人参皂苷Rb1对Aβ_(1-42)导致的Tau蛋白异常磷酸化的影响

为探讨人参皂苷Rb1对Aβ_(1-42)所致小鼠脑片微管相关蛋白(Tau)异常磷酸化的抑制作用及其可能机制,采用Aβ_(1-42)诱导小鼠海马脑片建立Tau蛋白过度磷酸化模型,运用免疫印迹方法观察人参皂苷Rb1对Aβ1-42导致小鼠脑片p-Tau、p-Erk1/2、Erk1/2蛋白水平的影响。实验结果显示,模型组p-Tau、p-Erk1/2表达水平明显高于空白对照组(P0.01);与模型组比较,人参皂苷Rb1各剂量组p-Tau、p-Erk1/2表达水平显著性降低(P0.01或P0.05),且大、中剂量组优于小剂量组;人参皂苷Rb1呈一定的剂量依赖性下调Aβ_(1-42)导致的p-Tau、p-Erk1/2的蛋白水平。本研究表明,人参皂苷Rb1可能通过抑制Erk1/2的激活逆转Aβ_(1-42)所导致的Tau蛋白水平的升高来减少神经纤维缠结。     

逍遥散对慢性束缚应激模型大鼠相关脑区CRF基因表达的影响

目的:观察慢性束缚应激大鼠相关脑区CRF mRNA(下丘脑、垂体、海马、皮层)含量变化以及逍遥散对其影响.方法:用RT-PCR和图像分析方法测定相关脑区CRF mRNA含量变化.结果:应激组较正常对照组在下丘脑CRF-1基因表达下调(P<0.01).在下丘脑逍遥散组较应激组CRF-1基因表达显著下调(P<0.01),CRF-2基因表达显著上调(P<0.01);在海马区逍遥散组CRF-2基因表达较模型组上调(P<0.05);在皮层逍遥散组CRF-1基因表达较应激组则显著上调(P<0.01).结论:逍遥散组对慢性束缚应激中枢神经肽CRF的调节位点在下丘脑、垂体、海马和皮层,充分证实逍遥散的调节靶点与下丘脑、边缘系统及皮层中枢有关.     

细胞外信号调节激酶在乳腺癌组织中的活化

目的：探讨人乳腺癌中细胞外信号调节激酶（Erk2,p42MAP）在蛋白表达水平、mRNA表达水平和激酶活性水平的变化。方法：应用Western-blotting,免疫沉淀、激酶活性测定和RT-PCR方法检测37例人乳腺癌及其周围正常组织的Erk2表达及活性变化。结果：与周围正常组织相比,37例人乳腺癌中Erk2蛋白表达显增加（100％）;其激酶活性亦显增高（75.68％）;在mRNA水平,Erk2的表达亦明显增高;Erk2表达与其活性变化无相关性。结论：人乳腺癌中Erk2蛋白表达、mRNA表达和激酶活性均显高于周围正常组织。提示Erk2参与乳腺癌的信号转导,为乳腺癌的活化信号,可能成为人乳腺癌治疗的新靶点。     

主动脉弓缩窄诱导大鼠心肌肥大Raf/MEK/ERK通路的变化

目的:通过观察心肌肥大大鼠加速纤维肉瘤/丝裂素活化蛋白激酶激酶/胞外信号调节蛋白激酶(Raf/MEK/ERK)通路关键因子的基因和蛋白表达及蛋白磷酸化修饰水平上的变化,了解Raf/MEK/ERK通路在心肌肥大调控中的作用。方法: 20只SD大鼠随机分为假手术组和模型组,通过主动脉弓缩窄(TAC)法建立心肌肥大模型,12周后颌下静脉取血分离血清,检测氨基末端脑钠肽前体(NT-proBNP)含量,之后进行超声心动图测定和麻醉下的血流动力学测定,收集心肌标本,观察心肌组织的病理学改变,检测心肌组织Raf/MEK/ERK通路的关键因子基因、蛋白表达水平及蛋白磷酸化水平的变化。结果:与假手术组比较,TAC模型组大鼠超声心动图的左室舒张末期室间隔厚度(IVSd)、左室收缩末期室间隔厚度(IVSs)、左室后壁舒张末期厚度(LVPWd)、左室后壁收缩末期厚度(LVPWs)显著增厚(P＜0.05,P＜0.01),左室收缩末期内径(LVIDs)显著减小(P＜0.01),左心室质量(LV Mass)、左心系数LW(LV Mass/Weight)比值显著增加(P＜0.05,P＜0.01);大鼠心率(HR)、左心室最大收缩速率(+dp/dtmax)、左心室最大舒张速率(-dp/dtmax) 均显著降低(P＜0.01),血清中NT-pro BNP含量显著增加(P＜ 0.01);心肌细胞排列杂乱,心肌细胞肥大、胞质明显增多,炎症细胞浸润,出现大量胶原纤维沉积,大面积心肌细胞呈现蓝色;大鼠心肌组织中c-Raf在Ser259和Ser338上的磷酸化蛋白phospho-c-Raf (Ser259)和phospho-c-Raf (Ser338) 表达水平显著升高(P＜0.01),其下游MEK1/2、ERK1/2的磷酸化蛋白phospho-MEK1/2(Ser217/Ser221)和phospho-ERK1/2 (Thr202/Tyr204)表达水平也显著增高(P＜0.01)。结论: Raf/MEK/ERK通路在心肌肥大中的调控作用,可能通过激活关键因子c-Raf、MEK1、MEK2、ERK1和ERK2特异性位点的磷酸化实现的。     

Notch3在血管平滑肌细胞中对Erk1/2的调控作用研究

Erk1/2活性在血管许多细胞功能中具有重要影响,而Notch3主要表达在动脉平滑肌细胞中,并且是发育过程中动脉成熟所必需的.为了探讨Notch3在血管平滑肌细胞中对Erk1/2信号通路的调控作用,采用siRNA基因敲除Notch3,γ-分泌酶抑制剂DAPT抑制Notch信号通路,质粒转染过表达Notch3活性区等方法,用Western印迹检测Notch3对血管平滑肌细胞中Erk1/2磷酸化水平,即Erk1/2活性的影响.同时,利用活性氧自由基（ROS）诱导激活Erk1/2;siRNA敲除Notch3表达致使血管平滑肌细胞中Erk1/2的磷酸化水平显著降低,并且抑制了ROS诱导的Erk1/2激活;同样,Notch通路抑制剂DAPT也抑制了ROS诱导的Erk1/2激活;而Notch3活性区NICD的过表达并没有改变血管平滑肌细胞中Erk1/2的磷酸化水平,但其延缓了ROS激活后Erk1/2活性的衰减.上述结果表明,Notch3可在血管平滑肌细胞中调控Erk1/2活性以及ROS诱导的Erk1/2信号激活.     

大鼠内侧前额叶皮质内ERK1/2 活化参与脊髓损伤后抑郁情绪

目的:观察细胞外信号调节激酶1/2(ERK1/2)的活化在脊髓损伤引起抑郁中的作用。方法:应用Western blot和行为药理学方法,观察脊髓损伤后(SCI)大鼠内侧前额叶皮质内(mPFC)ERK1/2及磷酸化-ERK1/2(p-ERK1/2)的表达情况及ERK1/2磷酸化抑制剂U0126对抑郁样行为的影响。结果:脊髓损伤后的第2天到第8周,SCI模型大鼠的BBB评分均显著低于假手术组,差异具有统计学意义(p0.05)。脊髓损伤后8周-12周,SCI模型大鼠强迫游泳不动时间与假手术组相比明显缩短,mPFC内pERK1/2蛋白表达水平明显升高,总ERK 1/2的蛋白水平则未见组间差异,而给予U0126的大鼠的不动时间与给药之前相比明显延长增加,mPFC内pERK1/2蛋白表达水平较SCI模型大鼠明显降低,差异均具有统计学意义(P0.05)。结论:内侧前额叶皮质内ERK1/2的激活参与了脊髓损伤后引起的突触可塑性,在相关的抑郁样行为的产生中发挥了重要的作用。     

GRP75经由Raf/Mek/Erk1/2信号转导通路抑制缺糖诱导的细胞凋亡

本文旨在探讨促存活信号通路Raf/Mek/Erk1/2是否参与了葡萄糖调节蛋白75(glucose-regulated protein75,GRP75)对缺糖诱导的细胞凋亡的抑制作用。GRP75过表达的PC12细胞给予Raf/Mek/Erk1/2通路抑制剂U0126预处理之后,无糖培养6、12和24h,同时以DMSO预处理的GRP75过表达PC12细胞组为对照。Western blot检测Erk1/2的磷酸化和表达水平,MTT实验检测细胞存活率,Hoechst 33258染色观察凋亡细胞核的形态学改变,流式细胞仪检测细胞亚二倍体峰,免疫荧光检测细胞色素c(cytochrome c,Cytc)向胞浆的弥散情况。结果显示:U0126在没有影响Erk1/2表达水平的前提下,阻断了GRP75对Erk1/2磷酸化水平的维持;U0126处理组的凋亡率明显高于对照组;U0126处理组Cytc从线粒体向胞浆释放的时间明显早于对照组,同时Cytc向胞浆的弥散程度大于对照组。以上结果提示,U0126通过抑制Erk1/2磷酸化,阻断了缺糖状态下GRP75对Cytc释放和细胞凋亡的抑制作用,这表明GRP75是通过Raf/Mek/Er...     

肝郁脾虚证模型大鼠血流变及TXB2、PGFla的变化

目的:探查中医肝郁脾虚证模型的血流变及相关调节因子的状态。方法:采用慢性束缚应激+过度疲劳+饮食失节法建立大鼠肝郁脾虚证模型,测定大鼠造模三周、自然恢复一周时的血流变和血浆TXB2、PGF1a。结果:与正常组相比,模型组大鼠造模三周150/s、38/s、10/s、5/s切变率下的全血粘度、还原粘度均显著升高(P<0.001),红细胞聚集指数显著降低(P<0.001),红细胞压积显著升高(P<0.01),红细胞变形指数无显著性差异(P>0.05);血浆TXB2显著升高(P<0.001),6-keto-PGF1a显著降低(P<0.05),TXB2/PGF1a显著升高(P<0.01);模型组大鼠第四周150/s、38/s、10/s、5/s切变率下的全血粘度、还原粘度仍显著升高(P<0.001或P<0.01);红细胞聚集指数显著降低(P<0.001);红细胞压积与变形指数无显著性差异(P>0.05);血浆TXB2和TXB2/PGF1a显著降低(P<0.05),6-keto-PGF1a显著升高(P<0.05)。结论:肝郁脾虚证大鼠存在血液高粘和血栓易形成状态,恢复期血液高粘同时伴有扩血管因素的加强。提示肝郁脾虚证有血流...     

吴茱萸次碱对高糖诱导的阿尔茨海默病大鼠认知障碍的影响*

目的: 探讨吴茱萸次碱对高糖诱导的阿尔茨海默病(AD)大鼠认知功能障碍的影响及其机制。方法: 健康成年雄性SD大鼠随机分为3组(n=20):对照组、高糖组和吴茱萸次碱组。对照组大鼠行常规饲料和自来水饲养;高糖组大鼠行常规饲料和20%蔗糖水饲养;吴茱萸次碱组行0.01%吴茱萸次碱饲料和20%蔗糖水饲养。三组大鼠饲养24周后行Morris水迷宫实验检测大鼠学习记忆和认知功能,Western blot实验检测各组大鼠tau蛋白在Thr205和Ser214位点以及GSK-3β在丝氨酸9位点糖原合成酶激酶-3β(S9-GSK-3β)和PP2A在络氨酸307位点蛋白磷酸酯酶-2A(Y307-PP2A)的磷酸化水平;免疫组织化学进一步验证各组大鼠大脑海马和皮层tau蛋白在Thr205位点上的表达情况。结果: 与对照组比较,高糖组Morris水迷宫大鼠潜伏期明显升高,穿越平台次数和目标象限停留时间均明显降低(P均＜0.05),免疫组织化学染色中tau蛋白在Thr205位点上的磷酸化水平显著增高(P＜ 0.05),Western blot实验tau蛋白在Thr205和Ser214位点的磷酸化水平显著增高,pS9-GSK-3β的磷酸化水平显著降低(P均＜0.05);与高糖组相比,吴茱萸次碱组Morris水迷宫大鼠潜伏期明显降低,穿越平台次数和目标象限停留时间明显升高(P均＜0.05),免疫组织化学染色中tau蛋白在Thr205位点的磷酸化水平显著降低(P＜0.05);Western blot实验tau蛋白在Thr205和Ser214位点磷酸化水平显著降低,pS9-GSK-3β的磷酸化水平显著增高(P均＜ 0.05)。结论: 吴茱萸次碱可减轻高糖诱导的AD样大鼠认知功能障碍,其机制可能是通过增强海马pS9-GSK-3β磷酸化水平,下调GSK-3β活性,进而降低tau蛋白相关位点的过度磷酸化实现的。     

莪术油注射液对慢性低氧大鼠学习与记忆的影响

本文旨在探讨莪术油注射液对慢性低氧大鼠学习与记忆的影响及其可能机制.将Sprague.Dawley大鼠随机分为对照组、慢性低氧组、5 mg/kg体重莪术油组、10 mg/kg体重莪术油组、20 mg/kg体重莪术油组,每组14只.慢性低氧处理采用低氧舱内吸入大约10%O2、5%CO2,饲养10 h/d,持续饲养28 d.莪术油组大鼠低氧处理前腹腔注射相应浓度的莪术油注射液.实验结束次日,通过Morris水迷宫测试各组动物学习和记忆成绩的变化;测定各组大鼠血清和海马组织丙二醛(malonaldehyde,MDA)含量和超氧化物歧化酶(superoxide dismutase,SOD)活性以及海马组织Ca2 浓度([Ca2 i]);通过免疫组织化学和Western blot检测磷酸化Ca2 /钙调蛋白依赖性蛋白激酶Ⅱ(phosphorylated Ca2 /calmodulin-dependent pro-tein kinase Ⅱ,p-CaMKII)在海马组织和胞膜上的表达.结果显示,与对照组相比,慢性低氧组大鼠隐蔽平台的逃避潜伏期明显延长(P<0.05),血清和海马组织MDA含量明显增高,SOD活性显著降低(P<0.05,P<0.01),海马组织[Ca2 ]i明显增高(P<0.01),海马P-CaMKII表达量显著降低(P<0.01).与慢性低氧组比较,莪术油各组发生以下变化:10、20 mg/kg体重莪术油组大鼠隐蔽平台的逃避潜伏期显著缩短(P<0.05):5、10、20 mg/kg体重莪术油组大鼠血清和海马组织MDA含量均显著降低(P相似文献   

A panic attack-like unusual stress reaction

Ever since the seminal studies of Hans Selye, activation of hypothalamus-pituitary-adrenal (HPA) axis is emblematic of stress. Consequently, the lack of HPA axis responses following the undisputable psychological stress of a panic attack stands out as one of the most intriguing findings of contemporary psychiatry. On the other hand, the defensive behaviors and aversive emotions produced by stimulation of the dorsal periaqueductal gray matter (DPAG) have been proposed as a model of panic attacks. Therefore, we examined whether the plasma levels of ‘stress hormones’ corticotropin and prolactin show any change following the DPAG-evoked freezing and flight behaviors of the rat. Rats bearing an electrode into the DPAG and an intra-atrial catheter were stimulated at 9:00 a.m., 18–24 h after the catheter implantation. Blood samples were withdrawn just before 1-min stimulation of DPAG, immediately after (5 or 15 min) and throughout 3 to 27 h following stimulation. In another experiment, samples were withdrawn either before or following a prolonged stimulation (5 min) of the DPAG with flight threshold intensity. Hormones were measured by either chemiluminescent or double-antibody immunoassays. Hormone plasma levels following freezing and flight behaviors were compared to those of resting or restraint-stressed rats. Data show that stress hormones remain unaltered following the DPAG-evoked defensive behaviors. Not even the 5-min stimulation of DPAG with the flight threshold intensity changed corticotropin plasma levels significantly. As far as we known, this is the first demonstration of the lack of stress hormone responses following the intense emotional arousal and physical exertion of a fear-like behavior in rats. Data add new evidence of DPAG involvement in spontaneous panic attacks.     

A panic attack-like unusual stress reaction

Ever since the seminal studies of Hans Selye, activation of hypothalamus-pituitary-adrenal (HPA) axis is emblematic of stress. Consequently, the lack of HPA axis responses following the undisputable psychological stress of a panic attack stands out as one of the most intriguing findings of contemporary psychiatry. On the other hand, the defensive behaviors and aversive emotions produced by stimulation of the dorsal periaqueductal gray matter (DPAG) have been proposed as a model of panic attacks. Therefore, we examined whether the plasma levels of ‘stress hormones’ corticotropin and prolactin show any change following the DPAG-evoked freezing and flight behaviors of the rat. Rats bearing an electrode into the DPAG and an intra-atrial catheter were stimulated at 9:00 a.m., 18–24 h after the catheter implantation. Blood samples were withdrawn just before 1-min stimulation of DPAG, immediately after (5 or 15 min) and throughout 3 to 27 h following stimulation. In another experiment, samples were withdrawn either before or following a prolonged stimulation (5 min) of the DPAG with flight threshold intensity. Hormones were measured by either chemiluminescent or double-antibody immunoassays. Hormone plasma levels following freezing and flight behaviors were compared to those of resting or restraint-stressed rats. Data show that stress hormones remain unaltered following the DPAG-evoked defensive behaviors. Not even the 5-min stimulation of DPAG with the flight threshold intensity changed corticotropin plasma levels significantly. As far as we known, this is the first demonstration of the lack of stress hormone responses following the intense emotional arousal and physical exertion of a fear-like behavior in rats. Data add new evidence of DPAG involvement in spontaneous panic attacks.     

5-HT1A receptors of the prelimbic cortex mediate the hormonal impact on learned fear expression in high-anxious female rats

Hormones highly influence female behaviors. However, research on this topic has not usually considered the variable hormonal status. The prelimbic cortex (PrL) is commonly engaged in fear learning. Connections from and to this region are known to be critical in regulating anxiety, in which serotonin (5-HT) plays a fundamental role, particularly through changes in 5-HT_1A receptors functioning. Also, hormone fluctuations can greatly influence anxiety in humans and anxiety-related behavior in rodents, and this influence involves the functioning of 5-HT brain systems. The present investigation sought to determine whether fluctuations in ovarian hormones relative to the estrous cycle would influence the expression of learned fear in female rats previously selected as low- (LA) or high-anxious (HA). Furthermore, we investigate the role of the 5-HT system of the PrL, particularly the 5-HT_1A receptors, as a possible modulator of estrous cycle influence on the expression of learned fear through intra-PrL microinjections of 5-HT itself or the full 5-HT_1A agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamine)tetralin). Behavioral changes were assessed using the fear-potentiated startle (FPS) procedure. The results showed that fear intensity is associated with hormonal decay, being more accentuated during the estrus phase. This increase in fear levels was found to be negatively correlated with the expression of potentiated startle. In rats prone to anxiety and tested during the proestrus and estrus phases, 5-HT mechanisms of the PrL seem to play a regulatory role in the expression of learned fear. These results were not replicated in the LA rats. Similar but less intense results were found regarding the early and late diestrus. Our data indicate that future studies on this subject need to take into account the dissociation between low- and high-responsive females to understand how hormones affect emotional behavior.     

Involvement of nitric oxide (NO) in the regulation of stress susceptibility and adaptation in rats

The present study evaluated the regulatory role of nitric oxide (NO) in stress susceptibility and adaptation in rats. Acute restraint stress (RS x1) reduced the number of entries and time spent in the open arms in the elevated plus maze (EPM) test and raised plasma corticosterone levels. RS (x1)-induced neurobehavioral suppression and raised corticosterone levels were attenuated by pretreatment with the NO precursor, L-arginine (500 and 1000 mg/kg)and unaffected or further aggravated by NO synthase inhibitor, L-NAME or 7-nitroindazole (10 and 50 mg/kg). Biochemical assay of plasma and brain homogenates showed that these RS - induced behavioral and neuroendocrinal changes were associated with lowered levels of plasma and brain total nitrates/nitrites (NOx). L-Arginine attenuated the RS-induced suppression of NOx levels in plasma and brain, whereas, the NO synthase inhibitors tended to produce reverse effects. In the experiments involving repeated stress i.e. RS (x5), exposure resulted in attenuation/reversal of (a) neurobehavioral suppression in the EPM test and (b) lowered brain NOx, that was seen after RS (x1). The RS (x5)-induced changes in EPM parameters and brain Nox were further potentiated after L-arginine pretreatment, whereas, the NO synthase inhibitors were less effective. Rats were screened as high and low emotional in the open-field test, and high emotional rats showed greater(a) behavioral suppression in the EPM, (b) corticosterone responses (c) brain NOx suppression, and (d) cold-restraint stress (CRS) induced gastric mucosal lesions as compared to their low emotional counterparts. L-Arginine pretreatment was more effective in modulating the above RS induced stress responses/markers in the high emotional group of rats. Our data suggest that NO plays a differential role during exposure to acute and repeated stress situations, and that the relationship between stress and emotionality status may be under the regulatory influence of NO.     

Mineralocorticoid receptors in control of emotional arousal and fear memory

The stress hormone corticosterone acts via two receptor types in the brain: the mineralocorticoid (MR) and the glucocorticoid receptor (GR). Both receptors are involved in processing of stressful events. A disbalance of MR:GR functions is thought to promote stress-related disorders. Here we studied the effect of stress on emotional and cognitive behaviors in mice with forebrain-specific inactivation of the MR gene (MR^CaMKCre, 4 months old; and control littermates). MR^CaMKCre mice responded to prior stress (5 min of restraint) with higher arousal and less locomotor activity in an exploration task. A fear conditioning paradigm allowed assessing in one experimental procedure both context- and cue-related fear. During conditioning, MR^CaMKCre mice expressed more cue-related freezing. During memory test, contextual freezing remained potentiated, while control mice distinguished between cue (more freezing) and context episodes (less freezing) in the second memory test. At this time, plasma corticosterone levels of MR^CaMKCre mice were 40% higher than in controls. We conclude that control of emotional arousal and adaptive behaviors is lost in the absence of forebrain MR, and thus, anxiety-related responses are and remain augmented. We propose that such a disbalance in MR:GR functions in MR^CaMKCre mice provides the conditions for an animal model for anxiety-related disorders.     

Acute and chronic restraint stress alter the incidence of social conflict in male rats

Stress and elevated stress hormone levels are known to alter cognition, learning, memory, and emotional responses. Three weeks of chronic stress or glucocorticoid exposure is reported to alter neuronal morphology in the hippocampus, the amygdala, and the prefrontal cortex, and to decrease neurogenesis in the dentate gyrus. Here we examine the effects of acute and chronic restraint stress exposure on the incidence of emotional responses throughout a 3-week period among adult rat conspecifics. Our data indicate that acute restraint stress (i.e., a single 6-h exposure) results in a significant reduction in aggressive conflicts among stressed males compared to experimental controls. In contrast, on Days 14 and 21, repeatedly restrained rats exhibited significantly more aggressive behaviors than controls. Blood samples taken 18 h after the last restraint session indicate that plasma concentrations of the stress hormone corticosterone (CORT) in stressed rats were equivalent to those of unstressed rats; however, the number of individually initiated aggressive acts observed positively correlated with plasma CORT measures taken at the end of the study. In contrast to studies of psychosocial stress or intruder paradigms, here we observe spontaneous emotional responses to an uncontrollable stressor in the homecage. This study provides a novel examination of the effects of chronic restraint stress on emotional responses in the home environment among cagemates. These results indicate that acute and chronic restraint stress alter the incidence of aggression, and emphasize the relevance of this model of chronic stress to studies of stress-responsive disorders characterized by aggressive behavior.     

慢性复合应激对大鼠学习记忆功能及脑ERK表达活化的影响

目的：研究慢性复合应激对大鼠学习记忆的影响,以及大脑细胞外信号调节激酶（ERK）表达活化的变化,探讨慢性应激致学习记忆损害的分子机制。方法：采用低温暴露、足电击、白噪声、束缚、尾部悬吊、睡眠剥夺、水平震荡等刺激方式,建立慢性复合应激大鼠模型。Morris水迷宫实验观察应激对学习记忆的影响;放射免疫法检测血清皮质酮（CORT）含量;Western blot检测ERK的表达。结果：应激组大鼠水迷宫训练潜伏期较对照组延长,应激3周时有所恢复,但4周时大鼠的训练潜伏期再次显著延长（P〈0.05）。同时应激组大鼠血清CORT水平增高,海马、前额皮质P-ERK水平降低（P〈0.05）,两者在应激3周时均出现短时恢复,但4周时再次下调。结论：海马、前额皮质ERK蛋白磷酸化水平的改变可能参与了慢性复合应激损害学习记忆的分子机制。     

N-3 PUFA improved post-menopausal depression induced by maternal separation and chronic mild stress through serotonergic pathway in rats—effect associated with lipid mediators

Early life maternal separation (MS) increases the vulnerability to depression in rats with chronic mild stress (CMS). N-3 polyunsaturated fatty acids (PUFA) improved depressive behaviors in rats with acute stress; however, their effects on rats with MS+CMS were not apparent. The purpose of the present study was to investigate the hypothesis that lifetime n-3 PUFA supplementation improves post-menopausal depression through the serotonergic and glutamatergic pathways while modulating n-3 PUFA-derived metabolites. Female rats were fed diets of either 0% n-3 PUFA during lifetime or 1% energy n-3 PUFA during pre-weaning, post-weaning, or lifetime periods. Rats were allocated to non-MS or MS groups and underwent CMS after ovariectomy. N-3 PUFA increased brain n-3 PUFA-derived endocannabinoid/oxylipin levels, and reversed depressive behaviors. N-3 PUFA decreased blood levels of adrenocorticotropic hormone and corticosterone, and brain expressions of corticotropin-releasing factor and miRNA-218, which increased the expression of the glucocorticoid receptor. N-3 PUFA decreased the expression of tumor necrosis factor-α, interleukin (IL)-6, IL-1β, and prostaglandin E₂, while increased the expression of miRNA-155. N-3 PUFA also increased brainstem serotonin levels and hippocampal expression of the serotonin-1A receptor, cAMP response element-binding protein (CREB), phospho-CREB, and brain-derived neurotrophic factor. However, n-3 PUFA did not affect brain expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subtype 1, N-methyl-D-aspartate receptor subtype 2B, or miRNA-132. Moreover, n-3 PUFA exposure during lifetime caused greater effects than pre- and post-weaning periods. The present study suggested that n-3 PUFA improved depressive behaviors through serotonergic pathway while modulating the metabolites of n-3 PUFA in post-menopausal depressed rats with chronic stress.     

Behavioral characterization of P311 knockout mice

P311 is an 8-kDa protein that is expressed in many brain regions, particularly the hippocampus, cerebellum and olfactory lobes, and is under stringent regulation by developmental, mitogenic and other physiological stimuli. P311 is thought to be involved in the transformation and motility of neural cells; however, its role in normal brain physiology is undefined. To address this point, P311-deficient mice were developed through gene targeting and their behaviors were characterized. Mutants displayed no overt abnormalities, bred normally and had normal survival rates. Additionally, no deficiencies were noted in motor co-ordination, balance, hearing or olfactory discrimination. Nevertheless, P311-deficient mice showed altered behavioral responses in learning and memory. These included impaired responses in social transmission of food preference, Morris water maze and contextual fear conditioning. Additionally, mutants displayed altered emotional responses as indicated by decreased freezing in contextual and cued fear conditioning and reduced fear-potentiated startle. Together, these data establish P311 as playing an important role in learning and memory processes and emotional responses.