羟苯磺酸钙与培哚普利对早期糖尿病肾病大鼠的治疗作用比较

观察羟莘磺酸钙和培哚普利对早期糖尿病肾病大鼠肾脏的治疗作用的差别.测定24h尿白蛋白,血浆及肾皮质ET(内皮素,endothelin)舍量,肾皮质PAI-1(纤溶酶原激活物抑制剂-1,plasminogen activator inhibitor-1)、MMp-9(基质金属蛋白酶-9,matrix metalioproteinase-9)表达.观察肾脏病理形态变化.从结果看,羟苯磺酸钙可以减轻实验大鼠肾脏损伤,作用与培哚普利无明显差别.     

贝那普利对糖尿病大鼠肾小管上皮细胞转分化的干预作用

探讨贝那普利对糖尿病大鼠肾小管上皮细胞转分化的干预作用.雄性SD大鼠30只,随机选取8只作为正常对照组(N组),其余22只注射链脲佐菌素(STZ)制作糖尿病模型,并随机分为糖尿病组(DM组)、贝那普利组(B组).12周后测量结果表明,DM组血糖、肾重/体重、24h尿蛋白定量、血肌酐、尿素氮、肾小管-间质损伤指数(TII)均明显高于N组(P＜0.01),B组除血糖、体重外(P＞0.05),其余指标均明显低于DM组(P＜0.01);免疫组化显示DM组肾小管上皮细胞中α-SMA表达明显高于N组(P＜0.01),B组明显低于DM组(P＜0.01);Western Blot显示DM组肾组织α-SMA表达较N组增加3.27倍,B组肾组织α-SMA表达较DM组下降45％.研究显示贝那普利能显著下调糖尿病大鼠肾小管上皮细胞α-SMA的表达,抑制肾小管上皮细胞转分化,从而起到肾脏保护作用.     

隔区或皮质顶叶损毁对大鼠空间认知能力的影响及大鼠搜索策略差异的研究

本研究的目的是探讨隔区或皮质顶叶在大鼠空间认知加工中的作用。实验观察到隔区或皮质顶叶损毁大鼠Morris迷宫学习或记忆作业成绩显著低于控制组,并发现隔区损毁大鼠主要采用与皮质顶叶或控制组不同的“非国类”搜索策略。搜索策略的差异提示:隔区和皮质顶叶在大鼠图认知加工系统中处于不同的功能层次,隔区具有更重要的作用。     

脑内腺苷介导白介素-1β引起的大鼠的行为性抑郁

目的：研究腺苷在白细胞介素-1诱导的大鼠行为性抑郁中的作用。方法：应用Porsolt游泳试验观察大鼠脑室注射白介素-1β引起的行为性抑郁,通过注射非特异性腺苷受体拮抗剂咖啡因和特异性A1和A2腺苷受体拮抗剂,确定脑内腺苷在白细胞介素-1β引起的大鼠行为性抑郁中的作用以及介导这种作用的受体。结果：脑内注射白细胞介素-1β(8-32ng／kg,icv)可导致大鼠在Porsolt游泳试验中漂浮时间明显地延长,非特异性腺苷受体拮抗剂咖啡因(7mg／kg,ip)和特异性A2a腺苷受体拮抗剂(1mg／kg,ip)预处理能够缩短漂浮时间的延长。结论：脑内注射白细胞介素-1β可引起大鼠的行为性抑郁,脑内腺苷通过A2a受体介导白细胞介素-1β的这种作用。     

慢性束缚应激对大鼠脑内Fas、FasL含量的影响

为探讨慢性束缚应激对大鼠脑内不同部位Fas/FasL系统表达的不同影响。将24只雄性SD大鼠随机分为束缚应激组、装置对照组和正常对照组（n=8）。分别对三组大鼠给予相应的干预14天,用Western-blotting方法测定应激后大鼠大脑前脑皮质、内嗅皮质以及海马区域Fas、FasL蛋白含量。结果表明,应激后各脑区三组大鼠Fas含量差异具有统计学意义（p < 0.01）,束缚应激组明显高于正常对照组或装置对照组（p < 0.01）。在海马区域,三组大鼠FasL含量差异具有统计学意义（p < 0.01）,束缚应激组大鼠FasL蛋白水平显著高于正常对照组或装置对照组(p < 0.01)。三组大鼠自身大脑前脑皮质、内嗅皮质以及海马Fas含量的差异比较均无统计学意义( p > 0.05) 。束缚应激组大鼠海马的FasL含量高于前脑皮质和内嗅皮质(p < 0.05);正常对照组或装置对照组自身不同脑区间FasL含量的变化无统计学意义。提示慢性束缚应激能诱导大鼠脑内Fas/FasL系统表达水平的改变,对不同的脑区,其影响程度明显不同     

慢性强迫游泳应激对大鼠情绪和脑细胞外信号调节激酶的影响

为探讨慢性强迫游泳应激对动物情绪和脑组织细胞外信号调节激酶（extracellular signal-regulated kinase, ERK1/2）的影响,动物情绪和脑组织ERK1/2之间的关系,将动物随机分为游泳应激组、装置对照组和控制组。分别对三组大鼠给予相应的干预14天, 然后进行行为观察,免疫印记法测定海马和前脑皮质ERK1/2水平。结果表明强迫游泳应激组和装置对照组都出现明显的情绪障碍。两组大鼠ERK1/2在前脑皮质的表达水平均显著升高,海马无显著变化。前脑皮质ERK2与糖精水摄入量呈显著负相关。提示慢性强迫游泳应激能够诱导大鼠的情绪障碍,提高ERK1/2在前脑皮质的表达水平,ERK1/2与情绪关系密切,可能是脑组织应激性情绪调节的重要生理机制。强迫游泳应激能够导致动物明显的抑郁反应,是比较理想的抑郁动物模型     

中药复方对铅染毒大鼠学习记忆障碍的改善作用

应用行为药理学方法研究铅对大鼠学习记忆影响的可能机制,并观察中药复方（驱铅灵）对铅染毒大鼠学习记忆障碍的改善效果。结果：（1）各染毒组大鼠Morris（第一、二、三、五、七轮）测试潜伏期显著延长;记忆保持百分率显著下降。（2）治疗后中药组的大鼠Morris水迷宫第2、3轮测试潜伏期显著短于阳性对照组,记忆保持率显著大于阳性对照组。（4）EDTA组和中药组。结论：中药复方对铅染毒大鼠学习记忆障碍具有良好的改善作用。     

损毁大鼠双侧内嗅皮质对束缚应激反应的影响

采用大鼠急性束缚应激动物模型,用鹅羔氨酸损毁大鼠双侧内嗅皮质来建立内嗅皮质损伤模型,观察束缚应激1小时后下丘脑室旁核快反应基因c-Fos表达情况以及应激后血浆促肾上腺皮质激素含量的动态变化,并与对照组相比较,探讨内嗅皮质与束缚应激反应的关系。结果表明,损毁内嗅皮质,明显抑制了应激诱导的下丘脑室旁核c-Fos的表达和血浆促肾上腺皮质激素含量的上升。结果提示,内嗅皮质参与调节束缚应激反应时HPA轴功能。     

纳络酮、地卓西平(MK-801)对大鼠食物渴求的影响

实验以条件性位置偏爱（CPP）的表达为渴求模型观察纳络酮及MK-801对大鼠食物CPP表达,探讨摄食行为调控的心理机制。48只SD大鼠分成食物组（24）与对照组（24）,3轮食物匹配训练后,在CPP表达前分别注射生理盐水、纳络酮（1.0 mg˙kg -1）及MK-801(0.1 mg˙kg -1),观察各组动物在食物匹配训练侧停留时间的变化。结果发现,MK-801促进食物CPP的表达,但纳络酮对食物CPP的表达没有显著影响。以上结果表明MK-801（0.1mg˙kg -1）增强动物的食物渴求至少是其增加摄食量的原因之一,而1.0 mg˙kg -1的纳络酮降低动物的摄食量并不是由于食物渴求的下降导致的。MK-801与纳络酮调节动物摄食行为的心理机制可能不一致。     

主动性人格对小学教师工作满意度的影响:一个有调节的中介模型

该研究探讨了主动性人格与小学教师工作满意度的关系,并提出一个有调节的中介模型,考察个人-工作匹配的中介效应和工作-家庭冲突对该效应的调节效应。研究采用主动性人格量表、个人-工作匹配量表、工作-家庭冲突量表和工作满意度量表对8所小学420名教师进行测查,结果表明：（1）主动性人格对个人-工作匹配和工作满意度均有显著的正向预测作用;（2）个人-工作匹配在主动性人格与工作满意度之间起着中介作用;（3）个人-工作匹配与工作满意度的关系（中介效应的后半段路径）受到工作-家庭冲突的调节,即工作-家庭冲突可以降低个人-工作匹配对工作满意度的正向影响。因此,主动性人格和工作满意度之间存在有调节的中介效应。     

Effect of chronic angiotensin converting enzyme inhibition on spatial memory and anxiety-like behaviours in rats

Angiotensin converting enzyme inhibitors (ACEis) are widely used anti-hypertensive agents that are also reported to have positive effects on mood and cognition. The present study examined the influence of the ACEi, perindopril, on cognitive performance and anxiety measures in rats. Two groups of rats were treated orally for one week with the ACEi, perindopril, at doses of 0.1 and 1.0mg/kg/day. Learning was assessed by the reference memory task in the water maze, comparing treated to control rats. Over five training days both perindopril-treated groups learnt the location of the submerged platform in the water maze task significantly faster than control rats. A 60s probe trial on day 6 showed that the 1.0mg/kg/day group spent significantly longer time in the training quadrant than control rats. This improved performance in the swim maze task was not due to the effect of perindopril on motor activity or the anxiety levels of the rats as perindopril-treated and control animals behaved similarly in activity boxes and on the elevated+maze. These results confirm the anecdotal human studies that ACEis have a positive influence on cognition and provide possibilities for ACEis to be developed into therapies for memory loss.     

Intracellular calcium chelation and pharmacological SERCA inhibition of Ca2+ pump in the insular cortex differentially affect taste aversive memory formation and retrieval

Variation in intracellular calcium concentration regulates the induction of long-term synaptic plasticity and is associated with a variety of memory/retrieval and learning paradigms. Accordingly, impaired calcium mobilization from internal deposits affects synaptic plasticity and cognition in the aged brain. During taste memory formation several proteins are modulated directly or indirectly by calcium, and recent evidence suggests the importance of calcium buffering and the role of intracellular calcium deposits during cognitive processes. Thus, the main goal of this research was to study the consequence of hampering changes in cytoplasmic calcium and inhibiting SERCA activity by BAPTA-AM and thapsigargin treatments, respectively, in the insular cortex during different stages of taste memory formation. Using conditioned taste aversion (CTA), we found differential effects of BAPTA-AM and thapsigargin infusions before and after gustatory stimulation, as well as during taste aversive memory consolidation; BAPTA-AM, but not thapsigargin, attenuates acquisition and/or consolidation of CTA, but neither compound affects taste aversive memory retrieval. These results point to the importance of intracellular calcium dynamics in the insular cortex during different stages of taste aversive memory formation.     

The localization over time of exogenous aldosterone and angiotensin II in various organs

Central nervous system effects have been demonstrated for angiotensin II and suggested for aldosterone. In order to determine whether either of these chemicals naturally crosses the blood-brain barrier, radioactive aldosterone and angiotensin II were introduced via intracardiac injections in rats. Samples of blood, liver, kidney, adrenals, cerebral cortex, and hypothalamus were collected at three, 15, and 60 minutes, frozen, dissolved, and counted. Blood levels for aldosterone and angiotensin II remained constant over 60 minutes. Aldosterone accumulated in the liver, kidney, adrenals and hypothalamus three minutes after injection, and levels diminished over time. Angiotensin II levels peaked in the adrenal, kidney, and liver after three minutes, and in the hypothalamus after 15 minutes. Cerebral cortex levels were lower than hypothalamic levels by 30% for aldosterone and 50% for angiotensin II. This suggests that both drugs may enter the central nervous system and selectively accumulate in the hypothalamus.     

Blockade of IP3-mediated SK channel signaling in the rat medial prefrontal cortex improves spatial working memory

Planning and directing thought and behavior require the working memory (WM) functions of prefrontal cortex. WM is compromised by stress, which activates phosphatidylinositol (PI)-mediated IP3-PKC intracellular signaling. PKC overactivation impairs WM operations and in vitro studies indicate that IP3 receptor (IP3R)-evoked calcium release results in SK channel-dependent hyperpolarization of prefrontal neurons. However, the effects of IP3R signaling on prefrontal function have not been investigated. The present findings demonstrate that blockade of IP3R or SK channels in the prefrontal cortex enhances WM performance in rats, suggesting that both arms of the PI cascade influence prefrontal cognitive function.     

Regulation and Mechanism of L-Type Calcium Channel Activation via V1a Vasopressin Receptor Activation in Cultured Cortical Neurons

We have sought to elucidate the biochemical mechanisms that underlie the memory enhancing properties of the neural peptide vasopressin. Toward that goal we have investigated vasopressin induction of calcium signaling cascades, long held to be involved in long-term memory function, in neurons derived from the cerebral cortex, a brain region associated with long-term memory. Our previous studies demonstrated that in cultured cortical neurons, V1a vasopressin receptor (V1aR) activation resulted in a sustained rise in intracellular calcium concentration that was dependent on calcium influx (Son & Brinton, 1998). To investigate the mechanism of V1aR-induced calcium influx, we investigated V1aR activation of the calcium channel subtype(s) in cortical neurons cultured from Sprague-Dawley rat embryonic day 18 fetuses. The results of these analyses demonstrated that the L-type calcium channel blocker nifedipine blocked 250 nM V1 vasopressin receptor agonist (V1 agonist)-induced calcium influx. Intracellular calcium imaging analyses using fura-2AM demonstrated that blockade of L-type calcium channels prevented the 250 nM V1 agonist-induced rise in intracellular calcium concentration. These results indicate that the influx of extracellular calcium via L-type calcium channels is an essential step in the initiation of the V1 agonist-induced rise in intracellular calcium concentration. To determine the mechanism of V1aR activation of L-type calcium channels, regulatory components of the phosphatidylinositol signaling pathway were investigated. The results of these analyses demonstrated that V1 agonist-induced calcium influx was blocked by both a phospholipase C inhibitor (U-73122) and a protein kinase C inhibitor (bisindolylmaleimide I). Further analysis of V1aR activation of protein kinase C (PKC) demonstrated that V1 agonist induced PKC activity within 1 min of exposure in cultured cortical neurons. These data indicate that in cultured cortical neurons, V1aR activation regulates the influx of extracellular calcium via L-type calcium channel activation through a protein kinase-C-dependent mechanism. The results of these studies provide biochemical mechanisms by which vasopressin could enhance memory function. Those mechanisms include a complex cascade that is initiated by activation of the phosphatidylinositol pathway, activation of protein kinase C, followed by phosphorylation of L-type calcium channels to initiate the influx of extracellular calcium to activate a cascade of calcium-dependent release of intracellular calcium.     

Short- and long-term memory are differentially affected by metabolic inhibitors given into hippocampus and entorhinal cortex

Rats were implanted with cannulae in the CA1 area of the dorsal hippocampus or in the entorhinal cortex and trained in one-trial step-down inhibitory avoidance. Two retention tests were carried out in each animal, one at 1.5 h to measure short-term memory (STM) and another at 24 h to measure long-term memory (LTM). The purpose of the present study was to screen the effect on STM of various drugs previously shown to affect LTM of this task when given posttraining at the same doses that were used here. The drugs and doses were the guanylyl cyclase inhibitor LY83583 (LY, 2.5 microMg), the inhibitor of Tyr-protein kinase at low concentrations and of protein kinase G (PKG) at higher concentrations lavendustin A (LAV, 0.1 and 0.5 microMg), the PKG inhibitor KT5823 (2.0 microMg), the protein kinase C (PKC) inhibitor staurosporin (STAU, 2.5 microMg), the inhibitor of calcium/ calmodulin protein kinase II (CaMKII) KN62 (3.6 microMg), the protein kinase A (PKA) inhibitor KT5720 (0.5 microMg), and the mitogen-activated protein kinase kinase (MAPKK) inhibitor PD098059 (PD, 0.05 microMg). PD was dissolved in saline; all the other drugs were dissolved in 20% dimethyl sulfoxide. In all cases the drugs affected LTM as had been described in previous papers. The drugs affected STM and LTM differentially depending on the brain structure into which they were infused. STM was inhibited by KT5720, LY, and PD given into CA1 and by STAU and KT5720 given into the entorhinal cortex. PD given into the entorhinal cortex enhanced STM. LTM was inhibited by STAU, KN62, KT5720, KT5823, and LAV (0.5 microMg) given into CA1 and by STAU, KT5720, and PD given into the entorhinal cortex. The results suggest that STM and LTM involve different physiological mechanisms but are to an extent linked. STM appears to require PKA, guanylyl cyclase, and MAPKK activity in CA1 and PKA and PKC activity in the entorhinal cortex; MAPKK seems to play an inhibitory role in STM in the entorhinal cortex. In contrast, LTM appears to require PKA and PKC activity in both structures, guanylyl cyclase, PKG, and CaMKII activity in CA1, and MAPKK activity in the entorhinal cortex.     

A model of bidirectional synaptic plasticity: from signaling network to channel conductance

In many regions of the brain, including the mammalian cortex, the strength of synaptic transmission can be bidirectionally regulated by cortical activity (synaptic plasticity). One line of evidence indicates that long-term synaptic potentiation (LTP) and long-term synaptic depression (LTD), correlate with the phosphorylation/dephosphorylation of sites on the alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit protein GluR1. Bidirectional synaptic plasticity can be induced by different frequencies of presynaptic stimulation, but there is considerable evidence indicating that the key variable is calcium influx through postsynaptic N-methyl-d-aspartate (NMDA) receptors. Here, we present a biophysical model of bidirectional synaptic plasticity based on [Ca2+]-dependent phospho/dephosphorylation of the GluR1 subunit of the AMPA receptor. The primary assumption of the model, for which there is wide experimental support, is that the postsynaptic calcium concentration, and consequent activation of calcium-dependent protein kinases and phosphatases, is the trigger for phosphorylation/dephosphorylation at GluR1 and consequent induction of LTP/LTD. We explore several different mathematical approaches, all of them based on mass-action assumptions. First, we use a first order approach, in which transition rates are functions of an activator, in this case calcium. Second, we adopt the Michaelis-Menten approach with different assumptions about the signal transduction cascades, ranging from abstract to more detailed and biologically plausible models. Despite the different assumptions made in each model, in each case, LTD is induced by a moderate increase in postsynaptic calcium and LTP is induced by high Ca2+ concentration.     

Molecular activity underlying working memory

The prefrontal cortex is necessary for directing thought and planning action. Working memory, the active, transient maintenance of information in mind for subsequent monitoring and manipulation, lies at the core of many simple, as well as high-level, cognitive functions. Working memory has been shown to be compromised in a number of neurological and psychiatric conditions and may contribute to the behavioral and cognitive deficits associated with these disorders. It has been theorized that working memory depends upon reverberating circuits within the prefrontal cortex and other cortical areas. However, recent work indicates that intracellular signals and protein dephosphorylation are critical for working memory. The present article will review recent research into the involvement of the modulatory neurotransmitters and their receptors in working memory. The intracellular signaling pathways activated by these receptors and evidence that indicates a role for G(q)-initiated PI-PLC and calcium-dependent protein phosphatase calcineurin activity in working memory will be discussed. Additionally, the negative influence of calcium- and cAMP-dependent protein kinase (i.e., calcium/calmodulin-dependent protein kinase II (CaMKII), calcium/diacylglycerol-activated protein kinase C (PKC), and cAMP-dependent protein kinase A (PKA)) activities on working memory will be reviewed. The implications of these experimental findings on the observed inverted-U relationship between D(1) receptor stimulation and working memory, as well as age-associated working memory dysfunction, will be presented. Finally, we will discuss considerations for the development of clinical treatments for working memory disorders.     

A role for prefrontal calcium-sensitive protein phosphatase and kinase activities in working memory

The prefrontal cortex is involved in the integration and interpretation of information for directing thoughts and planning action. Working memory is defined as the active maintenance of information in mind and is thought to lie at the core of many prefrontal functions. Although dopamine and other neurotransmitters have been implicated, the intracellular events activated by their receptors that influence working memory are poorly understood. We demonstrate that working memory involves transient changes in prefrontal G(q/11)-signaling and in calcium-dependent intracellular protein phosphatase and kinase activity. Interestingly, inhibition of the calcium activated phosphatase calcineurin impaired, while calcium/calmodulin dependent kinase II (CaMKII) and calcium-dependent protein kinase C (PKC) enhanced, working memory. Our findings suggest that the active maintenance of information required for working memory involves transient changes in the balance of these enzymes' activities.     

Conditional forebrain deletion of the L-type calcium channel Ca V 1.2 disrupts remote spatial memories in mice

To determine whether L-type voltage-gated calcium channels (L-VGCCs) are required for remote memory consolidation, we generated conditional knockout mice in which the L-VGCC isoform Ca(V)1.2 was postnatally deleted in the hippocampus and cortex. In the Morris water maze, both Ca(V)1.2 conditional knockout mice (Ca(V)1.2(cKO)) and control littermates displayed a marked decrease in escape latencies and performed equally well on probe trials administered during training. In distinct contrast to their performance during training, Ca(V)1.2(cKO) mice exhibited significant impairments in spatial memory when examined 30 d after training, suggesting that Ca(V)1.2 plays a critical role in consolidation of remote spatial memories.