神经病理性疼痛大鼠海马促炎性 细胞因子的表达水平变化

目的 观察腰5脊神经横断(L5-SNT)所致的神经病理性疼痛大鼠模型海马TNF-α、IL-1β、IL-6的不同时程表达水平变化。方法 将36只雄性SD大鼠随机分成3组:正常组(Z组)、假手术组(J组)和模型组(M组),每组各12只; 术后观察大鼠行为学变化并测量各组大鼠术前1 d及术后1～15 d机械缩足痛阈值(MWT); 选择术后不同时间点2、7、11、15 d随机取大鼠(3只/时间点/组),应用RT-PCR法检测海马TNF-α、IL-1β及IL-6的表达水平。结果 ①与术前1 d比较,M组大鼠术后手术侧MWT迅速降低(P<0.01),与Z组及J组比较,M组大鼠手术侧50% MWT明显下降(P<0.01); ②与J组比较,M组大鼠海马TNF-α于术后第2 d开始增高,第7 d达高峰,并且直到术后11 d仍保持较高水平(P<0.05); IL-1β在术后第11 d表达水平明显上调(P<0.05); IL-6在术后第2 d表达水平增高(P<0.05),并且在术后第7、11及15 d仍处于较高水平。结论 SNT导致大鼠海马TNF-α、IL-1β、IL-6表达水平上调,其机制可能与海马参与神经病理性疼痛的调控密切相关。     

炎性细胞因子在缺血性脑损伤中的作用

近年来缺血性脑损伤的病理生理方面的研究进展很快 ,并在此基础上进行了许多药物治疗研究 ,其中飞速发展并有希望的领域之一是炎症在卒中中的作用 ,这种作用涉及 :(1)缺血性损伤后形成部分炎性反应和参与病理生理级联的分子 ;(2 )可能促使动脉血栓性卒中的炎症或感染过程。炎性细胞因子作为炎症介质 ,发挥重要的作用 ,我们谨就此作一综述。1　白细胞介素 - 1(IL - 1)IL- 1以两种分离的形式存在 (α,β) ,二者仅有 1/ 3的序列同源性。 IL- 1在脑缺血期间过度表达 ,已在持久大脑中动脉 (MCA)闭塞、短暂大脑前半球缺血或结扎颈动脉伴缺氧的…     

生命早期应激对成年后认知功能的影响及其机制的研究进展

生命早期是人类和啮齿类动物发育中大脑高度敏感的时期。生命早期应激（early life stress,ELS）能持久地影响大脑神经元的发育,进而对成年后认知功能起作用。文章对ELS 对成年后相 关认知功能的影响及其机制的研究进展进行了综述。大量文献表明,ELS 可能是通过调节DNA 甲基化、 激活下丘脑- 垂体-肾上腺皮质（HPA）轴、影响神经营养因子表达、改变脑区结构与功能等机制对成年 后个体的认知功能产生影响。与此同时,ELS 也能引起成年后焦虑抑郁样精神障碍,这也可导致认知功 能的受损。     

茶氨酸对大鼠局灶性脑缺血性损伤后炎性细胞因子表达的影响

目的研究茶氨酸对局灶性脑缺血性损伤后大鼠脑组织肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、细胞间粘附分子-1（ICAM-1）以及单核细胞趋化蛋白-1（MCP-1）含量的影响,以探讨其减轻脑缺血性损伤的机制。方法健康雄性SD大鼠36只,按随机数字表随机分为假手术组、脑缺血组和实验组（脑缺血前1h腹腔注射茶氨酸）,采用线栓法建立大鼠大脑中动脉栓塞模型。采用放射免疫法测定脑组织TNF-α、IL-6含量,酶联免疫吸附法检测脑组织ICAM-1及MCP-1含量。结果与假手术组相比,脑缺血组大鼠脑组织TNF-α、IL-6、ICAM-1及MCP-1含量明显升高（P〈0.05）,茶氨酸可以明显地抑制缺血脑组织中上述细胞因子含量的增加（P〈0.05）。结论茶氨酸可抑制大鼠局灶性脑缺血再灌注早期炎性细胞因子的表达,对缺血脑组织具有保护作用。     

脑缺血对阿尔茨海默病大鼠认知功能的影响及炎性机制探讨

目的：探讨脑缺血对阿尔茨海默病（AD）大鼠认知功能的影响及可能机制。方法：大鼠海马注射Aβ1-40成功建立AD大鼠模型后，于AD大鼠右侧纹状体注射内皮素-1建立脑缺血模型，Morris水迷宫检测脑缺血后AD大鼠认知功能的变化，免疫组化、原位杂交和RT-PCR检测海马内星形胶质细胞和IL-1、TNF—α的变化。结果；脑缺血后AD大鼠认知功能明显下降（P〈0．01），海马内星形胶质细胞和炎性细胞因子IL-1、TNF—α的表达都较单纯AD显著增加（P〈0．01）。结论：脑缺血加重了AD大鼠的认知功能障碍，炎性机制参与了脑缺血促进AD进展的过程。     

慢性应激刺激成年小鼠对其老年期认知功能的影响

目的:观察慢性应激刺激成年小鼠对其老年期认知功能及海马区神经结构的影响。方法:将8周龄成年雄性小鼠予以慢性束缚性刺激6周(Stress,S组),束缚结束后成年S组小鼠即刻进行水迷宫行为学测试并断头以免疫组化学及硫堇染色方法观察海马区突触素及尼氏小体的变化,并利用医学图像分析系统计算突触素免疫组化反应阳性产物数量;而老年S组小鼠于慢性束缚6周后普通环境下继续饲养11周至老年期(25周龄)再进行上述行为学及病理学检测。对照组小鼠正常环境下饲养并分别于14周龄、25周龄进行上述行为学及病理学检测。结果:成年及老年S组小鼠学习记忆能力明显受损(P<0.05);海马区脑组织突触素免疫反应阳性产物和尼氏小体数量较同龄对照组小鼠明显减少(P<0.01)。结论:给予成年期小鼠慢性应激刺激可导致老年期小鼠认知功能损害,其记忆的损害与年龄老化之间可能具有协同作用。     

早期母子分离对大鼠成年后认知功能及海马区神经型一氧化氮合酶表达的影响

目的研究早期母子分离(maternal separation, MS)对雄性大鼠成年后认知功能与海马区神经型一氧化合酶(neural nitric oxide synthase, nNOS)表达的影响,以探讨生命早期应激(early life stress, ELS)对大鼠神经发育的影响。方法健康SD孕鼠随机分为MS组和非母子分离(no maternal separation group, NMS)组,每组6只,MS组新生幼鼠在出生后第3～22 d,每天与母鼠分离3 h,NMS组不采取任何干预措施。饲养至10周龄时两组各取24只子代雄性大鼠,采用Morris水迷宫进行学习记忆能力测试,采用NeuN免疫荧光染色观察其海马齿状回(dentate gyrus, DG)神经元数目及分布情况,Western Blot法检测海马区nNOS、eNOS、Bax/BCL2、caspase-3及P53的含量,Ki67/DCX免疫荧光染色观察海马DG区神经元增殖、分化情况,TUNEL染色检测海马DG区神经元变性死亡情况。结果行为学测试提示MS组子代雄性大鼠相对于NMS组,逃逸潜伏期延长(P0.05),目标象限停留时间和穿越平台次数减少(P0.05)。MS组子代雄性大鼠相对于NMS组,海马DG区正常及变性神经元的数目无明显变化(P0.05),神经元增殖减少、分化减缓、凋亡增多(P0.05),海马区nNOS、eNOS表达减低(P0.05),Bax/BCL2表达增高(P0.05),caspase-3、P53表达无统计学差异(P0.05)。结论早期母子分离能够减少子代大鼠成年后海马区nNOS含量,影响海马DG区神经元功能,可能对神经发育有长远影响,与成年后学习、记忆能力相关的认知功能改变有关。     

硫胺素缺乏早期对成年小鼠认知功能及海马突触长时程增强的影响

目的 研究硫胺素缺乏(TD)早期对成年小鼠认知功能及其海马突触长时程增强fLTP)的影响. 方法成年小鼠24只按照随机数字表法均分为实验组和对照组,实验组给予硫胺素剥夺饮食喂养9 d制作TD9模型小鼠,对照组则给予含有硫胺素的正常饲料喂养9 d.利用Y迷宫检测小鼠的学习记忆能力,利用电生理技术检测小鼠海马CA1及CA3区LTP. 结果实验组小鼠出现学习能力的下降,与对照组相比差异有统计学意义(P<0.05);记忆功能无显著改变,与对照组相比差异无统计学意义(P>0.05).实验组和正常组小鼠海马CA1及CA3区都可以诱导出LTP,两组相比差异无统计学意义(P>0.05). 结论 TD早期损害了小鼠学习能力,其损害机理与海马突触可塑性关系不明显.     

硫胺素缺乏早期对成年小鼠认知功能及海马突触长时程增强的影响

Objective To investigate the changes of cognitive function and the hippocampal long-term potentiation (LTP) in adult mice in early stage of thiamine deficiency (TD). Methods Twenty-four adult mice were randomized into normal control group and experimental group, and in the latter group, the mice were given thiamine-depleted diet for 9 days to induce TD. The learning and memory abilities of the mice were tested with Y-maze test, and the LTP in the hippocampal CA1 and CA3 regions was measured electrophysiologically. Results Feeding on thiamine-depleted diet for 9 days significantly increased the total training trials in the learning task as compared with those of the normal control mice (23±0.86 vs 13.50±1.28, P<0.05), but the memory ability of the two groups remained comparable (P>0.05). By field potential recording in the hippocampal CA1 and CA3 regions, theta burst stimulation induced similarly robust LTP in the control and experimental groups (P>0.05). Conclusion The learning ability of adult mice is impaired in early stage of TD, the mechanism of which does not obviously involve hippocampai synaptic plasticity.     

Effects of maternal separation during early postnatal development on male sexual behavior and female reproductive function

The endocrine response to stress is an important homoeostatic mechanism, and the secretion of glucocorticoids from the adrenal cortex is a central feature of this response. During early postnatal development, the neonatal rat displays a reduced hypothalamic-pituitary-adrenal (HPA) response to stress. This early period has been termed the 'stress hyporesponsive period' (SHRP). Maternal separation (Sep) of neonates from their mothers during early postnatal development alters the HPA response to stress. In this study, we report the effects of Sep during the SHRP. Female rats were time mated and randomly divided into control or Sep groups before birth. The Sep litters were removed from the mothers during the dark cycle for 6 h per day from postnatal day (PND) 2 to 10. On PND 28, the pups from both groups were weighed, the anogenital distance (AGD) was measured and the animals weaned. At 40 days of age, male and female animals from both groups were tested for open-field activity. As the animals matured, vaginal opening and estrous cycles were measured in females, and males were tested for male sexual behavior at adulthood. Basal, stress, and stress recovery serum corticosterone levels were measured from control and Sep male and female animals. Open-field activity was not significantly different between control or Sep male or female animals. Sep did not affect either vaginal opening or estrous cycles in female animals. Corticosterone secretion in response to stress was similar in control and Sep males and females; however, the recovery levels were significantly higher in Sep females than in Sep males or female control values. In male sexual behavior tests, Sep males had significantly longer mount latencies (time to the first mount), longer intromission latencies (time to the first intromission) and a significant reduction in the percent of animals ejaculating versus control values (controls 84 and Sep 50%). Therefore, Sep males as adults displayed altered reproductive behavior, whereas their stress recovery levels of corticosterone returned to near basal levels in a similar fashion to that observed for control non-handled males. In contrast, females displayed normal reproductive physiology, while their recovery levels of corticosterone remained high, unlike that observed with control females. Thus, significant gender differences in response to Sep (during the dark phase of the circadian cycle) were observed in the paradigm used in the present study.     

Experiencing early life maternal separation increases pain sensitivity in adult offspring

Maternal separation is a widely accepted model for studying long-term behavioral changes produced by events during early life and its association with changes in pain sensitivity. Thus, our objective was to evaluate sensitivity to pain, under different stimuli in adult male and female rats that had undergone early life maternal separation. Animals were subjected to maternal separation from postnatal day (PND) 2–15. Maternal behavior and litter weight were evaluated during this period. Sensitivity to pain was assessed in offsprings during adulthood by exposing them to stimuli, including formalin (5%; 20 μl), a hot plate, and the electronic von Frey test, 4, 7, 10, and 24 h after the administration of saline or Freund’s complete adjuvant (CFA) injection. Maternal separation did not affect maternal behavior or litter weight during PND 2–15. However, experiencing maternal separation increased pain sensitivity in the rats subjected to formalin by increasing number of flinches and licking time Further, females appeared more sensitive than males to thermal stimuli, as they showed a decrease in latency in the hot plate test. In this test, male and female offsprings that were exposed to early life maternal separation and received the CFA injection also showed a reduction in latency to react to the painful stimuli. In the von Frey test, there was a reduction in withdrawal threshold in maternal separation animals injected with CFA, thus demonstrating a greater sensitivity to the mechanical stimuli. In conclusion, experiencing early life maternal separation increased pain sensitivity in adult offsprings. Thus, our data are important to understand the impact of environmental influences, such as stressful life events during critical developmental periods, on pain vulnerability.     

A meta-analytic study of the effects of early maternal separation on cognitive flexibility in rodent offspring

Adverse early life experiences, such as maternal separation, are associated with an increased risk for several mental health problems. Symptoms induced by maternal separation that mirror clinically relevant aspects of mental problems, such as cognitive inflexibility, open the possibility of testing putative therapeutics prior to clinical development. Although several animal (e.g., rodent) studies have evaluated the effects of early maternal separation on cognitive flexibility, no consistent conclusions have been drawn. To clarify this issue, in this study, a meta-analysis method was used to systematically explore the relationship between early maternal separation and cognitive flexibility in rodent offspring. Results indicate that early maternal separation could significantly impair cognitive flexibility in rodent offspring. Moderator analyses further showed that the relationship between early maternal separation and cognitive flexibility was not consistent in any case, but was moderated by variations in the experimental procedures, such as the deprivation levels, task characteristics, and rodent strains. These clarify the inconsistent effects of maternal separation on cognitive flexibility in rodents and help us better understand the association between early life adversity and cognitive development.     

Adolescent social isolation influences cognitive function in adult rats

Adolescence is a critical period for neurodevelopment. Evidence from animal studies suggests that isolated rearing can exert negative effects on behavioral and brain development. The present study aimed to investigate the effects of adolescent social isolation on latent inhibition and brain-derived neurotrophic factor levels in the forebrain of adult rats. Male Wistar rats were randomly divided into adolescent isolation (isolated housing, 38-51 days of age) and social groups. Latent inhibition was tested at adulthood. Brain-derived neurotrophic factor levels were measured in the medial prefrontal cortex and nucleus accumbens by an enzyme-linked immunosorbent assay. Adolescent social isolation impaired latent inhibition and increased brain-derived neurotrophic factor levels in the medial prefrontal cortex of young adult rats. These data suggest that adolescent social isolation has a profound effect on cognitive function and neurotrophin levels in adult rats and may be used as an animal model of neurodevelopmental disorders.     

头孢曲松钠对大鼠蛛网膜下腔出血后认知功能的影响

目的 探讨头孢曲松钠（CEF）对大鼠蛛网膜下腔出血（SAH）后的认知功能的影响及其机制。方法 将68只成年SD大鼠随机分为4组:正常组（n=12）、对照组（n=24）、CEF低剂量治疗组（n=8）和CEF高剂量治疗组（n=24）。采用枕大池双次注血方法建立大鼠SAH模型。SAH后3 h经小脑延髓池缓慢注射100 μl CEF（高剂量组浓度为100 μmol/L,低剂量组浓度为50 μmol/L）,对照治疗组注射等体积生理盐水。采用Morris水迷宫检测各组动物学习记忆能力;Western blot检测各组大鼠海马 Caspase-3和兴奋性氨基酸转运体2（EAAT2）的表达水平。结果 与对照组相比,CEF治疗组SAH后动物的水迷宫实验中的逃逸时间显著减少（P<0.05）,大鼠海马组织中EAAT2的表达增加（P<0.05）,Caspase-3的表达减少（P<0.05）。结论 CEF对SAH后具有显著的神经保护作用,CEF治疗可能通过上调星形胶质细胞EAAT2的表达逆转SAH诱导的神经损伤。     

托吡酯对成人癫(癎)患者认知功能的影响

目的 探讨托吡酯(TPM)对成人癫(癎)患者认知功能的影响.方法 对采用TMP治疗的35例成人癫(癎)患者分别在治疗前和治疗3个月、6个月、12个月和24个月时进行简易精神状态检查(MMSE)量表和事件相关电位(ERP)P300检测.结果 与治疗前相比,治疗3个月时MMSE评分明显降低(P＜0.01);治疗3个月及6个月时P300潜伏期明昆延长(P＜0.01～0.05);12个月时恢复至治疗前水平.结论 TPM对癫(癎)患者认知功能的影响出现在加量期,并且是可逆的.     

Neonatal maternal separation reduces hippocampal mossy fiber density in adult Long Evans rats

Neonatal maternal separation of rat pups leads to a stable stress hyper-responsive phenotype characterized by increased basal levels of corticotropin releasing factor (CRF) mRNA in the hypothalamic and extra-hypothalamic nuclei, increased hypothalamic CRF release, and enhanced adrenocorticotrophin hormone (ACTH) and corticosterone (CORT) responses to psychological stressors. Stress and exposure to glucocorticoids either early in life or in adulthood have been associated with hippocampal atrophy and impairments in learning and memory. In this study, male Long Evans rat pups were exposed to daily 3-h (HMS180) or 15-min (HMS15) periods of maternal separation on postnatal days (PND) 2–14 or normal animal facility rearing. Maternal separation and subsequent reunion with the dam resulted in elevated plasma CORT levels versus HMS15 animals at PND7, a time when rat pups are normally hyporesponsive to stressors and show limited pituitary–adrenal responses. As adults, HMS180 rats exhibited elevated indices of anxiety, startle-induced pituitary–adrenal hyper-responsiveness, and slight, but significant impairment on acquisition in the Morris water maze task. In addition, HMS180 rats exhibited decreased mossy fiber density in the stratum oriens region of the hippocampus as measured by Timm’s staining, but no change in volume of the dentate gyrus. These changes may be the result of neonatal exposure to elevated glucocorticoids and/or changes in other signaling systems in response to maternal separation. Overall the results suggest that repeated, daily, 3-h maternal separations during critical periods of hippocampal development can disrupt hippocampal cytoarchitecture in a stable manner. The resulting change in morphology may contribute to the subtle, but consistent learning deficit and overall stress hyper-responsive phenotype observed in these animals.     

Increased adult hippocampal brain-derived neurotrophic factor and normal levels of neurogenesis in maternal separation rats

Repeated maternal separation of rat pups during the early postnatal period may affect brain-derived neurotrophic factor (BDNF) or neurons in brain areas that are compromised by chronic stress. In the present study, a highly significant increase in hippocampal BDNF protein concentration was found in adult rats that as neonates had been subjected to 180 min of daily separation compared with handled rats separated for 15 min daily. BDNF protein was unchanged in the frontal cortex and hypothalamus/paraventricular nucleus. Expression of BDNF mRNA in the CA1, CA3, or dentate gyrus of the hippocampus or in the paraventricular hypothalamic nucleus was not affected by maternal separation. All animals displayed similar behavioral patterns in a forced-swim paradigm, which did not affect BDNF protein concentration in the hippocampus or hypothalamus. Repeated administration of bromodeoxyuridine revealed equal numbers of surviving, newly generated granule cells in the dentate gyrus of adult rats from the 15 min or 180 min groups. The age-dependent decline in neurogenesis from 3 months to 7 months of age did not differ between the groups. Insofar as BDNF can stimulate neurogenesis and repair, we propose that the elevated hippocampal protein concentration found in maternally deprived rats might be a compensatory reaction to separation during the neonatal period, maintaining adult neurogenesis at levels equal to those of the handled rats.     

Possible effects of early separation experiences on subsequent immune function in adult macaque monkeys

The authors studied the immunological influences of maternal or peer separation in adult monkeys. Monkeys with early separation experiences were found to have reduced proliferative responses to B and T cell mitogens but no differences in other immunological parameters compared with nonseparated control subjects.     

右美托咪定对老年患者食管癌根治术后早期认知功能及血清炎症因子水平的影响

目的研究老年患者行食管癌根治术过程中应用右美托咪定对其早期认知功能和血清炎症因子水平的影响。方法选取2018-02—2019-02在郑州大学第二附属医院接受食管癌根治术的80例老年患者进行研究,随机分为试验组和对照组各40例。在全麻双腔支气管插管后,试验组静脉泵注右美托咪定,对照组静脉泵入等量生理盐水。采用简易智力状态检查法(MMSE)对2组老年患者在麻醉开始前(T1)、手术结束后第1天(T3)、手术结束后第3天(T4)的认知功能进行评价,同时记录T1、手术结束时(T2)、T3、T4时的炎症因子肿瘤坏死因子(TNF-α)、血清白细胞介素-1β(IL-1β)以及血清神经生物学标志物(S100β)和神经特异性烯醇化酶(NSE)。结果与T1时间点相比,2组在T3、T4时间点的MMSE评分降低(P<0.05)。与对照组相比,试验组在T3、T4时间点的MMSE评分增高(P<0.05);与T1时间点相比,2组在T2、T3、T4时间点的TNF-α、IL-1β水平均增高(P<0.05),与对照组相比,试验组在T2、T3、T4时间点的TNF-α、IL-1β水平均降低(P<0.05);与T1时间点相比,2组在T2、T3时间点的S100β和NSE水平均增高(P<0.05),与对照组相比,试验组在T2、T3时间点的S100β和NSE水平均降低(P<0.05)。结论全麻插管后静脉泵入右美托咪定,不仅可有效减轻老年食管癌患者术后的认知功能下降水平,还可降低炎症因子和血清S100β、NSE水平。