内源性阿片物质可调制胆囊收缩素所致的胰岛素释放

近年来,人们感兴趣的内源性阿片样物质(如脑啡肽、β-内啡肽等),不仅存在于中枢神经系统,而且也分布在胃肠胰内。最近,在人和狗身上发现,这些内源性阿片物质参与进食后对胰腺内分泌功能的调节。由于胃肠激素(例如CCK)可由于饭后胃肠道内的营养物质刺激而释放,并参与胰腺内分泌功能的调节,因此,在CCK与内源性阿片物质之间就可能存在着某种相互作用。     

小脑间位核和顶核对下丘脑外侧区神经元电活动的影响

电刺激猫小脑问位核和顶核可以影响下丘脑外侧区神经元的电活动,其中有一些神经元是葡萄糖敏感神经元.这一结果揭示小脑不仅具有经典的躯体运动调节功能,同时也可以通过小脑-下丘脑通路参与机体非躯体活动的调节.     

阿片类物质在中枢神经系统的免疫调控作用

内源及外源性阿片具有调节神经元与胶质细胞的功能,这些调节具有保护或损伤脑功能的双重作用。吗啡具有促进受病毒复制及继发感染的作用。另一方面,阿片受体中的ｋａｐｐａ受体可能具有保护神经元的作用。更深层次的研究应是了解阿片通过什么机制作用在胶质细胞和神经元上,藉此以促进研制出具有明显疗效的新药。     

抑制炎症大鼠前列腺素合成致阿片介导的痛觉减退北大核心CSCD

本研究旨在探讨前列腺素在炎性痛维持中的作用。大鼠右侧足跖皮下注射角叉菜胶1 h后,于炎症局部注射环氧合酶非选择性抑制剂吲哚美锌,测定大鼠对伤害性热刺激的缩足反射潜伏期(paw withdrawal latency,PWL)。用免疫组织化学、ELISA和RT-PCR方法检测炎症组织中β-内啡肽(β-END)和μ-阿片受体(μopioid receptor,MOR)的表达。结果显示,吲哚美锌能够剂量依赖性地延长大鼠在第2天和第3天的PWL,显著超过正常基础值,产生痛觉减退;吲哚美锌痛觉减退作用可被阿片受体非选择性抑制剂纳洛酮所翻转;吲哚美锌可显著提高模型大鼠炎症组织内β-END阳性细胞数量、β-END蛋白含量及MOR m RNA表达水平。本研究揭示了前列腺素致痛的新机制,即抑制炎症引起的内源性阿片活动,为开发以抑制外周炎症组织前列腺素为目标的镇痛药提供了新的理论依据。     

抑制炎症大鼠前列腺素合成致阿片介导的痛觉减退

本研究旨在探讨前列腺素在炎性痛维持中的作用。大鼠右侧足跖皮下注射角叉菜胶1 h后,于炎症局部注射环氧合酶非选择性抑制剂吲哚美锌,测定大鼠对伤害性热刺激的缩足反射潜伏期(paw withdrawal latency,PWL)。用免疫组织化学、ELISA和RT-PCR方法检测炎症组织中β-内啡肽(β-END)和μ-阿片受体(μopioid receptor,MOR)的表达。结果显示,吲哚美锌能够剂量依赖性地延长大鼠在第2天和第3天的PWL,显著超过正常基础值,产生痛觉减退;吲哚美锌痛觉减退作用可被阿片受体非选择性抑制剂纳洛酮所翻转;吲哚美锌可显著提高模型大鼠炎症组织内β-END阳性细胞数量、β-END蛋白含量及MOR m RNA表达水平。本研究揭示了前列腺素致痛的新机制,即抑制炎症引起的内源性阿片活动,为开发以抑制外周炎症组织前列腺素为目标的镇痛药提供了新的理论依据。     

植物微管结合蛋白的研究进展

微管结合蛋白是一类能够特异地与微管结合, 参与调节微管结构与功能的结合蛋白。目前已经鉴定出多种植物微管结合蛋白, 并对其结构及功能进行了深入研究。本文综述了植物微管结合蛋白——剑蛋白、MAP65、MAPEB1、MOR1、SPR 和WVD2的最新研究进展。     

植物微管结合蛋白的研究进展

微管结合蛋白是一类能够特异地与微管结合,参与调节微管结构与功能的结合蛋白。目前已经鉴定出多种植物微管结合蛋白,并对其结构及功能进行了深人研究。本文综述了植物微管结合蛋白——剑蛋白、MAP65、MAPEB1、MOR1、SPR和WVD2的最新研究进展。     

小脑皮质结构年龄相关变化的研究进展

衰老过程中小脑皮质出现明显的形态学变化,包括体积萎缩、重量减轻、皮层厚度下降、神经元数量减少,树突丢失、细胞超微结构改变、神经递质紊乱以及胶质细胞增生等。神经元数量丢失与结构退变以及神经递质改变可能会导致老年小脑皮质神经环路破坏和信息传输紊乱,与老年个体运动调节功能及运动学习能力下降有关;神经胶质活动增强对维持老年小脑皮质的形态和功能可能起保护作用。     

小脑间位核对淋巴细胞功能的调节作用

目的:研究小脑深部核团之一间位核对淋巴细胞功能的调节作用,以拓宽对小脑功能的认识进而增加神经免疫学的知识.方法:在大鼠双侧小脑间位核内注射海人酸(KA)以损毁间位核内神经元的胞体,并设对照组,于小脑间位核内注入等量生理盐水.在手术后的第8、16、32 d分别用血细胞计数法检测动物外周血中淋巴细胞的数量;用四甲基偶氮唑(MTT)比色法检测动物肠系膜淋巴结细胞对刀豆蛋白A(Con A)刺激的增殖反应;用ELISA法检测动物血清中抗绵羊红细胞(SRBC)特异性IgM抗体的生成能力;用流式细胞术测定脾脏自然杀伤(NK)细胞的活性.结果:小脑间位核损毁后的第8、16、32 d,动物外周血中淋巴细胞数都明显低于损毁手术前的淋巴细胞数,也显著低于生理盐水对照组相应时间段的淋巴细胞数.在小脑间位核注射KA后的第8、16、32 d,动物的肠系膜淋巴结细胞由Con A诱导的增殖反应、血清中特异性抗SRBC IgM抗体的生成能力和脾脏NK细胞杀伤靶细胞YAC-1的活性均明显低于生理盐水对照组,但比较损毁后不同时间段的T、B和NK细胞功能的变化,没有发现显著的差异.结论:小脑双侧间位核损毁可导致总淋巴细胞数以及T、B和NK细胞功能均发生不可逆的降低,充分说明小脑间位核可调节淋巴细胞的功能,并提示在正常体内,小脑间位核对淋巴细胞功能具有增强效应.     

阿片受点与腺苷酸环化酶

本文简要介绍了阿片受点与腺苷酸环化酶之间关系的研究近况及主要观点.虽然仍有一些矛盾的结果,但大量材料支持阿片受点与腺苷酸环化酶偶联,发挥对此酶的抑制性调节.并且对阿片受点与酶之间的偶联因子(G/F蛋白)的作用做了简单介绍.杂交瘤细胞已广泛应用于阿片受点研究,并能在这种细胞上充分证实阿片受点与环化酶的偶联;但问题的最终解决,仍取决于正常脑组织的实验结果.     

mGluR1-Mediated Excitation of Cerebellar GABAergic Interneurons Requires Both G Protein-Dependent and Src–ERK1/2-Dependent Signaling Pathways

Stimulation of type I metabotropic glutamate receptors (mGluR1/5) in several neuronal types induces slow excitatory responses through activation of transient receptor potential canonical (TRPC) channels. GABAergic cerebellar molecular layer interneurons (MLIs) modulate firing patterns of Purkinje cells (PCs), which play a key role in cerebellar information processing. MLIs express mGluR1, and activation of mGluR1 induces an inward current, but its precise intracellular signaling pathways are unknown. We found that mGluR1 activation facilitated spontaneous firing of mouse cerebellar MLIs through an inward current mediated by TRPC1 channels. This mGluR1-mediated inward current depends on both G protein-dependent and -independent pathways. The nonselective protein tyrosine kinase inhibitors genistein and AG490 as well as the selective extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitors PD98059 and SL327 suppressed the mGluR1-mediated current responses. Following G protein blockade, the residual mGluR1-mediated inward current was significantly reduced by the selective Src tyrosine kinase inhibitor PP2. In contrast to cerebellar PCs, GABA_B receptor activation in MLIs did not alter the mGluR1-mediated inward current, suggesting that there is no cross-talk between mGluR1 and GABA_B receptors in MLIs. Thus, activation of mGluR1 facilitates firing of MLIs through the TRPC1-mediated inward current, which depends on not only G protein-dependent but also Src–ERK1/2-dependent signaling pathways, and consequently depresses the excitability of cerebellar PCs.     

Synaptic responses evoked by tactile stimuli in Purkinje cells in mouse cerebellar cortex Crus II in vivo

Background

Sensory stimuli evoke responses in cerebellar Purkinje cells (PCs) via the mossy fiber-granule cell pathway. However, the properties of synaptic responses evoked by tactile stimulation in cerebellar PCs are unknown. The present study investigated the synaptic responses of PCs in response to an air-puff stimulation on the ipsilateral whisker pad in urethane-anesthetized mice.

Methods and Main Results

Thirty-three PCs were recorded from 48 urethane-anesthetized adult (6–8-week-old) HA/ICR mice by somatic or dendritic patch-clamp recording and pharmacological methods. Tactile stimulation to the ipsilateral whisker pad was delivered by an air-puff through a 12-gauge stainless steel tube connected with a pressurized injection system. Under current-clamp conditions (I = 0), the air-puff stimulation evoked strong inhibitory postsynaptic potentials (IPSPs) in the somata of PCs. Application of SR95531, a specific GABA_A receptor antagonist, blocked IPSPs and revealed stimulation-evoked simple spike firing. Under voltage-clamp conditions, tactile stimulation evoked a sequence of transient inward currents followed by strong outward currents in the somata and dendrites in PCs. Application of SR95531 blocked outward currents and revealed excitatory postsynaptic currents (EPSCs) in somata and a temporal summation of parallel fiber EPSCs in PC dendrites. We also demonstrated that PCs respond to both the onset and offset of the air-puff stimulation.

Conclusions

These findings indicated that tactile stimulation induced asynchronous parallel fiber excitatory inputs onto the dendrites of PCs, and failed to evoke strong EPSCs and spike firing in PCs, but induced the rapid activation of strong GABA_A receptor-mediated inhibitory postsynaptic currents in the somata and dendrites of PCs in the cerebellar cortex Crus II in urethane-anesthetized mice.     

Modulation of the dynamics of cerebellar Purkinje cells through the interaction of excitatory and inhibitory feedforward pathways

The dynamics of cerebellar neuronal networks is controlled by the underlying building blocks of neurons and synapses between them. For which, the computation of Purkinje cells (PCs), the only output cells of the cerebellar cortex, is implemented through various types of neural pathways interactively routing excitation and inhibition converged to PCs. Such tuning of excitation and inhibition, coming from the gating of specific pathways as well as short-term plasticity (STP) of the synapses, plays a dominant role in controlling the PC dynamics in terms of firing rate and spike timing. PCs receive cascade feedforward inputs from two major neural pathways: the first one is the feedforward excitatory pathway from granule cells (GCs) to PCs; the second one is the feedforward inhibition pathway from GCs, via molecular layer interneurons (MLIs), to PCs. The GC-PC pathway, together with short-term dynamics of excitatory synapses, has been a focus over past decades, whereas recent experimental evidence shows that MLIs also greatly contribute to controlling PC activity. Therefore, it is expected that the diversity of excitation gated by STP of GC-PC synapses, modulated by strong inhibition from MLI-PC synapses, can promote the computation performed by PCs. However, it remains unclear how these two neural pathways are interacted to modulate PC dynamics. Here using a computational model of PC network installed with these two neural pathways, we addressed this question to investigate the change of PC firing dynamics at the level of single cell and network. We show that the nonlinear characteristics of excitatory STP dynamics can significantly modulate PC spiking dynamics mediated by inhibition. The changes in PC firing rate, firing phase, and temporal spike pattern, are strongly modulated by these two factors in different ways. MLIs mainly contribute to variable delays in the postsynaptic action potentials of PCs while modulated by excitation STP. Notably, the diversity of synchronization and pause response in the PC network is governed not only by the balance of excitation and inhibition, but also by the synaptic STP, depending on input burst patterns. Especially, the pause response shown in the PC network can only emerge with the interaction of both pathways. Together with other recent findings, our results show that the interaction of feedforward pathways of excitation and inhibition, incorporated with synaptic short-term dynamics, can dramatically regulate the PC activities that consequently change the network dynamics of the cerebellar circuit.     

Electrophysiological Representation of Scratching CPG Activity in the Cerebellum

We analyzed the electrical activity of neuronal populations in the cerebellum and the lumbar spinal cord during fictive scratching in adult decerebrate cats before and after selective sections of the Spino-Reticulo Cerebellar Pathway (SRCP) and the Ventral-Spino Cerebellar Tract (VSCT). During fictive scratching, we found a conspicuous sinusoidal electrical activity, called Sinusoidal Cerebellar Potentials (SCPs), in the cerebellar vermis, which exhibited smaller amplitude in the paravermal and hemisphere cortices. There was also a significant spino-cerebellar coherence between these SCPs and the lumbar sinusoidal cord dorsum potentials (SCDPs). However, during spontaneous activity such spino-cerebellar coherence between spontaneous potentials recorded in the same regions decreased. We found that the section of the SRCP and the VSCT did not abolish the amplitude of the SCPs, suggesting that there are additional pathways conveying information from the spinal CPG to the cerebellum. This is the first evidence that the sinusoidal activity associated to the spinal CPG circuitry for scratching has a broad representation in the cerebellum beyond the sensory representation from hindlimbs previously described. Furthermore, the SCPs represent the global electrical activity of the spinal CPG for scratching in the cerebellar cortex.     

Functional origins of the vertebrate cerebellum from a sensory processing antecedent

The structure of the cerebellar cortex is remarkably similar across vertebrate phylogeny. It is well developed in basaljawed fishes, such as sharks and rays with many of the same cell types and organizational features found in other vertebrategroups, including mammals. In particular, the lattice-like organization of cerebellar cortex (with a molecular layer of parallel fibres,interneurons, spiny Purkinje cell dendrites, and climbing fires) is a common defining characteristic. In addition to the cerebell...     

The Output Signal of Purkinje Cells of the Cerebellum and Circadian Rhythmicity

Measurement of clock gene expression has recently provided evidence that the cerebellum, like the master clock in the SCN, contains a circadian oscillator. The cerebellar oscillator is involved in anticipation of mealtime and possibly resides in Purkinje cells. However, the rhythmic gene expression is likely transduced into a circadian cerebellar output signal to exert an effective control of neuronal brain circuits that are responsible for feeding behavior. Using electrophysiological recordings from acute and organotypic cerebellar slices, we tested the hypothesis whether Purkinje cells transmit a circadian modulated signal to their targets in the brain. Extracellular recordings from brain slices revealed the typical discharge pattern previously described in vivo in single cell recordings showing basically a tonic or a trimodal-like firing pattern. However, in acute sagittal cerebellar slices the average spike rate of randomly selected Purkinje cells did not exhibit significant circadian variations, irrespective of their specific firing pattern. Also, frequency and amplitude of spontaneous inhibitory postsynaptic currents and the amplitude of GABA- and glutamate-evoked currents did not vary with circadian time. Long-term recordings using multielectrode arrays (MEA) allowed to monitor neuronal activity at multiple sites in organotypic cerebellar slices for several days to weeks. With this recording technique we observed oscillations of the firing rate of cerebellar neurons, presumably of Purkinje cells, with a period of about 24 hours which were stable for periods up to three days. The daily renewal of culture medium could induce circadian oscillations of the firing rate of Purkinje cells, a feature that is compatible with the behavior of slave oscillators. However, from the present results it appears that the circadian expression of cerebellar clock genes exerts only a weak influence on the electrical output of cerebellar neurons.     

Spontaneous spiking and synaptic depression underlie noradrenergic control of feed-forward inhibition

Inhibitory interneurons across diverse brain regions commonly exhibit spontaneous spiking activity, even in the absence of external stimuli. It is not well understood how stimulus-evoked inhibition can be distinguished from background inhibition arising from spontaneous firing. We found that noradrenaline simultaneously reduced spontaneous inhibitory inputs and enhanced evoked inhibitory currents recorded from principal neurons of the mouse dorsal cochlear nucleus (DCN). Together, these effects produced a large increase in signal-to-noise ratio for stimulus-evoked inhibition. Surprisingly, the opposing effects on background and evoked currents could both be attributed to noradrenergic silencing of spontaneous spiking in glycinergic interneurons. During spontaneous firing, glycine release was decreased due to strong short-term depression. Elimination of background spiking relieved inhibitory synapses from depression and thereby enhanced stimulus-evoked inhibition. Our findings illustrate a simple yet powerful neuromodulatory mechanism to shift the balance between background and stimulus-evoked signals.     

Identification of an inhibitory circuit that regulates cerebellar Golgi cell activity

Here we provide evidence that revises the inhibitory circuit diagram of the cerebellar cortex. It was previously thought that Golgi cells, interneurons that are the sole source of inhibition onto granule cells, were exclusively coupled via gap junctions. Moreover, Golgi cells were believed to receive GABAergic inhibition from molecular layer interneurons (MLIs). Here we challenge these views by optogenetically activating the cerebellar circuitry to determine the timing and pharmacology of inhibition onto Golgi cells and by performing paired recordings to directly assess synaptic connectivity. In contrast to current thought, we find that Golgi cells, not MLIs, make inhibitory GABAergic synapses onto other Golgi cells. As a result, MLI feedback does not regulate the Golgi cell network, and Golgi cells are inhibited approximately 2?ms before Purkinje cells, following a mossy fiber input. Hence, Golgi cells and Purkinje cells receive unique sources of inhibition and can differentially process shared granule cell inputs.     

Distribution and morphology of ghrelin-immunopositive cells in the cerebellum of the African ostrich

Ghrelin, the endogenous ligand for the growth hormone secretagogue receptor, has been found in the cerebellum of many vertebrates and in the gastrointestinal tract of African ostrich chicks, but little is known about its distribution in the cerebellum of the African ostrich. In the present study, the distribution and morphological characteristics of ghrelin-producing cells in the cerebellum of the African ostrich were investigated using immunohistochemistry. The results indicate that the cerebellum is divided into two sections: the outer cerebellar cortex and the inner medulla of cerebellum. The cerebellar cortex comprises a molecular layer, a Purkinje cell layer and a granular layer; ghrelin-immunopositive (ghrelin-ip) cells were localized throughout the entire cerebellum, but sparsely in the medulla. The greatest number of ghrelin-ip cells was found in the stratum granulosum, and the density decreased gradually from the molecular layer to the Purkinje cell layer in the cerebellar cortex. The ghrelin-ip cells were fusiform or irregular polygons and their cytoplasm was stained intensely. These results clearly demonstrate the presence of ghrelin-ip cells in the cerebellum of the African ostrich. It is speculated that ghrelin may have a physiological function in the cerebellum.