慢性应激及氟西汀治疗后大鼠海马细胞支架的改变

目的 探讨慢性不可预见性应激及氟西汀治疗后大鼠细胞支架微管系统的动态性变化及其可能机制.方法 将24只大鼠按随机数字表法分为对照组(空白对照+生理盐水)、慢性不可预见性温和应激(CUMS)组(CUMS+生理盐水)和氟西汀组(CUMS+氟西汀),每组8只.对大鼠进行连续21 d CUMS后,氟西汀组给予氟西汀(10 mg/kg)治疗21 d,对照组和CUMS组给予生理盐水.实验结束后进行行为学观察,并使用免疫印迹法(western blot)检测大鼠海马乙酰化微管蛋白(Acet-Tub),酪氨酸化微管蛋白(Tyr-Tub),微管结合蛋白2(MAP-2)及磷酸化微管结合蛋白2(phospho-MAP-2).结果 (1)CUMS组糖水偏好[(55.13±11.80)%],总行程[(2736.59±511.20)cm],运动平均速度[(5.69±1.08)cm/s]及直立次数[(2.50±2.00)次]均低于对照组,差异有统计学意义(P＜0.01);氟西汀组上述指标与对照组比较差异无统计学意义(P＞0.05).(2)CUMS组与对照组相比,Acet-Tub表达升高[(171.84±10.34)%],Tyr-Tub[(62.06±9.24)%]和phospho-MAP-2[(68.81±8.93)%]的表达降低,差异有统计学意义(P均＜0.01),MAP-2的表达与对照组比较无统计学意义(P＞0.05);经氟西汀治疗后,Acet-Tub的表达降低为[(96.18±8.92)%],Tyr-Tub和phospho-MAP-2的表达分别升高为[(95.06±8.00)%]、[(100.60±7.30)%],与对照组比较均无统计学意义(P＞0.05).结论 慢性应激后微管动态性减低,神经可塑性受损,氟西汀可以逆转海马的这些损伤,上述过程可能与微管相关蛋白磷酸化水平的变化有关.     

慢性不可预见性温和应激后大鼠行为及海马细胞支架的改变

目的研究慢性不可预见性温和应激所致的动物行为学改变及细胞支架微管系统的动态性改变。方法将大鼠随机分为应激模型组（8只,以下简称模型组）和对照组（8只）,对模型组大鼠进行连续21d的慢性不可预见性应激。进行行为学观察,使用western blotting检测乙酰化微管蛋白（Acet—Tub）,酪氨酸微管蛋白（Tyr—Tub）。结果（1）模型组大鼠慢性应激后糖水偏好及自主活动显著减低,与对照组有显著差异;（2）模型组大鼠慢性应激后海马Acet—Tub表达升高,Tyr—Tub表达减低,与对照组有显著差异。结论慢性应激后微管动态性减低,神经可塑性受损。     

氟西汀预处理对大鼠脑缺血再灌注海马区BDNF和bcl-2表达的影响

目的探讨氟西汀对大鼠缺血后再灌注海马的影响及可能机制。方法将40只Wistar大鼠随机等分成4组：①单纯用药组（氟西汀灌胃20d）；②正常对照组（氯化钠灌胃20d）：③术前用药组（氟西汀灌胃20d制作脑缺血再灌注模型）；④单纯手术组（氯化钠灌胃20d制作脑缺血再灌注模型）．于实验终点进行苏木精-伊红染色及免疫组化检查．检测bcl-2和脑源性神经营养因子（BDNF）表达情况。结果与正常对照组比较，单纯用药组bcl-2检测指标无显著性差异（P〉0．05），BDNF表达显著性增多（P〈0．05）。术前用药组与单纯手术组比较，bcl-2表达无显著性差异（P〉0．05），BDNF表达显著性增高（P〈0．05）。结论氟西汀可以诱导增加BDNF表达．但不增加bcl-2的表达．从而减轻缺血后的再灌注损伤．产生神经保护作用。     

脑梗死后认知功能障碍患者血清BDNF水平及氟西汀的治疗作用

目的探讨脑梗死后认知功能障碍与血清BDNF的关系,观察氟西汀对血清BDNF和认知功能的影响。方法应用ELISA法检测血清BDNF水平,比较脑梗死后认知功能障碍组患者和认知功能正常组患者血清BDNF水平。将脑梗死后认知功能障碍组患者按照有无接受氟西汀治疗随机分为对照组和氟西汀组,观察两组治疗前后血清BDNF水平及MMSE分值的变化。分析血清BDNF与MMSE分值的相关性。结果脑梗死后认知功能障碍组患者血清BDNF水平低于认知功能正常组;对照组治疗前、后MMSE分值及血清BDNF水平无明显变化;氟西汀治疗组治疗后MMSE分值及血清BDNF水平均较治疗前升高;氟西汀治疗组治疗后MMSE分值及血清BDNF水平均较对照组治疗后升高;脑梗死后认知功能障碍患者MMSE分值与血清BDNF水平呈正相关。结论脑梗死后认知功能障碍的发生和程度与血清BDNF水平有关,氟西汀能改善脑梗死后认知功能患者的认知功能,并可能部分是通过增加血清BDNF来实现的。     

脑卒中后抑郁病因临床表现及相关治疗分析

目的 探讨脑卒中后抑郁发生与临床表现及相关治疗效果分析.方法 对198例住院的脑卒中患者发病因素进行分析,并分组进行比较,对服药后表现随访调查.结果 脑卒中后抑郁与脑卒中的病灶部位,累积面积及社会心理因素有关.结论 抗抑郁药物治疗和心理治疗可显著改善脑卒中后抑郁症.     

卒中后抑郁大鼠模型的建立及评估

目的 建立卒中后抑郁（poststroke depression，PSD）有效动物模型。方法 大脑中动脉闭塞（MCAO）制备大鼠局灶脑缺血模型，加以慢性不可预见的温和刺激结合孤养建立PSD模型并予氟西汀干预。分为对照组、卒中组、抑郁组、PSD组和PSD+氟西汀组。分别采用糖水消耗试验、旷野试验（open-field test，OFT)、强迫游泳评估大鼠快感缺失、活动减少、行为绝望等行为。结果 应激14 d时，与对照组及卒中组相比，PSD组体重增长幅度显著降低（P<0.05），经氟西汀干预后体重增长幅度明显增加（P<0.01）。PSD组水平得分在应激第7天时与对照组相比显著降低（P<0.05）；到应激14 d时，PSD组与对照组及卒中组相比水平得分进一步下降（P<0.01），并持续到应激18 d（P<0.01）。PSD组垂直得分在应激14 d时与对照组、卒中组相比均显著下降（P<0.05或P<0.01），强迫游泳的不动时间明显延长（P<0.05）；而氟西汀干预后水平得分与垂直得分均显著增加（P<0.05或P<0.01），不动时间明显缩短（P<0.01）。结论 PSD模型大鼠较充分而持续表现快感缺乏、活动减少等“抑郁”核心症状，可操作性和重复性较好，是研究PSD较为理想的大鼠模型。氟西汀能改善PSD模型大鼠行为学异常。     

双歧杆菌对慢性应激抑郁大鼠学习记忆的影响

目的观察双歧杆菌对抑郁模型大鼠行为及学习记忆的影响,探讨双歧杆菌潜在的抗抑郁作用及机制。方法选取48只成年雄性SD大鼠,按照随机数字表法分为模型组、氟西汀组、双歧杆菌组和对照组各12只。对照组在标准环境下饲养6周,另外三组分别单笼孤养并釆用连续6周慢性不可预见性温和刺激(CUMS)的方法建立慢性抑郁大鼠模型。于第3周末至第6周末对双歧杆菌组和氟西汀组分别给予双歧杆菌和氟西汀灌胃,模型组和对照组给予同体积生理盐水灌胃。CUMS前后及干预后,以糖水消耗实验、体质量测量及旷场实验评估大鼠行为,采用Morris水迷宫试验评估大鼠学习记忆能力。结果干预后,与对照组相比,模型组的糖水消耗量及体质量增加更少、水平运动距离更短、直立次数更少、粪便粒数更多(P均0.05);与模型组相比,双歧杆菌组与氟西汀组大鼠的糖水消耗量更多、体质量增加更多、水平运动距离更远、直立次数更多、粪便粒数更少,逃避潜伏期更短、空间探索时间更长、跨平台次数更多(P均0.05)。双歧杆菌组与氟西汀组的上述指标差异均无统计学意义。结论双歧杆菌可能有助于改善抑郁模型大鼠的抑郁行为并提高其学习记忆能力,效果与氟西汀类似,其可能通过改善抑郁行为和提高学习记忆能力而发挥抗抑郁作用。     

氟西汀及认知治疗对脑卒中后抑郁的疗效

目的 :了解氟西汀及认知治疗对脑卒中后抑郁的疗效。　方法 :对 34例脑卒中后抑郁患者以氟西汀治疗 ,其中部分病例合并认知治疗进行临床对照研究 ;采用汉密尔顿抑郁量表 (HAMD)进行疗效评定。　结果 :两组均有效 ,合并认知治疗组起效早 ,疗效好。　结论 :氟西汀合并认知治疗对治疗脑卒中后抑郁疗效较好     

脑出血后抑郁患者抗抑郁治疗的临床观察

目的探讨抗抑郁症药物辅助治疗脑出血后伴抑郁症患者的临床疗效。方法50例脑出血伴抑郁症患者随机分为治疗组、对照组各25例。对照组常规脑出血治疗,治疗组在常规脑出血治疗的基础上加氟西汀20mg/d,观察期为6个月。结果用NIHSS及ADL评定两组神经功能康复情况,治疗组基本治愈5例,显效10例,有效8例,无效2例,总有效率92%;对照组基本治愈2例,显效9例,有效9例,无效5例,总有效率80%。两组比较差异有统计学意义(P<0.01)。结论对脑出血后伴抑郁症患者,加用氟西汀抗抑郁治疗效果良好。     

氟西汀对慢性应激大鼠海马S100B和糖基化代谢终产物受体表达的影响

目的 探讨氟西汀对慢性应激大鼠海马S100B和晚期糖基化代谢终产物受体（RAGE）含量的影响。方法 将雄性sD大鼠4J0只随机分为正常对照组（以下简称对照组）、抑郁组、氟西汀（10mg·kg^-1，腹腔注射）＋抑郁组（F＋抑郁组）、氟西汀（10mg·kg^-1，腹腔注射）＋对照组（F＋对照组），每组各10只。采用21d不可预见性中等强度应激造成大鼠抑郁模型，于应激前及应激第22天观察大鼠行为（体质量、24h饮用1％蔗糖溶液量、旷场实验）；以Western blotting和激光共聚焦显微镜测定药物对各组大鼠海马S100B及RAGE表达水平的影响。结果 （1）在应激第22天，抑郁组大鼠体质量、蔗糖溶液消耗量、直立次数均低于对照组（P〈0．05），水平运动格子数低于对照组（P〈0．01），粪便颗粒数多于对照组（P〈0．05）；F＋抑郁组体质量、蔗糖溶液消耗量、水平运动格子数、直立次数均高于抑郁组（P〈0．05）。（2）抑郁组大鼠海马S100B[荧光强度18±5，吸光度（A）值3．24土0．45]、RAGE（荧光强度16±5，A值2．89±0．24）水平较对照组S100B（荧光强度25±7，A值5．28±0．48）、RAGE（荧光强度24±6，A值5．68±0．29）明显降低（P〈0．05），F＋对照组S100B（荧光强度31±5，A值7．34±0．29）、RAGE（荧光强度30±4，A值7．43±0．32）表达水平高于对照组（P〈0．05），而F＋抑郁组S100B（荧光强度23±3，A值5．00±0．34）、RAGE（荧光强度22±4，A值4．93±0．54）表达水平明显高于抑郁组（P〈0．05）。结论 慢性应激下调大鼠S100B，RAGE蛋白表达水平，而氟西汀上调S100B，RAGE的表达水平。     

慢性不可预见性温和应激后大鼠行为及微管相关蛋白tau磷酸化的改变

目的研究慢性不可预见性温和应激所致的动物行为学改变及微管相关蛋白tau磷酸化的改变。方法将大鼠随机分为慢性不可预见性温和应激抑郁（CUMS）组和对照组,对模型组大鼠进行连续21d的慢性不可预见性应激。进行行为学观察,使用western blotting检测总tau,tau磷酸化（Ser356,Thr231）水平的改变。结果CUMS组大鼠慢性应激后糖水偏好及自主活动显著减低,与对照组比较差异有统计学意义（P〈0．05）;CUMS组大鼠慢性应激后海马tau磷酸化表达升高,与对照组比较差异有统计学意义（P〈0．05）。结论慢性应激后微管相关蛋白tau磷酸化水平升高,神经可塑性受损,提示了新的抑郁症和阿尔茨海默病联系的生化机制。     

Brain derived neurotrophic factor (BDNF) containing neurons in the hypothalamic paraventricular and supraoptic nuclei of juvenile and middle-aged rats after chronic stress

The type and duration of stress stimulation are postulated to affect the expression of the brain derived neurotrophic factor (BDNF) differentially during ontogenetic life. The aim of our study was to investigate the influence of two different stressors, i.e. chronic (15 min daily for 21 days) exposure to the forced swim (FS) test or the high light open field (HL-OF) test, on the BDNF contained in magnocellular (PVm) and parvocellular (PVp) neurons of the hypothalamic paraventricular (PV) and the supraoptic (SO) nuclei. The immunofluorescence (-ir) method was used to detect BDNF-ir cells. The research showed that only the PVp part of the PV in juvenile (P28; P-postnatal day) control rats had a significantly lower density of BDNF-ir neurons than that in middle-aged (P360) control subjects. After chronic FS, a significant decrease in BDNF-ir cells was observed in the studied hypothalamic nuclei of the juvenile rats, but no changes were noted in the middle-aged individuals. The PV (PVm, PVp) and the SO nuclei in juvenile rats showed a significantly lower density of BDNF-ir neurons than the corresponding area of the hypothalamus in middle-aged rats. However, following the HL-OF test, the density of BDNF-ir neurons remained unaltered both in the P28 and the P360 groups. The data suggest that the type of the stressor applied was the factor that differentiated the number of BDNF-ir cells in the PVm and the SO only in juvenile rats: chronic HL-OF was more severe than FS. The age of the animals was the main factor that conditioned the BDNF hypothalamic PV (PVm, PVp) and the SO response to FS stimulation. The different density of BDNF-ir containing cells in the PVp of juvenile versus middle-aged rats can be explained by a functional, age-related change in the demand of PVp neurons for BDNF.     

Differential modulation of motor cortex excitability in BDNF Met allele carriers following experimentally induced and use-dependent plasticity

The purpose of this study was to investigate how healthy young subjects with one of three variants of the brain‐derived neurotrophic factor (BDNF) gene modulate motor cortex excitability following experimentally induced and use‐dependent plasticity interventions. Electromyographic recordings were obtained from the right first dorsal interosseous (FDI) muscle of 12 Val/Val, ten Val/Met and seven Met/Met genotypes (aged 18–39 years). Transcranial magnetic stimulation of the left hemisphere was used to assess changes in FDI motor‐evoked potentials (MEPs) following three separate interventions involving paired associative stimulation, a simple ballistic task and complex visuomotor tracking task using the index finger. Val/Val subjects increased FDI MEPs following all interventions (≥ 25%, P < 0.01), whereas the Met allele carriers only showed increased MEPs after the simple motor task (≥ 26%, P < 0.01). In contrast to the simple motor task, there was no significant change in MEPs for the Val/Met subjects (7%, P = 0.50) and a reduction in MEPs for the Met/Met group (?38%, P < 0.01) following the complex motor task. Despite these differences in use‐dependent plasticity, the performance of both motor tasks was not different between BDNF genotypes. We conclude that modulation of motor cortex excitability is strongly influenced by the BDNF polymorphism, with the greatest differences observed for the complex motor task. We also found unique motor cortex plasticity in the rarest form of the BDNF polymorphism (Met/Met subjects), which may have implications for functional recovery after disease or injury to the nervous system in these individuals.     

Cytoskeletal alterations in rat hippocampus following chronic unpredictable mild stress and re-exposure to acute and chronic unpredictable mild stress

The intrinsic dynamic instability of the cytoskeletal microtubular system is essential for neuronal development and organization. The modulation of microtubule dynamics depends on the phosphorylation of neuronal microtubule-associated proteins (MAPs). Chronic unpredicted mild stress (CUMS) affects hippocampal structure and function in the rat. The aim of the present work was to investigate the possible alteration of cytoskeleton in the hippocampus of rats exposed to CUMS and re-exposed to CUMS to mimic depression and the recurrence of depression of human. We investigated the effects of CUMS, fluoxetine and re-exposure to CUMS on α-tubulin isoforms associated with microtubule dynamics, MAP-2 and phospho-MAP-2 in the hippocampus of rats. Our results showed that rats submitted to CUMS once showed a significant reduction in locomotion and sucrose preference which indicate a state of anhedonia. These behavioral alterations were accompanied by specific alterations in hippocampal α-tubulin isoforms and phospho-MAP-2 expression, indicating less microtubule dynamics and the possible mechanism. Treatment of fluoxetine could reverse CUMS-induced impairment. Moreover, there were more dramatically changes in behaviors, α-tubulin isoforms and phospho-MAP-2 of rats re-exposed to CUMS compared to the rats exposed to CUMS once. These findings provide evidence that rats exposed to CUMS and re-exposed to CUMS showed impairment of microtubule dynamics accompanied with the decreased level of phospho-MAP-2, providing insight into the role of cytoskeleton in the depression and recurrent of depression.     

Decreased levels of BDNF protein in Alzheimer temporal cortex are independent of BDNF polymorphisms

Levels of brain-derived neurotrophic factor (BDNF) are reduced in specific brain regions in Alzheimer's disease (AD) and BDNF gene polymorphisms have been suggested to influence AD risk, hippocampal function, and memory. We investigated whether the polymorphisms at the BDNF 196 and 270 loci were associated with AD in a clinical and neuropathological cohort of 116 AD cases and 77 control subjects. To determine how BDNF protein levels relate to BDNF polymorphisms and AD pathology, we also measured BDNF in temporal association cortex, frontal association cortex, and cerebellum in 57 of the AD and 21 control cases. BDNF protein levels in temporal neocortex of the AD brains were reduced by 33% compared to control brains, whereas levels were unchanged in frontal and cerebellar cortex. The BDNF genotypes were not significantly associated with a diagnosis of AD, although the BDNF 270 C allele was slightly overrepresented among carriers of the APOEepsilon4 allele. Moreover, BDNF protein levels did not differ between the various BDNF genotypes and alleles. Neuropathologically, the loss of BDNF in AD showed a weak correlation with accumulation of neuritic amyloid plaques and loss of the neuronal/synaptic marker synaptophysin. The results suggest that the investigated BDNF polymorphisms are neither robust genetic risk factors nor determinants of BDNF protein levels in AD.     

不同刺激参数rTMS对慢性不可预见应激大鼠行为的作用及大脑BDNF水平的影响

目的 观察不同刺激参数重复经颅磁刺激（rTMS）对慢性不可预见应激（CUS）模型大鼠行为学的作用,并观察其对大鼠脑源性神经营养因子（BDNF）水平的影响.方法 64只SD大鼠随机分为对照组（8只）、模型组（8只）和干预组（共6个亚组,每组8只）.对照组正常饲养21d后连续7d给予rTMS假刺激;模型组在造模后连续7d给予rTMS假刺激;干预组在造模后每天给予不同频率和强度的rTMS刺激,连续7d.实验期间观察大鼠体质量的变化,并采用运动箱和强迫游泳实验评估大鼠抑郁样行为,最后以酶联免疫吸附法测定大脑BDNF的水平.结果 （1）造模结束后,对照组大鼠的体质量、强迫游泳静止时间与其他两组相比均存在显著性差异（P＜0.01,P＜0.05）,而模型组和干预组大鼠比较没有上述差异（P＞ 0.05）.各组大鼠水平运动距离没有显著性差异（P＞0.05）.（2）rTMS干预后,①模型组大鼠的体质量显著低于对照组及干预组（5 Hz,0.84/1.26 T和10 Hz,0.84/1.26 T） （P ＜0.05）.②各组大鼠水平运动距离之间没有显著性差异;模型组强迫游泳静止时间百分比明显高于对照组及干预组（P＜0.05）.③模型组BDNF的水平低于对照组,而一定刺激条件的rTMS可以改善这一现象.④双因素方差分析显示,刺激频率可能是改善大鼠抑郁行为和调节BDNF的关键因素,而且5 Hz的抗抑郁效应更为显著.结论 不同刺激参数的rTMS对CUS动物抑郁行为的改善作用存在差异,大脑BDNF水平的变化可能参与了这一改善过程.     

Interaction of BDNF with cytokines in chronic schizophrenia

Brain-derived neurotrophic factor (BDNF) interacts with cytokines. Although both BDNF and cytokines occur at abnormal levels in schizophrenia patients, their interactions have not yet been examined. We therefore compared serum BDNF, TNF-α, interleukin (IL)-2, IL-6, and IL-8 levels in 92 chronically medicated schizophrenia patients and 60 healthy controls. We correlated these serum levels within these subject groups with each other and with clinical symptoms assessed according to the Positive and Negative Syndrome Scale (PANSS). Compared to the control group, the schizophrenia patients had significantly lower BDNF and TNF-α levels, and higher IL-2, IL-6, and IL-8 levels. The patients also showed a significant positive correlation between BDNF and both IL-2 and IL-8 levels, and low BDNF and TNF-α levels together were associated with poor performance on the PANSS cognitive factor. Thus, an interaction between cytokines and neurotrophic factors may be implicated in the pathophysiology of chronic schizophrenia. In particular, the cytokine TNF-α may interact with BNDF causing cognitive impairment.