosis, while most mammalian Syts are non-Ca2+-affinitive and play critical roles in neurotransmission and synaptic plasticity with unclear mechanisms. Here, we show that high-alkaline non-Ca2+-binding Syt11 exhibits higher affinity for acidic phospholipids and Ca2+-inhibited liposome-binding, thereby competing with the Ca2+-binding Syt1. Physiological levels of Ca2+ eliminate this competition by promoting Ca2+-dependent membrane insertion of Syt1 while suppressing Syt11's binding through electrostatic shielding of the membrane surface. Site-directed mutagenesis reveals a dual-regional lipid-binding mode (a lysine-rich motif for Ca2+-independent binding and Ca2+-binding loops for Ca2+-facilitation) for Syt1, and a redundant multi-point lipid-binding interface for Syt11. Consistent with the Ca2+-dependent competition, Syt11 inhibits both the early stages of exocytosis and endocytosis in neurons, while the maximal rate of exocytosis remains intact. This Ca2+-sensitivity of Syt11 proposes Syt1-Syt11 inter-switching in membrane-occupancy as a critical step precisely controlling exocytosis and endocytosis during synaptic transmission.

Sociosexual preference is critical for reproduction and survival. However, neural mechanisms encoding social decisions on sex preference remain unclear. In this study, we show that both male and female mice exhibit female preference but shift to male preference when facing survival threats; their preference is mediated by the dimorphic changes in the excitability of ventral tegmental area dopaminergic (VTA DA ) neurons. In males, VTA DA projections to the nucleus accumbens (NAc) mediate female preference, and those to the medial preoptic area mediate male preference. In females, firing-pattern (phasic-like versus tonic-like) alteration of the VTA DA -NAc projection determines sociosexual preferences. These findings define VTA DA neurons as a key node for social decision-making and reveal the sexually dimorphic DA circuit mechanisms underlying sociosexual preference.

Relapsed refractory primary central nervous system lymphoma (R/R PCNSL) has no recognized optimal therapy due to its grave prognosis and high mortality. This report describes a 69-year-old patient with primary central nervous system lymphoma (PCNSL) who rapidly relapsed after achieving complete remission (CR) on first-line treatment and subsequently received treatment with glofitamab to achieve CR again. Grade 1 cytokine release syndrome was observed and there were no fatal side effects. However, limited reports on glofitamab therapy are applied for relapsed and refractory PCNSL. Further ex vivo data demonstrated that glofitamab drove T cell activation and killing ability against lymphoma cells. Our study suggested that glofitamab may be a viable option for relapsed PCNSL patients.

BACKGROUND:Augmented reality (AR) has been widely used in neurosurgery in recent years. The combination of AR and brain surface morphology for localization has not been reported. The aim of this work was to report the outcomes of combined method for locating supratentorial lesions in neurosurgery. METHODS:After multimodal image registration, brain tissue, the lesion, and blood vessels were reconstructed using a three-dimensional Slicer. AR was conducted using a smartphone application named Persp three-dimensional to project intracranial lesions on the scalp. The incision and size of the craniotomy were designed according to the location of the lesions. After craniotomy, the lesions were precisely located using brain surface morphology. Three types of morphology were used to localize the lesions: 1) the morphology of sulci and gyri; 2) superficial cerebral veins; and 3) combination of both. Then, the lesions were resected. Postoperative magnetic resonance imaging confirmed the extent of the resection. RESULTS:Of the 34 patients included in this study, 13 (38.2%) had gliomas, 15 (44.1%) had focal cortical dysplasia, and 6 (17.6%) had cavernous hemangiomas. The first type of morphology was used in 8 (23.5%) patients, the second type in 5 (14.7%), and the third in 21 (61.8%). In all cases, the lesions were accurately located and completely removed. No complications were recorded. CONCLUSIONS:AR combined with brain surface morphology could accurately locate lesions. This combined approach is convenient to use, and helpful for planning craniotomy and removing lesions.

Endocytosis is a fundamental biological process that couples exocytosis to maintain the homeostasis of the plasma membrane and sustained neurotransmission. Super-resolution microscopy enables optical imaging of exocytosis and endocytosis in live cells and makes an essential contribution to understanding molecular mechanisms of endocytosis in neuronal somata and other types of cells. However, visualization of exo-endocytic events at the single vesicular level in a synapse with optical imaging remains a great challenge to reveal mechanisms governing the synaptic exo-endocytotic coupling. In this protocol, we describe the technical details of stimulated emission depletion (STED) imaging of synaptic endocytosis at the single-vesicle level, from sample preparation and microscopy calibration to data acquisition and analysis.

The central mechanisms underlying pain chronicity remain elusive. Here, we identify a reciprocal neuronal circuit in mice between the anterior cingulate cortex (ACC) and the ventral tegmental area (VTA) that mediates mutual exacerbation between hyperalgesia and allodynia and their emotional consequences and, thereby, the chronicity of neuropathic pain. ACC glutamatergic neurons (ACC Glu ) projecting to the VTA indirectly inhibit dopaminergic neurons (VTA DA ) by activating local GABAergic interneurons (VTA GABA ), and this effect is reinforced after nerve injury. VTA DA neurons in turn project to the ACC and synapse to the initial ACC Glu neurons to convey feedback information from emotional changes. Thus, an ACC Glu –VTA GABA –VTA DA –ACC Glu positive-feedback loop mediates the progression to and maintenance of persistent pain and comorbid anxiodepressive-like behavior. Disruption of this feedback loop relieves hyperalgesia and anxiodepressive-like behavior in a mouse model of neuropathic pain, both acutely and in the long term.

Synaptic plasticity is a key cellular model for learning, memory and chronic pain. Most previous studies were carried out in rats and mice, and less is known about synaptic plasticity in non-human primates. In the present study, we used integrative experimental approaches to study long-term potentiation (LTP) in the anterior cingulate cortex (ACC) of adult tree shrews. We found that glutamate is the major excitatory transmitter and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid (AMPA) receptors mediate postsynaptic responses. LTP in tree shrews was greater than that in adult mice and lasted for at least 5 h. N-methyl-d-aspartic acid (NMDA) receptors, Ca2+ influx and adenylyl cyclase 1 (AC1) contributed to tree shrew LTP. Our results suggest that LTP is a major form of synaptic plasticity in the ACC of primate-like animals. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Schizophrenia is a severe neuropsychiatric disease, but the initiation mechanisms are unclear. Although antipsychotics are effective against positive symptoms, therapeutic interventions for negative symptoms are limited due to the lack of pathophysiological mechanisms. Here we identify synaptotagmin-11 (Syt11) as a potential genetic risk factor and dopamine over-transmission as a mechanism in the development of schizophrenia. Syt11 expression is reduced in individuals with schizophrenia but restored following the treatment with antipsychotics. Syt11 deficiency in dopamine neurons in early adolescence, but not in adults, leads to persistent social deficits and other schizophrenia-like behaviors by mediating dopamine over-transmission in mice. Accordingly, dopamine neuron over-excitation before late adolescence induces persistent schizophrenia-associated behavioral deficits, along with the structural and functional alternations in the mPFC. Notably, local intervention of D2R with clinical drugs presynaptically or postsynaptically exhibits both acute and long-lasting therapeutic effects on social deficits in schizophrenia mice models. These findings not only define Syt11 as a risk factor and DA over-transmission as a potential risk factor initiating schizophrenia, but also propose two D2R-targeting strategies for the comprehensive and long-term recovery of schizophrenia-associated social withdrawal.

Migraines are a common medical condition. From a basic science point of view, the central mechanism for migraine and headache is largely unknown. In the present study, we demonstrate that cortical excitatory transmission is significantly enhanced in the anterior cingulate cortex (ACC)-a brain region which is critical for pain perception. Biochemical studies found that the phosphorylation levels of both the NMDA receptor GluN2B and AMPA receptor GluA1 were enhanced in ACC of migraine rats. Both the presynaptic release of glutamate and postsyn-aptic responses of AMPA receptors and NMDA receptors were enhanced. Synap-tic long-term potentiation (LTP) was occluded. Furthermore, behavioral anxiety and nociceptive responses were increased, which were reversed by application of AC1 inhibitor NB001 within ACC. Our results provide strong evidence that cortical LTPs contribute to migraine-related pain and anxiety. Drugs that inhibit cortical excitation such as NB001 may serve as potential medicines for treating migraine in the future.

Significance Precise and efficient coupling of endocytosis to exocytosis is critical for neurotransmission. The activity-dependent facilitation of endocytosis has been well established for efficient membrane retrieval; however, whether neural activity clamps endocytosis to avoid excessive membrane retrieval remains debatable with the mechanisms largely unknown. The present work provides compelling evidence that synaptotagmin-1 (Syt1) functions as a primary bidirectional Ca 2+ sensor to promote slow, small-sized clathrin-mediated endocytosis but inhibit the fast, large-sized bulk endocytosis during elevated neural activity, the disruption of which leads to inefficient vesicle recycling under mild stimulation but excessive membrane retrieval following sustained neurotransmission. Thus, Syt1 serves as a fine-tuning Ca 2+ sensor to ensure both efficient and precise coupling of endocytosis to exocytosis in response to different neural activities.

目的 探讨后路寰枢关节松解融合内固定手术治疗不稳定型颅颈交界区畸形伴难复性寰枢椎脱位的效果.方法 对我院在2015年1月?2018年12月行后路寰枢关节松解复位内固定手术治疗的31例不稳定型颅颈交界区畸形患者进行回顾性分析,通过对比手术前后的日本骨科协会(JOA)评分、延髓脊髓角度(CMA)、寰齿间距(ADI)值及齿状突超过钱氏线的距离,分别评估患者术后症状的改善情况和脊髓受压情况及寰枢椎水平、垂直脱位情况.结果 平均手术时间(168.38±38.21)min,平均术中出血量(147.09±59.84)mL,平均住院时间(9.54±2.81)d;术中未出现椎动脉、脊髓损伤等严重并发症.术后6 d时患者的JOA、ADI、齿状突超过钱氏线的距离、CMA分别为(11.94±1.37)分、(2.72±1.08)mm、(3.03±0.78)mm、(145.35±8.00)°,与术前的(9.94±1.26)分、(4.96±1.60)mm、(6.89±1.36)mm、(122.16±9.58)°相比,均有明显改善,差异具有统计学意义(P<0.001).经过6～25(14.90±6.70)个月随访,未见内固定松动、移位情况,末次随访时患者的JOA评分增加到(13.16±1.19)分,与术前相比差异具有统计学意义(P<0.001).结论 经后路寰枢关节松解手术治疗不稳定型颅颈交界区畸形伴难复性寰枢椎脱位安全有效.

Migraines are a common medical condition, currently without effective treatment. The recently developed CGRP treatment is expensive and with limited beneficial effect. From a basic science point of view, the central mechanism for migraine and headache is largely unknown. In the present study, we demonstrate that cortical excitatory transmission is significantly enhanced in the ACC - a brain region which is critical for pain perception. Biochemical studies found that both of NMDA receptor GluN2B serine 1303 phosphorylation and AMPA receptor GluA1 serine 831 and serine 845 phosphorylation levels were enhanced in ACC of migraine rats. Both the presynaptic release of glutamate, and postsynaptic responses of AMPA receptors and NMDA receptors were enhanced. Furthermore, behavioral anxiety and nociceptive responses, were increased. Synaptic long-term potentiation (LTP) is occluded since theta-burst stimulation (TBS) failed to induce LTP in migraine rats. Inhibition of cortical excitation by application of a selective AC1 chemical inhibitor NB001 within the ACC significantly reduced behavioral sensitization and anxiety. Our results provide strong evidence that cortical LTPs contribute to migraine-related pain and anxiety, and drugs that inhibit cortical excitation such as NB001 may serves as potential new medicines for treating migraine in the future.

目的 探讨神经内镜下改良后颅窝减压术治疗Chiari畸形Ⅰ型的临床疗效.方法 回顾性分析2015年1月至2019年12月西安交通大学第一附属医院神经外科收治的63例Chiari畸形Ⅰ型患者的临床资料.其中,28例行神经内镜下改良后颅窝减压术(观察组),35例行后颅窝减压硬膜成形术(对照组).对比两组术后Tator分级、脊髓空洞改善及并发症的发生,评估术后疗效.结果 63例患者手术顺利,无死亡等严重并发症.其中,观察组术后有效率为78.6％,对照组为54.3％,差异有统计学意义(P<0.05);观察组术后脊髓空洞改善程度明显优于对照组(P<0.05);观察组术后并发症的发生与对照组相比差异无统计学意义(P>0.05).结论 神经内镜下改良后颅窝减压术治疗Chiari畸形Ⅰ型安全、有效,术中硬膜水密缝合加硬膜肌肉悬吊有利于减少术后皮下积液的发生.

目的 评价改良选择性脊神经后根切断术与传统脊神经后根切断术治疗痉挛性脑瘫的疗效和并发症.方法 回顾性分析52例痉挛性脑瘫患者临床资料,其中23例采用传统选择性脊神经后根切断术,29例采用改良选择性脊神经后根切断术.比较两组手术时间、出血量、术中切断脊神经后根的比例、术后并发症以及术后1年痉挛指数、踝阵挛、Holden步行能力的变化情况.结果 改良选择性脊神经后根切断术手术时间长于传统术式(P<0.05),两组的术中出血量、术后并发症、术后1年痉挛指数、Holden步行能力方面无统计学差异(P>0.05).改良组术中切断脊神经后根的比例小于传统组(P<0.05),踝阵挛消失优于传统组(P<0.05).结论 改良选择性脊神经后根切断术在消除踝阵挛方面更有优势.术中实时评判肌张力和踝阵挛变化情况来定量切断脊神经后根,可以减少术中切断脊神经后根的比例,为减少手术并发症保留了解剖和功能基础.

目的 探讨泽兰水提取物对脂多糖(LPS)诱导的PC12细胞增殖、凋亡、炎症反应的影响及其可能作用机制.方法 采用LPS诱导的大鼠肾上腺嗜铬细胞瘤PC-12建立细胞损伤模型,加入不同剂量的泽兰水提取物处理细胞,分别将anti-miR-NC、anti-miR-148a-3p转染至LPS诱导的PC12细胞后加入泽兰水提取物处理24 h;采用MTT实验检测细胞增殖;采用流式细胞术检测细胞凋亡率;qRT-PCR法检测miR-148a-3p的表达水平;Western blot 法检测 Cleaved-caspase-3、IL-1β、IL-6、TNF-α 蛋白表达量.结果 LPS诱导的 PC12细胞 A值及 miR-148a-3p 的表达水平降低(P＜0.05),凋亡率及 Cleaved-caspase-3、IL-1β、IL-6、TNF-α蛋白水平升高(P＜0.05);泽兰水提取物可明显提高A值及miR-148a-3p的表达水平(P＜0.05),降低凋亡率及Cleaved-caspase-3、IL-1β、IL-6、TNF-α 蛋白水平(P＜0.05);anti-miR-148a-3p 与泽兰水提取物联合处理后可明显逆转泽兰水提取物对LPS诱导的PC12细胞增殖、凋亡及炎症反应的作用.结论 泽兰水提取物可通过上调miR-148a-3p而促进增殖及抑制细胞凋亡、炎症反应从而减轻LPS诱导的PC12细胞损伤.

目的 探讨胶质瘤组织长链非编码RNA(lncRNA)HOXA反义转录物髓系异构体1(HOTAIRM1)、微小RNA-129-5p(miR-129-5p)表达变化及其临床意义.方法 选择胶质瘤患者83例(观察组)、因颅脑损伤接受手术治疗者55例(对照组),分别取手术切除的胶质瘤组织和正常脑组织,采用RT-qPCR法检测lncRNA HOTAIRM1、miR-129-5p表达,分析胶质瘤组织lncRNA HOTAIRM1表达与miR-129-5p表达的关系,以及二者表达与患者临床病理特征和预后的关系.结果 观察组lncRNA HOTAIRM1相对表达量高于对照组,miR-129-5p相对表达量低于对照组(P均<0.05).Pearson积矩相关分析显示,胶质瘤组织lncRNA HOTAIRM1相对表达量与miR-129-5p相对表达量呈负相关关系(r=-0.726,P<0.05).分别以胶质瘤组织lncRNA HOTAIRM1、miR-129-5p相对表达量的中位数为临界值,将患者分为lncRNA HOTAIRM1低表达者40例与lncRNA HOTAIRM1高表达者43例、miR-129-5p低表达者46例与miR-129-5p高表达者37例.lncRNA HOTAIRM1、miR-129-5p表达与肿瘤直径和WHO分级有关(P均<0.05),与患者性别、年龄、肿瘤位置、病理类型无关(P均>0.05).lncRNA HOTAIRM1高表达者累积生存时间低于lncRNA HOTAIRM1低表达者,而miR-129-5p高表达者累积生存时间高于miR-129-5p低表达者(P均<0.05).结论 胶质瘤组织lncRNA HOTAIRM1表达上调、miR-129-5p表达下调,二者表达变化与肿瘤直径、WHO分级和患者预后密切相关.

FBXO17 is a newly studied F-box protein associated with high-grade glioma. However, its exact role in glioma remains unclear. In the present study, we aimed to investigate the role of FBXO17 in glioma both in vitro and in vivo and explore the underlying mechanism. Our results showed that FBXO17 mRNA and protein levels were upregulated in glioma cells including U87, U251, SHG44, and U-118-MG cells as compared to the HA1800 cells. Downregulation of FBXO17 significantly suppressed the cellular behaviors of glioma cells including cell proliferation, migration, and invasion. In addition, FBXO17 knockdown induced E-cadherin expression and inhibited N-cadherin and vimentin expression at mRNA and protein levels in glioma cells. In contrast, overexpression of FBXO17 promoted cell proliferation, migration, invasion and EMT process. Furthermore, FBXO17 regulated the Akt/GSK-3β/snail signaling pathway in glioma cells with significant changes in the expression levels of p-Akt, p-GSK-3β and snail. Additionally, inhibition of Akt by LY294002 reversed the effects of FBXO17 overexpression on cellular behaviors of glioma cells. Finally, in vivo mouse xenograft assay proved that downregulation of FBXO17 suppresses the tumorigenesis of glioma. In conclusion, these findings demonstrated that FBXO17 acted as a promotor of glioma development via modulating Akt/GSK-3β/snail signaling pathway.

目的 定量分析内镜下经鼻入路齿状突磨除的手术自由度.方法 对7例成人头颅标本实施内镜下经鼻入路鞍区和颅颈交界区解剖,暴露出鞍底中央(CenSF)、外侧视神经管颈内动脉隐窝(LOCR)、枕骨大孔、寰椎、寰枕关节和齿状突尖(TOP).利用神经导航的空间坐标定位系统,计算TOP的手术自由度,并与LOCR和CenSF进行比较分析.结果 CenSF和LOCR是在经鼻内镜手术中常见的容易暴露的骨性标志,TOP与其手术自由度比较结果显示:①轴面自由度分析,TOP、LOCR和CenSF 3组间差异有统计学意义(中位数5.7°vs.6.9°vs.8.5°,P=0.004),其中TOP小于CenSF(P=0.003);②矢状面自由度分析,TOP、LOCR和CenSF 3组间差异有统计学意义(中位数6.3°vs.7.0°vs.9.5°,P=0.009),TOP小于CenSF(P=0.008);③TOP与LOCR手术自由度差异均无统计学意义(P=0.604,P=0.688).结论 内镜下经鼻入路可以为齿状突切除术提供足够的手术自由度.