Motion-sensitive neurones in V5/MT modulate perceived spatial position

Until recently, it was widely believed that object position and object motion were represented independently in the visual cortex. However, several studies have shown that adaptation to motion produces substantial shifts in the perceived position of subsequently viewed stationary objects. Two stages of motion adaptation have been proposed: an initial stage at the level of V1 and a secondary stage thought to be located in V5/MT. Indeed, selective adaptation can be demonstrated at each of these levels of motion analysis. What remains unknown is which of these cortical sites are involved in modulating the positional representation of subsequently viewed objects. To answer this question directly, we disrupted cortical activity by using transcranial magnetic stimulation (TMS) immediately after motion adaptation. When TMS was delivered to V5/MT after motion adaptation, the perceived offset of the test stimulus was greatly reduced. In marked contrast, TMS of V1 had no effect on the changes that normally occur in perceived position after motion adaptation. This result demonstrates that the anatomical locus at which motion and positional information interact is area V5/MT rather than V1/V2.     

Defining the V5/MT neuronal pool for perceptual decisions in a visual stereo-motion task

In the primate visual cortex, neurons signal differences in the appearance of objects with high precision. However, not all activated neurons contribute directly to perception. We defined the perceptual pool in extrastriate visual area V5/MT for a stereo-motion task, based on trial-by-trial co-variation between perceptual decisions and neuronal firing (choice probability (CP)). Macaque monkeys were trained to discriminate the direction of rotation of a cylinder, using the binocular depth between the moving dots that form its front and rear surfaces. We manipulated the activity of single neurons trial-to-trial by introducing task-irrelevant stimulus changes: dot motion in cylinders was aligned with neuronal preference on only half the trials, so that neurons were strongly activated with high firing rates on some trials and considerably less activated on others. We show that single neurons maintain high neurometric sensitivity for binocular depth in the face of substantial changes in firing rate. CP was correlated with neurometric sensitivity, not level of activation. In contrast, for individual neurons, the correlation between perceptual choice and neuronal activity may be fundamentally different when responding to different stimulus versions. Therefore, neuronal pools supporting sensory discrimination must be structured flexibly and independently for each stimulus configuration to be discriminated.This article is part of the themed issue ‘Vision in our three-dimensional world''.     

A Neural Mechanism for Time-Window Separation Resolves Ambiguity of Adaptive Coding

The senses of animals are confronted with changing environments and different contexts. Neural adaptation is one important tool to adjust sensitivity to varying intensity ranges. For instance, in a quiet night outdoors, our hearing is more sensitive than when we are confronted with the plurality of sounds in a large city during the day. However, adaptation also removes available information on absolute sound levels and may thus cause ambiguity. Experimental data on the trade-off between benefits and loss through adaptation is scarce and very few mechanisms have been proposed to resolve it. We present an example where adaptation is beneficial for one task—namely, the reliable encoding of the pattern of an acoustic signal—but detrimental for another—the localization of the same acoustic stimulus. With a combination of neurophysiological data, modeling, and behavioral tests, we show that adaptation in the periphery of the auditory pathway of grasshoppers enables intensity-invariant coding of amplitude modulations, but at the same time, degrades information available for sound localization. We demonstrate how focusing the response of localization neurons to the onset of relevant signals separates processing of localization and pattern information temporally. In this way, the ambiguity of adaptive coding can be circumvented and both absolute and relative levels can be processed using the same set of peripheral neurons.     

A Possible Role of Translation Ambiguity in Gene Evolution (A Hypothesis)

A hypothesis is put forward that the variability of translation machinery is one of the key factors of evolutionary transformations of genetic material. It considers the module principle of the evolution theory based on the concepts of duplication and divergence of genetic material, which is required for origination of new genes and proteins with new functions. The duplication results in the appearance of pseudogenes, functionally inactive, but serving a material for creating new functions. The possible mechanisms changing the translation machinery have been considered, which may lead to sporadic pseudogene activation supplying natural selection with mutational changes accumulated by pseudogenes to assess their adaptive value. This takes into account not only potential possibilities of mutational variability of the translation machinery, but also the possibility of protein prionization: also considered is a prion mechanism of inheritance, which is intensely studied nowadays.     

Orexin能神经元在依托咪脂麻醉中的促觉醒作用

目的:观察orexin能神经元在依托咪脂麻醉中的促觉醒作用。方法:选择雄性SD大鼠36只,体重230～250g。将18只SD大鼠随机分为脂肪乳剂组(60 mg·kg~(-1)·h~(-1)),依托咪脂麻醉(50 mg·kg~(-1)·h~(-1))30 min组和60 min组(每组n=6),用放射免疫法检测3组大鼠血浆中orexin含量;3天后,将脂肪乳剂组大鼠颈椎脱臼处死后灌注取脑,另外两组在依托咪脂麻醉下灌注取脑,采用免疫荧光双标染色,分别观察3组大鼠orexin神经元活性。另取18只SD大鼠随机分为乳酸林格氏液组,orexin-A 30 pmol组和100pmol组(每组n=6),记录大鼠翻正反射消失时间为麻醉诱导时间及翻正反射恢复时间为觉醒时间。结果:与脂肪乳剂组相比,依托咪脂麻醉30 min和60 min后,血浆orexin-A含量下降(P0.05),有活性的orexin神经元数目减少(P0.01);与依托咪脂麻醉30 min组相比,60 min组有活性的orexin神经元数目减少(P0.05),但血浆orexin-A含量与30 min组无差异(P0.05);与乳酸林格氏溶液组相比,基底前脑区微注射orexin-A 30 pmol或100 pmol对麻醉诱导无影响,但能显著缩短依托咪脂麻醉觉醒时间(P0.05,P0.01);但orexin-A 30 pmol组和100 pmol组诱导和觉醒时间比较均无统计学差异(P0.05)。结论:依托咪脂麻醉抑制大鼠下丘脑orexin神经元的活性,orexin-A对依托咪脂麻醉具有促觉醒作用。     

Role of cell surface metalloprotease MT1-MMP in epithelial cell migration over laminin-5

Laminin-5 (Ln-5) is an extracellular matrix substrate for cell adhesion and migration, which is found in many epithelial basement membranes. Mechanisms eliciting migration on Ln-5 need to be elucidated because of their relevance to tissue remodeling and cancer metastasis. We showed that exogenous addition of activated matrix metalloprotease (MMP) 2 stimulates migration onto Ln-5 in breast epithelial cells via cleavage of the gamma2 subunit. To investigate the biological scope of this proteolytic mechanism, we tested a panel of cells, including colon and breast carcinomas, hepatomas, and immortalized hepatocytes, selected because they migrated or scattered constitutively in the presence of Ln-5. We found that constitutive migration was inhibited by BB94 or TIMPs, known inhibitors of MMPs. Limited profiling by gelatin zymography and Western blotting indicated that the ability to constitutively migrate on Ln-5 correlated with expression of plasma membrane bound MT1-MMP metalloprotease, rather than secretion of MMP2, since MMP2 was not produced by three cell lines (one breast and two colon carcinomas) that constitutively migrated on Ln-5. Moreover, migration on Ln-5 was reduced by MT1-MMP antisense oligonucleotides both in MMP2+ and MMP2- cell lines. MT1-MMP directly cleaved Ln-5, with a pattern similar to that of MMP2. The hemopexin-like domain of MMP2, which interferes with MMP2 activation, reduced Ln-5 migration in MT1-MMP+, MMP2+ cells, but not in MT1-MMP+, MMP2- cells. These results suggest a model whereby expression of MT1-MMP is the primary trigger for migration over Ln-5, whereas MMP2, which is activated by MT1-MMP, may play an ancillary role, perhaps by amplifying the MT1-MMP effects. Codistribution of MT1-MMP with Ln-5 in colon and breast cancer tissue specimens suggested a role for this mechanism in invasion. Thus, Ln-5 cleavage by MMPs may be a widespread mechanism that triggers migration in cells contacting epithelial basement membranes.     

Lmo Mutants Reveal a Novel Role for Circadian Pacemaker Neurons in Cocaine-Induced Behaviors

Drosophila has been developed recently as a model system to investigate the molecular and neural mechanisms underlying responses to drugs of abuse. Genetic screens for mutants with altered drug-induced behaviors thus provide an unbiased approach to define novel molecules involved in the process. We identified mutations in the Drosophila LIM-only (LMO) gene, encoding a regulator of LIM-homeodomain proteins, in a genetic screen for mutants with altered cocaine sensitivity. Reduced Lmo function increases behavioral responses to cocaine, while Lmo overexpression causes the opposite effect, reduced cocaine responsiveness. Expression of Lmo in the principal Drosophila circadian pacemaker cells, the PDF-expressing ventral lateral neurons (LN_vs), is sufficient to confer normal cocaine sensitivity. Consistent with a role for Lmo in LN_v function, Lmo mutants also show defects in circadian rhythms of behavior. However, the role for LN_vs in modulating cocaine responses is separable from their role as pacemaker neurons: ablation or functional silencing of the LN_vs reduces cocaine sensitivity, while loss of the principal circadian neurotransmitter PDF has no effect. Together, these results reveal a novel role for Lmo in modulating acute cocaine sensitivity and circadian locomotor rhythmicity, and add to growing evidence that these behaviors are regulated by shared molecular mechanisms. The finding that the degree of cocaine responsiveness is controlled by the Drosophila pacemaker neurons provides a neuroanatomical basis for this overlap. We propose that Lmo controls the responsiveness of LN_vs to cocaine, which in turn regulate the flies' behavioral sensitivity to the drug.     

Decoding Reveals Plasticity in V3A as a Result of Motion Perceptual Learning

Visual perceptual learning (VPL) is defined as visual performance improvement after visual experiences. VPL is often highly specific for a visual feature presented during training. Such specificity is observed in behavioral tuning function changes with the highest improvement centered on the trained feature and was originally thought to be evidence for changes in the early visual system associated with VPL. However, results of neurophysiological studies have been highly controversial concerning whether the plasticity underlying VPL occurs within the visual cortex. The controversy may be partially due to the lack of observation of neural tuning function changes in multiple visual areas in association with VPL. Here using human subjects we systematically compared behavioral tuning function changes after global motion detection training with decoded tuning function changes for 8 visual areas using pattern classification analysis on functional magnetic resonance imaging (fMRI) signals. We found that the behavioral tuning function changes were extremely highly correlated to decoded tuning function changes only in V3A, which is known to be highly responsive to global motion with human subjects. We conclude that VPL of a global motion detection task involves plasticity in a specific visual cortical area.     

A Role for Ribosomal Protein L5 in the Nuclear Import of 5S rRNA inXenopusOocytes

Prior to ribosome assembly, 5S ribosomal RNA (5S rRNA) binds to ribosomal protein L5 to form a stable ribonucleoprotein particle (5S RNP). We have analyzed the role of L5 binding in the nuclear targeting of 5S rRNA inXenopusoocytes, and have compared the nuclear import pathway of 5S RNPs with other karyophilic molecules. Nuclear import ofin vitro-generated 5S RNPs was found to be sensitive to three general inhibitors of nuclear pore complex-mediated translocation: ATP depletion, chilling, and wheat germ agglutinin. The initial rate and extent of net nuclear import was threefold greater with preassembled 5S RNPs than with 5S rRNA microinjected alone, suggesting that L5 binding is a prerequisite for nuclear accumulation. Nuclear import of 5S rRNA/5S RNPs is a facilitated process dependent on limiting factors, since nuclear import exhibited saturation kinetics. Not only was nuclear import of labeled 5S rRNA reduced in the presence of excess unlabeled 5S rRNA, but also in the presence of the synthetic karyophilic protein P(lys)-BSA. In contrast, import was not inhibited by U1 small nuclear RNA (snRNA) or U3 small nucleolar RNA (snoRNA). 5S rRNA/5S RNP nuclear import therefore appears to follow a pathway of molecular interactions similar to many karyophilic proteins, but not the methylguanosine cap-dependent U1 snRNA pathway or the cap-independent U3 snoRNA pathway.     

A New Role for TIMP-1 in Modulating Neurite Outgrowth and Morphology of Cortical Neurons

Background

Tissue inhibitor of metalloproteinases-1 (TIMP-1) displays pleiotropic activities, both dependent and independent of its inhibitory activity on matrix metalloproteinases (MMPs). In the central nervous system (CNS), TIMP-1 is strongly upregulated in reactive astrocytes and cortical neurons following excitotoxic/inflammatory stimuli, but no information exists on its effects on growth and morphology of cortical neurons.

Principal Findings

We found that 24 h incubation with recombinant TIMP-1 induced a 35% reduction in neurite length and significantly increased growth cones size and the number of F-actin rich microprocesses. TIMP-1 mediated reduction in neurite length affected both dendrites and axons after 48 h treatment. The effects on neurite length and morphology were not elicited by a mutated form of TIMP-1 inactive against MMP-1, -2 and -3, and still inhibitory for MMP-9, but were mimicked by a broad spectrum MMP inhibitor. MMP-9 was poorly expressed in developing cortical neurons, unlike MMP-2 which was present in growth cones and whose selective inhibition caused neurite length reductions similar to those induced by TIMP-1. Moreover, TIMP-1 mediated changes in cytoskeleton reorganisation were not accompanied by modifications in the expression levels of actin, βIII-tubulin, or microtubule assembly regulatory protein MAP2c. Transfection-mediated overexpression of TIMP-1 dramatically reduced neuritic arbour extension in the absence of detectable levels of released extracellular TIMP-1.

Conclusions

Altogether, TIMP-1 emerges as a modulator of neuronal outgrowth and morphology in a paracrine and autrocrine manner through the inhibition, at least in part, of MMP-2 and not MMP-9. These findings may help us understand the role of the MMP/TIMP system in post-lesion pre-scarring conditions.     

Sonic Hedgehog过表达下调后脑五羟色胺能神经元数量

目的:本研究主要是探索高浓度的Shh对后脑5-HT神经元数量的影响。方法:通过免疫荧光和原位杂交手段检测Shh在脑干的表达情况。离体培养5-HT神经元,用不同浓度Shh蛋白处理,观察5-HT神经元的数量变化以及对轴突的影响。通过胚胎宫内电转,检测Shh过表达后脑5-HT神经元的数量变化。结果:Shh在脑干5-HT神经元分布区域内表达。离体培养的5-HT神经元,250 ng/m L的Shh蛋白处理后神经元数量为41.25±0.52(n=4,P=0.0218),与对照组35±1.21(n=4)相比,神经元数量上调。相反,1250 ng/m L的Shh蛋白处理后神经元数量为7.5±0.43(n=4,P0.0001),与对照组相比,神经元数量极显著下降。250 ng/m L的Shh蛋白处理后5-HT神经元轴突长度为1.08±0.05(n=4,P=0.7555),与对照组1±0.01(n=4)相比,轴突长度没有显著性差异。然而1250 ng/m L的Shh蛋白处理后5-HT神经元轴突长度为0.44±0.03(n=4,P=0.0014),与对照组相比,轴突长度极显著缩短。胚胎宫内电转p IRES-Shh-EGFP和p IRES-EGFP,观察到Shh过表达缝核上行5-HT神经元数量为147±54.2(n=4,P=0.0053),相较于对照组459±49.0(n=4),神经元数量极显著下降。同样地,Shh过表达缝核下行5-HT神经元数量为187±18.4(n=4,P=0.0001),相较于对照组411±17.3(n=4),神经元数量也发生了极显著下降。结论:Shh过表达对5-HT神经元的发育有负向的调控作用,主要表现在引起后脑缝核5-HT神经元数量减少。