目的:采用光遗传学和化学遗传学技术调控中缝背核食欲素能神经元投射的方法，探讨七氟烷麻醉后大鼠觉醒的机制。方法:健康雄性Hcrt-Cre转基因大鼠45只，10~12周龄，体质量220~250 g，采用随机数字表法分为6组：光遗传兴奋组(CHR2组)、光遗传抑制组(eNpHR组)和光遗传对照组(O-CON组)，每组5只；化学遗传兴奋组(hm3Dq组)、化学遗传抑制组(hm4Di组)和化学遗传对照组(C-CON组)，每组10只。分别采用光遗传学和化学遗传学技术调控策略进行处理。在大鼠病毒注射3周后，采用2.7%七氟烷与纯氧1.5 L/min对大鼠进行麻醉诱导并维持稳定麻醉状态，全程脑电监测，记录光刺激前2 min与刺激时2 min大鼠脑电爆发性抑制率(%BSR)。结合光遗传及化学遗传策略，观察兴奋或抑制食欲素能神经元投射至中缝背核的神经末梢是否可引起七氟烷麻醉后大鼠翻正反射行为的改变。结果:与C-CON组比较，hm3Dq组大鼠七氟烷麻醉后翻正反射恢复(RORR)时间缩短，hm4Di组和eNpHR组RORR时间延长( P<0.05)；与O-CON组或光刺激前2 min %BSR比较，CHR2组光刺激期间%BSR降低( P<0.05)，eNpHR组光刺激期间%BSR差异无统计学意义( P>0.05)；与O-CON组比较，CHR2组大鼠七氟烷麻醉后RORR时间缩短( P<0.05)。 结论:大鼠中脑中缝背核的下丘脑外侧区食欲素能神经末梢发挥主动全麻后促觉醒效应。

目的 探讨血浆促食欲素A水平与路易体痴呆核心临床症状的相关性.方法 共纳入2019年1月至2021年12月首都医科大学附属北京天坛医院诊断与治疗的51例路易体痴呆患者以及性别、年龄、受教育程度相匹配的46例认知功能正常对照者,采用简易智能状态检查量表(MMSE)和蒙特利尔认知评价量表(MoCA)评估整体认知功能、临床痴呆评价量表(CDR)评估痴呆严重程度、日常生活活动能力量表(ADL)评估日常生活活动能力、汉密尔顿抑郁量表17项(HAMD-17)评估抑郁严重程度、神经精神科问卷(NPI)评估精神行为,测定血浆食欲素A水平;单因素和多因素Logistic回归分析筛查路易体痴呆影响因素,Pearson相关分析和偏相关分析探究血浆促食欲素A与路易体痴呆核心临床症状的相关性,多因素线性逐步回归分析探究血浆促食欲素A与神经心理学测验的线性相关关系.结果 路易体痴呆患者 MMSE(Z=-8.387,P=0.000)和 MoCA(Z=-8.479,P=0.000)评分均低于对照者,CDR(Z=-9.072,P=0.000)、ADL(Z=-8.692,P=0.000)、HAMD-17(Z=-7.568,P=0.000)、NPI(Z=-8.270,P=0.000)评分和血浆促食欲素A水平(Z=-2.688,P=0.007)均高于对照者;核心临床症状中有波动性认知功能障碍和有帕金森综合征患者血浆促食欲素A水平低于无波动性认知功能障碍(Z=-2.172,P=0.030)和无帕金森综合征(Z=-1.981,P=0.048)患者.Logistic回归分析显示,饮酒史是避免发生路易体痴呆的独立保护因素(OR=0.278,95％CI:0.095～0.808;P=0.019);血浆促食欲素A水平升高是路易体痴呆的独立危险因素(OR=6.878,95％CI:1.241～38.137;P=0.027).相关分析显示,血浆促食欲素A水平仅与核心临床症状中帕金森综合征呈负相关(r=-0.322,P=0.043).多因素线性逐步回归分析显示,血浆促食欲素A与神经心理学测验评分无线性相关关系(均P＞0.05).结论 路易体痴呆患者血浆促食欲素A水平高于认知功能正常老年人,血浆促食欲素A水平升高更易罹患路易体痴呆,但可降低核心临床症状中帕金森综合征的发生率,促食欲素能系统功能失调可能是路易体痴呆的潜在发生机制.

目的:探讨Orexins在雌性大鼠的摄取蔗糖的操作反应行为的作用,以及在线索诱导下恢复寻找蔗糖行为中的作用.方法:将雌性SD大鼠分为限制进食组和自由进食组,以固定比率和累进比率训练大鼠自己摄取蔗糖颗粒.通过OxR1受体拮抗剂SB-334867预处理,观察SB-334867对大鼠按固定比率摄取蔗糖行为和在线索诱导下恢复寻找蔗糖行为的影响.结果:限制进食的大鼠表现出按压有效杠杆次数和获取蔗糖颗粒数显著增多(P＜0.05),按压无效杠杆次数稍微增多.SB-334867可显著减少限制进食大鼠按压有效杠杆次数(P＜0.05).与对照组相比,SB-334867在消退期间可显著增加按压有效杠杆的次数(P＜0.05);在恢复期间,限制进食大鼠按压有效杠杆的次数显著增多(P＜0.05).结论:Orexins系统在大鼠条件刺激诱导摄取蔗糖中可能存在性别差异.

缺血性脑卒中是严重威胁我国人民生命和健康的疾病,具有高发病率、高死亡率和高致残率.食欲素是下丘脑分泌的一种神经肽,包括食欲素A和食欲素B有调节能量平衡、刺激食欲、内分泌、睡眠-苏醒、心血管系统的功能.近年来有研究发现食欲素通过对血糖、血压、炎症以及缺血性脑卒中后抑郁及认知功能的调节,进而影响缺血性脑卒中的预后.本文将对食欲素与缺血性脑卒中的关系做一综述.

Orexins, produced in the lateral hypothalamus, are important neuropeptides that participate in the sleep/wake cycle, and their expres-sion coincides with the projection area of the vagus nerve in the brain. Vagus nerve stimulation has been shown to decrease the amounts of daytime sleep and rapid eye movement in epilepsy patients with traumatic brain injury. In the present study, we investigated whether vagus nerve stimulation promotes wakefulness and affects orexin expression. A rat model of traumatic brain injury was established using the free fall drop method. In the stimulated group, rats with traumatic brain injury received vagus nerve stimulation (frequency, 30 Hz;current, 1.0 mA; pulse width, 0.5 ms; total stimulation time, 15 minutes). In the antagonist group, rats with traumatic brain injury were intracerebroventricularly injected with the orexin receptor type 1 (OX1R) antagonist SB334867 and received vagus nerve stimulation. Changes in consciousness were observed after stimulation in each group. Enzyme-linked immunosorbent assay, western blot assay and immunohistochemistry were used to assess the levels of orexin-A and OX1R expression in the prefrontal cortex. In the stimulated group, consciousness was substantially improved, orexin-A protein expression gradually increased within 24 hours after injury and OX1R expres-sion reached a peak at 12 hours, compared with rats subjected to traumatic brain injury only. In the antagonist group, the wake-promoting effect of vagus nerve stimulation was diminished, and orexin-A and OX1R expression were decreased, compared with that of the stim-ulated group. Taken together, our findings suggest that vagus nerve stimulation promotes the recovery of consciousness in comatose rats after traumatic brain injury. The upregulation of orexin-A and OX1R expression in the prefrontal cortex might be involved in the wake-promoting effects of vagus nerve stimulation.

食欲素(orexins)是由下丘脑分泌的能促进食欲的一种神经肽. 近年来研究发现,食欲素与睡眠-觉醒周期、能量稳态、饮酒行为、镇痛、注意力、学习和记忆的调节有关,但它们对癫痫活动的影响尚不清楚.食欲素是否会引起癫痫活动仍存在一定的争议.本文将对食欲素与癫痫之间的关系作一综述.

目的 观察orexin对急性酒精中毒昏迷大鼠是否有促觉醒作用.方法 30只大鼠随机分为对照组和生理盐水组,orexin-A和orexin-B组(2 nmol),SB334867和TCS-OX2-29组(10 nmol) (n=5),观察腹腔注射各种药物对大鼠昏迷时间的影响.另取30只大鼠随机分为对照组,生理盐水组,orexin-A和orexin-B组(2 nmol和4 nmol)(n=5),观察腹腔注射不同剂量的orexins对昏迷大鼠8脑电波的影响.结果 与对照组觉醒时间(3.49±0.08)h相比,腹腔注射orexin-A和orexin-B使大鼠昏迷时间缩短为(2.20±0.13)h和(2.47±0.07)h(P ＜0.01);SB334867和TCS-OX2-29延长大鼠昏迷时间为(4.30±0.12)h和(3.79±0.10)h(P＜O.01).脑电结果显示:与对照组96.0％±3.2％相比,2 nmol和4 nmol orexin-A使δ波百分比分别下降为80.8％±3.3％和76.5％±2.9％(P＜0.01);2 nmol和4 nmol orexin-B使δ波百分比分别下降为85.0％±3.2％和80.3％±3.1％(P＜0.01).结论 Orexin可促进急性酒精中毒昏迷大鼠的觉醒.

目的:探究 Ghrelin 对大鼠摄食的影响及 orexins 信号通路的调控作用.方法:采用免疫组织化学染色的方法观察 Ghrelin 免疫阳性神经元轴突末梢与 orexin 神经元的突触联系以及下丘脑外侧区(LHA)内 c-fos 的表达.侧脑室注射抗-orexin-A IgG 和抗-orexin-B IgG 混合液、抗-黑色素浓集激素(MCH)IgG、NPY-1 受体拮抗剂后测量大鼠摄食量,观察其对 ghrelin 诱导摄食的影响.结果:Ghrelin 免疫阳性神经元轴突末梢与 orexin 神经元的突触相接触.侧脑室注射 ghrelin 可诱导 orexin 神经元内 c-fos 表达,但是没有引起 MCH 神经元内 c-fos 的表达.预先注射抗-NPY IgG 抗体,ghrelin 仍然可诱导 orexin 神经元内 c-fos 表达.侧脑室预先注射抗-orexin-A IgG 和抗-orexin-B IgG 抗体可减弱 ghrelin 促摄食作用,但是预先注射抗-MCH IgG 抗体对 ghrelin 诱导的摄食作用没有明显影响.注射 NPY 受体拮抗剂可进一步加强抗-orexin-A IgG 抗体和抗-orexin-B IgG 抗体对 ghrelin 诱导摄食的抑制效应.结论:ghrelin 可能与 orexin 系统相互作用共同参与摄食和能量平衡的调控.

Orexins comprise two neuropeptides produced by orexin neurons in the lateral hypothalamus and are released by extensive projections of these neurons throughout the central nervous system.Orexins bind and activate their associated G protein-coupled orexin type 1 receptors (OX1Rs) and OX2Rs and act on numerous physiological processes,such as sleep-wake regulation,feeding,reward,emotion,and motivation.Research on the development of orexin receptor antagonists has dramatically increased with the approval of suvorexant for the treatment of primary insomnia.In the present review,we discuss recent findings on the involvement of the orexin system in the pathophysiology of psychiatric disorders,including sleep disorders,depression,anxiety,and drug addiction.We discuss the actions of orexin receptor antagonists,including selective OX1R antagonists (SORA1s),selective OX2R antagonists (SORA2s),and dual OX1/2R antagonists (DORAs),in the treatment of these disorders based on both preclinical and clinical evidence.SORA2s and DORAs have more pronounced efficacy in the treatment of sleep disorders,whereas SORA1s may be promising for the treatment of anxiety and drug addiction.We also discuss potential challenges and opportunities for the application of orexin receptor antagonists to clinical interventions.

目的 探讨丘脑深部电刺激(DBS)对脑外伤后昏迷大鼠的促醒作用及对Orexins受体1(OX1R)表达的影响.方法 将54只SD大鼠随机分为3组:空白对照组(n=18,不做任何处理);对照组(n=18)和DBS组(n=18).通过自由落体撞击大鼠脑部建立脑外伤昏迷大鼠模型,造模成功后对照组大鼠丘脑植入电极,但不予DBS,DBS组大鼠丘脑植入电极,并予DBS.用意识状态六级评分法评估大鼠的意识状态和行为学变化,并用Western-blot(WB)、免疫荧光技术检测3组大鼠前额叶皮质(PFC)区OX1 R的表达水平.结果 DBS 1 h后,DBS组16只出现翻正反射(16/18),对照组7只出现翻正反射(7/18),DBS组意识状态水平好于对照组(U=96.00,P=0.026).在DBS刺激完成后的12 h,WB、免疫荧光技术检测Orexins受体OX1R的表达水平,DBS组均明显高于对照组(P<0.05);对照组明显低于空白对照组(P<0.05).结论 脑外伤昏迷大鼠可以通过DBS提高它的意识状态水平,其机制可能与DBS能上调PFC区OX1 R的表达水平有关.