Double dissociation of V1 and V5/MT activity in visual awareness

The critical time windows of the contribution of V1 and V5/MT to visual awareness of moving visual stimuli were compared by administering transcranial magnetic stimulation (TMS) to V1 or V5/MT in various time intervals from stimulus offset during performance of a simple motion detection task. Our results show a double dissociation in which the critical period of V1 both predates and postdates that of V5/MT, and where stimulation of either V1 at V5/MT's critical period or V5/MT at V1's critical period does not impair performance. These findings demonstrate the importance of back-projections from V5/MT to V1 in awareness of real motion stimuli.     

Visual motion responses in the posterior cingulate sulcus: a comparison to V5/MT and MST

Motion processing regions apart from V5+/MT+ are still relatively poorly understood. Here, we used functional magnetic resonance imaging to perform a detailed functional analysis of the recently described cingulate sulcus visual area (CSv) in the dorsal posterior cingulate cortex. We used distinct types of visual motion stimuli to compare CSv with V5/MT and MST, including a visual pursuit paradigm. Both V5/MT and MST preferred 3D flow over 2D planar motion, responded less yet substantially to random motion, had a strong preference for contralateral versus ipsilateral stimulation, and responded nearly equally to contralateral and to full-field stimuli. In contrast, CSv had a pronounced preference to 2D planar motion over 3D flow, did not respond to random motion, had a weak and nonsignificant lateralization that was significantly smaller than that of MST, and strongly preferred full-field over contralateral stimuli. In addition, CSv had a better capability to integrate eye movements with retinal motion compared with V5/MT and MST. CSv thus differs from V5+/MT+ by its unique preference to full-field, coherent, and planar motion cues. These results place CSv in a good position to process visual cues related to self-induced motion, in particular those associated to eye or lateral head movements.     

The spatial distribution of the antagonistic surround of MT/V5 neurons

The majority (217/325, 66%) of the neurons in the middle temporal (MT) area/V5 show strong antagonistic surrounds, defined here by a decrease of at least 50% in the summation curve. We mapped the antagonistic surround in 145 such cells, using eight circularly distributed surround stimulus patches (Surround Asymmetry Test, SAT) and also mapped the surround in 51 of these 145 cells using a grid consisting of 25 square patches (Surround Mapping Test, SMT). Both tests showed that the angular surround distribution was non-uniform in the majority of these neurons. In half the neurons, the antagonistic surround was asymmetric, and arose from a single region on one side of the excitatory receptive field (ERF). In another quarter of the sample the surround was bilaterally symmetric, and arose from a pair of regions on opposite sides of the ERF. Only the remaining 20% showed a circularly symmetric surround distribution. These three groups differed in their laminar distribution. The SMT showed that, radially, the surround antagonism reached a maximum, on average, at 1.5 times the ERF radius. Detailed comparisons of the spatial relationships of excitatory and inhibitory regions of the RF components shows that non-homogeneity of the surround influence appears to be an intrinsic property of the surround. Such a property may underly the extraction of the surface orientation and curvature from speed patterns.      

Differential localization of MT1-MMP in human prostate cancer tissue: role of IGF-1R in MT1-MMP expression

BACKGROUND: MT1-MMP is a metalloproteinase involved in prostate cancer metastasis. The IGF-1R is a tyrosine kinase receptor involved with tumor progression and metastasis. The purpose of this investigation was to examine MT1-MMP and IGF-1R expression and localization in prostate cancer tissues and explore the role of IGF-1R in regulating MT1-MMP in prostate cancer cell lines. METHODS: Immunohistochemistry was utilized to study MT1-MMP and IGF-1R expression in human prostate tissues. IGF-1R regulation of MT1-MMP expression was determined by gene promoter analysis, quantitative RT-PCR and Western blot analysis following pharmacological inhibition of the receptor in PC-3N cells and treatment of LNCaP cells with androgen and IGF-1. RESULTS: MT1-MMP expression was high in the apical regions of the luminal cells in PIN and prostate cancer and less intense in the basalateral regions of benign tissues. IGF-1R was expressed primarily in the basal cells of normal glands and highly expressed in prostate cancer. Inhibition of IGF-1R in PC-3N cells decreased MT1-MMP expression and treatment of LNCaP cells with a synthetic androgen and IGF-1 increased MT1-MMP expression. CONCLUSIONS: These data demonstrate that MT1-MMP is highly expressed in the apical cytoplasmic regions of the luminal cells in PIN and prostate cancer when compared to basalateral cytoplasmic membrane staining in benign glands. Additionally, we demonstrate that IGF-1R is highly expressed in human prostate carcinoma. These findings suggest that MT1-MMP localization and IGF-1R expression in prostate carcinoma could be predictive biomarkers for aggressive disease and support IGF-1R as a promising therapeutic target to decrease processes of prostate cancer metastasis.     

Priming of motion direction and area V5/MT: a test of perceptual memory

Presentation of supraliminal or subliminal visual stimuli that can (or cannot) be detected or identified can improve the probability of the same stimulus being detected over a subsequent period of seconds, hours or longer. The locus and nature of this perceptual priming effect was examined, using suprathreshold stimuli, in subjects who received repetitive pulse transcranial magnetic stimulation over the posterior occipital cortex, the extrastriate motion area V5/MT or the right posterior parietal cortex during the intertrial interval of a visual motion direction discrimination task. Perceptual priming observed in a control condition was abolished when area V5/MT was stimulated but was not affected by magnetic stimulation over striate or parietal sites. The effect of transcranial magnetic stimulation (TMS) on priming was specific to site (V5/MT) and to task - colour priming was unaffected by TMS over V5/MT. The results parallel, in the motion domain, recent demonstrations of the importance of macaque areas V4 and TEO for priming in the colour and form domains.     

Long-range clustered connections within extrastriate visual area V5/MT of the rhesus macaque

Visual area V5/MT in the rhesus macaque has a distinct functional organization, where neurons with specific preferences for direction of motion and binocular disparity are co-organized in columns or clusters. Here, we analyze the pattern of intrinsic connectivity within cortical area V5/MT in both parasagittal sections of the intact brain and tangential sections from flatmounted cortex using small injections of the retrograde tracer cholera toxin subunit b. Labeled cells were predominantly found in cortical layers 2, 3, and 6. Going along the cortical layers, labeled cells were concentrated in regularly spaced clusters. The clusters nearest to the injection site were approximately 2 mm from its center. In flatmounted cortex, along the dorsoventral axis of V5/MT, we identified further clusters of labeled cells up to 10 mm from the injection site. Quantitative analysis of parasagittal sections estimated average cluster spacing at 2.2 mm; in cortical flatmounts, spacing was 2.3 mm measured radially from the injection site. The results suggest a regular pattern of intrinsic connectivity within V5/MT, which is consistent with connectivity between sites with a common preference for both direction of motion and binocular depth. The long-range connections can potentially account for the large suppressive surrounds of V5/MT neurons.     

Segregation and convergence of functionally defined V2 thin stripe and interstripe compartment projections to area V4 of macaques

The organization of projections from V2 thin stripes and interstripes to V4 was investigated using a combination of physiological and anatomical techniques. The compartments of V2 were first characterized, in vivo, using optical recording of intrinsic signals. Multiple anterograde tracers were then injected into different V2 compartments. The distribution of labeled axons was analyzed in tangential or horizontal sections including V4. A small iontophoretic injection, either in a thin stripe or an interstripe, labeled a large primary and several secondary foci in V4. The primary foci from the thin stripe and interstripe were spatially segregated by a gap of approximately 1 mm. Furthermore, less dense regions within the primary foci were often 'filled-in' by secondary foci from the opposite V2 compartment. When two injections were made both at interstripes, their projections to V4 were almost entirely overlapping. These anatomical patterns indicate that segregation and convergence of intercortical pathways are both important features of V4 organization. Furthermore, the size of cortical modules increases considerably from the blobs of V1, through the stripes of V2, to the afferent domains of V4.     

联合检测泛素连接酶Cullin1和基质金属蛋白酶MT4-MMP在乳腺癌组织中的表达及临床意义

目的探究泛素连接酶Cullin1和基质金属蛋白酶MT4-MMP在不同类型乳腺癌组织中表达情况及临床意义。 方法2015年1月至8月,选择徐州市肿瘤医院80例乳腺癌组织及其对应的癌旁正常乳腺组织,应用免疫组织化学法和Western blotting法分别检测其中Cullin1和MT4-MMP的表达情况,并分析其相关性。 结果Cullin1、MT4-MMP蛋白在乳腺癌组织中的表达均高于癌旁正常乳腺组织,差异均有统计学意义（77.5% vs 28.8%,67.5% vs 17.5%,χ²=38.174、40.921,均P<0.01）;在乳腺癌组织中,Cullin1及MT4-MMP蛋白的表达呈正相关（P<0.05）。Cullin1及MT4-MMP在乳腺癌中的蛋白表达在分子分型、腋窝淋巴结是否转移及TNM分期组间差异有统计学意义（P<0.05）;在患者年龄、肿瘤大小、肿瘤部位、是否复发转移组间差异无统计学意义。 结论Cullin1及MT4-MMP可能参与了乳腺癌的形成及发展过程,且两者在此过程中有一定协同作用。在分型差、分期晚的乳腺癌中,Cullin1及MT4-MMP更高的表达状态提示其可能成为新的乳腺癌恶性程度指标。     

Analysis of ADAMTS4 and MT4-MMP indicates that both are involved in aggrecanolysis in interleukin-1-treated bovine cartilage

OBJECTIVE: To investigate the mechanism of aggrecanolysis in interleukin-1 (IL-1)-treated cartilage tissue by examining the time course of aggrecan cleavages and the tissue and medium content of membrane type 4-matrix metalloproteinases (MT4-MMP) and a disintegrin and metalloproteinase with thrombospondin type I motifs (ADAMTS)4. METHODS: Articular cartilage explants were harvested from newborn bovine femoropatellar groove. The effects of IL-1 treatment with or without aggrecanase blockade were investigated by Western analysis of aggrecan fragment generation, ADAMTS4 species (p68 and p53), and MT4-MMP, as well as by realtime PCR (polymerase chain reaction) for ADAMTS4 and 5. Aggrecanase was blocked with mannosamine (ManN), an inhibitor of glycosylphosphatidylinositol anchor synthesis, and esculetin (EST), an inhibitor of MMP-1, MMP-3, and MMP-13 gene expression. RESULTS: IL-1 treatment caused a major increase in MT4-MMP abundance in the tissue and medium. ADAMTS4 (p68) was abundant in fresh cartilage and this was retained in the tissue in untreated cartilage. IL-1 treatment for 6 days caused a marked loss of p68 from the cartilage and the appearance of p53 in the medium. Addition of either 1.35 mM ManN or 31-500 microM EST blocked IL-1-mediated aggrecanolysis and this was accompanied by nearly complete inhibition of the MT4-MMP increase, the p68 loss and the formation of p53. IL-1 treatment increased mRNA abundance for ADAMTS4 ( approximately 3-fold) and ADAMTS5 ( approximately 10-fold) but this was not accompanied by a marked change in enzyme protein abundance. CONCLUSION: These studies support a central role for MT4-MMP in IL-1-induced cartilage aggrecanolysis and are consistent with the identification of p68 as the aggrecanase that cleaves within the CS2 domain, and of p53 as the aggrecanase that generates G1-NITEGE. Since the induction by IL-1 was not accompanied by marked changes in total ADAMTS4 protein, but rather in partial conversion of p68 to p53 and release of both from the tissue, we conclude that aggrecanolysis in this model system results from MT4-MMP-mediated processing of a resident pool of ADAMTS4 and release of the p68 and p53 from their normal association with the cell surface.     

Differential regulation of lipogenesis and leptin production by independent signaling pathways and rosiglitazone during human adipocyte differentiation

Since leptin levels are independently correlated with risk of coronary heart disease, we have identified signaling pathways important in mediating leptin production and lipogenesis in human preadipocytes. We used inhibitors of p70(S6) kinase, p42/44 mitogen-activated protein kinase (MAPK), p38 MAPK, and phosphatidylinositol 3-kinase (PI3K). Human preadipocytes were induced to differentiate in insulin, dexamethasone, triiodothyronine, and 3-isobutyl-1-methylxanthine in the presence or absence of inhibitors and the peroxisome proliferator-activated receptor (PPAR)-gamma activator rosiglitazone. Differentiation was assessed by measuring leptin secretion, lipid content, and lipogenic activity. Rosiglitazone increased cell protein by 15%, the lipid content of the cell layer was doubled, and the lipogenic activity increased sevenfold but did not stimulate leptin secretion. None of the inhibitors significantly inhibited protein content over 20 days, but lipid content and lipogenic activity were inhibited by p70(S6) kinase and p38 MAPK inhibition but not by p42/44 MAPK or PI3K inhibition. All of the inhibitors significantly decreased leptin secretion, and these inhibitory effects were increased by coincubation with rosiglitazone. We conclude that PI3K and p42/44 MAPK pathways are not critical to the differentiation program leading to lipid accumulation, but stimulation of leptin secretion is dependent on these as well as the p70(S6) kinase and p38 MAPK signaling pathways.     

Activation of area MT/V5 and the right inferior parietal cortex during the discrimination of transient direction changes in translational motion

The perception of changes in the direction of objects that translate in space is an important function of our visual system. Here we investigate the brain electrical phenomena underlying such a function by using a combination of magnetoencephalography (MEG) and magnetic resonance imaging. We recorded MEG-evoked responses in 9 healthy human subjects while they discriminated the direction of a transient change in a translationally moving random dot pattern presented either to the right or to the left of a central fixation point. We found that responses reached their maximum in 2 main regions corresponding to motion processing area middle temporal (MT)/V5 contralateral to the stimulated visual field, and to the right inferior parietal lobe (rIPL). The activation latencies were very similar in both regions ( approximately 135 ms) following the direction change onset. Our findings suggest that area MT/V5 provides the strongest sensory signal in response to changes in the direction of translational motion, whereas area rIPL may be involved either in the sensory processing of transient motion signals or in the processing of signals related to orienting of attention.     

LRP4 association to bone properties and fracture and interaction with genes in the Wnt- and BMP signaling pathways

Osteoporosis is a common complex disorder in postmenopausal women leading to changes in the micro-architecture of bone and increased risk of fracture. Members of the low-density lipoprotein receptor-related protein (LRP) gene family regulates the development and physiology of bone through the Wnt/β-catenin (Wnt) pathway that in turn cross-talks with the bone morphogenetic protein (BMP) pathway. In two cohorts of Swedish women: OPRA (n=1002; age 75 years) and PEAK-25 (n=1005; age 25 years), eleven single nucleotide polymorphisms (SNPs) from Wnt pathway genes (LRP4; LRP5; G protein-coupled receptor 177, GPR177) were analyzed for association with Bone Mineral Density (BMD), rate of bone loss, hip geometry, quantitative ultrasound and fracture. Additionally, interaction of LRP4 with LRP5, GPR177 and BMP2 were analyzed. LRP4 (rs6485702) was associated with higher total body (TB) and lumbar spine (LS) BMD in the PEAK-25 cohort (p=0.006 and 0.005 respectively), and interaction was observed with LRP5 (p=0.007) and BMP2 (p=0.004) for TB BMD. LRP4 also showed significant interaction with LRP5 for femoral neck (FN) and LS BMD in this cohort. In the OPRA cohort, LRP4 polymorphisms were associated with significantly lower fracture incidence overall (p=0.008-0.001) and fewer hip fractures (rs3816614, p=0.006). Significant interaction in the OPRA cohort was observed for LRP4 with BMP2 and GPR177 for FN BMD as well as for rate of bone loss at TB and FN (p=0.007-0.0001). In conclusion, LRP4 and interaction between LRP4 and genes in the Wnt and BMP signaling pathways modulate bone phenotypes including peak bone mass and fracture, the clinical endpoint of osteoporosis.     

Configuration, in serial reconstruction, of individual axons projecting from area V2 to V4 in the macaque monkey.

The detailed morphology of long extrinsically projecting axons in the neocortex has been difficult to investigate and is in fact poorly understood. Some data, based on extracellular injections of Phaseolus vulgaris leucoagglutinin (PHA-L), are available for individual axons projecting from area V1 to area V2 or MT. Like geniculocortical projections, axons projecting from area V1 to area MT are readily identifiable (they typically have a bistratified termination pattern and large terminal specializations and are of large caliber), but those projecting from area V1 to V2 are more variable. To provide a broader basis for interpreting constant and variable features of axon morphology, we used high-resolution serial section reconstruction to analyze small populations of PHA-L-labeled axons projecting from area V2 to V4. Reconstruction of 20 axons suggests that this system is variable in terms of overall configuration and laminar distribution. Most terminal arbors are located at the border between layers 3 and 4, but some remain entirely within layer 3 or 4, some target preferentially the superficial layers (1, 2, and 3A), and some have collaterals in layer 5 or, rarely, layer 6. Arbor size is fairly constant among the three visual cortical projections examined so far (typically about 200 microns in diameter). In area V4, however, axons frequently have three or four separate arbors, which branch divergently (in one instance, over 2.6 mm x 3.0 mm). These features may be correlated with aspects of the particular functional organization of area V4, such as coarse topography, large receptive field size, and modularity. Axonal variability may also denote differences, morphological or physiological, among neurons of origin in area V2.     

A new anatomical landmark for reliable identification of human area V5/MT: a quantitative analysis of sulcal patterning

The location of human area V5 (or MT) has been correlated with the intersection of the ascending limb of the inferior temporal sulcus (ALITS) and the lateral occipital sulcus (LO). This study was undertaken to attempt a replication and quantification of these observations using functional magnetic resonance imaging. V5 was significantly activated in 19 hemispheres with alternating, low contrast, random checkerboard patterns. We confirmed the stereotaxic location of V5 and were able to describe a fairly consistent sulcal pattern in the parieto-temporo-occipital cortex. V5 was usually (95%) buried within a sulcus, most commonly within the inferior temporal sulcus (ITS) (11%), the ascending limb of the ITS (ALITS) (53%) and the posterior continuation of the ITS (26%). The average distance from V5 of two identified anatomical landmarks of V5, the junctions of the LO and the ALITS, and the ITS and ALITS, were both 1 cm. However, the LO-ALITS junction often had to be determined by interpolation (47%), and was not always present even with interpolation (21%). In contrast, the ITS-ALITS junction was always present and V5 was usually (90%) located in a sulcus intersecting with this junction, making it a more reliable landmark for localizing V5 with respect to gross morphological features on individual cortical surfaces.     

Spatial receptive field organization of macaque V4 neurons

Subfield analysis of the receptive fields (RFs) of parafoveal V4 complex cells demonstrates directly that most RFs are tiled by overlapping second-order excitatory inputs that for any given V4 cell are predominantly selective to the same preferred values of spatial frequency and orientation. These results extend hierarchical principles of RF organization in the spatial, orientation and spatial frequency domains, first recognized in V1, to an intermediate extrastriate cortex. Spatial interaction studies across subfields demonstrate that the responses of V4 neurons to paired stimuli may either decrease or increase as a function of inter-stimulus distance across the width axis. These intra-RF suppressions and facilitations vary independently in magnitude and spatial extent from cell to cell. These results taken together with the relatively large RF sizes of V4 neurons - as compared with RF sizes of their afferent inputs - lead us to hypothesize a novel property, namely that classes of stimulus configurations that enhance areal summation while reducing suppressive interactions between excitatory inputs will evoke especially robust responses. We tested, and found support for, this hypothesis by presenting stimuli consisting of optimally tuned sine-wave gratings visible only within an annular region and found that such stimuli vigorously activate V4 neurons at firing rates far higher than those evoked by comparable stimuli to either the full-field or central core. On the basis of these results we propose a framework for a new class of neural network models for the spatial RF organizations of prototypic V4 neurons.     

Cortical connections of area V4 in the macaque

To determine the locus, full extent, and topographic organization of cortical connections of area V4 (visual area 4), we injected anterograde and retrograde tracers under electrophysiological guidance into 21 sites in 9 macaques. Injection sites included representations ranging from central to far peripheral eccentricities in the upper and lower fields. Our results indicated that all parts of V4 are connected with occipital areas V2 (visual area 2), V3 (visual area 3), and V3A (visual complex V3, part A), superior temporal areas V4t (V4 transition zone), MT (medial temporal area), and FST (fundus of the superior temporal sulcus [STS] area), inferior temporal areas TEO (cytoarchitectonic area TEO in posterior inferior temporal cortex) and TE (cytoarchitectonic area TE in anterior temporal cortex), and the frontal eye field (FEF). By contrast, mainly peripheral field representations of V4 are connected with occipitoparietal areas DP (dorsal prelunate area), VIP (ventral intraparietal area), LIP (lateral intraparietal area), PIP (posterior intraparietal area), parieto-occipital area, and MST (medial STS area), and parahippocampal area TF (cytoarchitectonic area TF on the parahippocampal gyrus). Based on the distribution of labeled cells and terminals, projections from V4 to V2 and V3 are feedback, those to V3A, V4t, MT, DP, VIP, PIP, and FEF are the intermediate type, and those to FST, MST, LIP, TEO, TE, and TF are feedforward. Peripheral field projections from V4 to parietal areas could provide a direct route for rapid activation of circuits serving spatial vision and spatial attention. By contrast, the predominance of central field projections from V4 to inferior temporal areas is consistent with the need for detailed form analysis for object vision.