C E Connor | PubMed Health

PubMed2002

Mitochondrial cytochrome c release precedes transmembrane depolarisation and caspase-3 activation during ceramide-induced apoptosis of Jurkat T cells.

Whilst the role of ceramide, a second messenger of the sphingolipid family, in the initiation of receptor-mediated apoptosis is controversial, a growing body of evidence is emerging for a role of ceramide in the amplification of apoptosis via mitochondrial perturbations that culminate in the activation of execution caspases. Treatment of Jurkat T cells with the cell-permeable analog, C(2)-ceramide, resulted in the rapid onset of apoptosis as evidenced by Annexin V-FITC staining of externalised phosphatidylserine residues. Cells bearing this early apoptotic marker had a reduced mitochondrial transmembrane potential (Delta(Psi)m) that was preceded by the release of cytochrome c from mitochondria. Subsequent activation of caspase-3 provides the link between these ceramide-induced mitochondrial changes and execution caspases that ultimately result in the physical destruction of the cell. Collectively these results demonstrate that ceramide signalling results in caspase-mediated apoptosis via mitochondrial cytochrome c release and are further supportive of the role of ceramide in the amplification of apoptosis.

Annexin A5↗

PubMed2001

Visual perception: sunny side up.

Illumination, both natural and artificial, typically comes from above. Neurons in visual area V4--part of the object-processing pathway in the primate brain--may rely on this anisotropy to infer three-dimensional structure from shading cues.

Animals↗

PubMed2001

Circumventing tamoxifen resistance in breast cancers using antiestrogens that induce unique conformational changes in the estrogen receptor.

Tamoxifen inhibits estrogen receptor (ER) transcriptional activity by competitively inhibiting estradiol binding and inducing conformational changes in the receptor that may prevent its interaction with coactivators. In bone, the cardiovascular system, and some breast tumors, however, tamoxifen exhibits agonist activity, suggesting that the tamoxifen-ER complex is not recognized identically in all cells. We used phage display to demonstrate that the antiestrogen GW5638 induces a unique structural change in the ER. The biological significance of this conformational change was revealed in studies that demonstrated that tamoxifen-resistant breast tumor explants are not cross-resistant to GW5638. Because of these properties, this drug is currently being developed as a potential therapeutic for tamoxifen-resistant breast cancers.

Amino Acid Sequence↗

PubMed2001

Cell cycle arrest of hematopoietic cell lines after treatment with ceramide is commonly associated with retinoblastoma activation.

BACKGROUND: Leukaemia cells differ from their normal counterparts in that their ability to properly regulate survival, proliferation, differentiation, and apoptosis is aberrant. Understanding the molecular mechanisms controlling cell proliferation and developing therapeutic strategies to correct nonfunctional regulatory mechanisms are emerging areas of medical research. Ceramide, a metabolite of membrane sphingomyelin hydrolysis, has recently emerged as a key regulator of cellular proliferation, differentiation, and apoptosis in leukaemia cells. METHODS: Leukaemia cell lines were treated with a biologically active analogue of ceramide, C(2)-ceramide. Cell cycle status was assessed flow cytometrically using propidium iodide. Induction of apoptosis was confirmed by annexin V staining of externalised phosphatidylserine and retinoblastoma activation was determined by Western blotting. RESULTS: C(2)-ceramide induced activation of retinoblastoma tumour suppressor protein, G(0)/G(1) cell cycle arrest, or apoptosis in leukaemia cell lines. In addition, these effects differed depending upon cell type, thus confirming the pleiotropic nature of the ceramide signalling pathway. Most cells studied responded to exogenous C(2)-ceramide by entering growth arrest, evidently resulting from activation of retinoblastoma protein, and by displaying some degree of apoptosis. CONCLUSIONS: Taken together, these findings suggest that signalling via ceramide has novel therapeutic applications for treatment of leukaemia.

Cell Cycle↗

PubMed2001

Disparity tuning in macaque area V4.

Neural processing of stereoscopic depth is conventionally associated with the dorsal (spatial) pathway in primate visual cortex. The role of depth information in the ventral (object) pathway has been less certain. We found prominent tuning for stereoscopic disparity in area V4, an intermediate stage in the ventral pathway. Eighty percent of the cells in our sample exhibited significant disparity tuning over the -1.0 degree to 1.0 degree range, and the majority showed > 2:1 response differences. Tuning function shapes were similar to those reported previously in other visual areas. We observed a significant tuning bias towards crossed (near) disparities. This could reflect an emphasis in the ventral pathway on foreground objects or parts of objects projecting towards the viewer.

Animals↗

PubMed2001

Shifting receptive fields.

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Animals↗

PubMed2001

Shape representation in area V4: position-specific tuning for boundary conformation.

Visual shape recognition in primates depends on a multi-stage pathway running from primary visual cortex (V1) to inferotemporal cortex (IT). The mechanisms by which local shape signals from V1 are transformed into selectivity for abstract object categories in IT are unknown. One approach to this issue is to investigate shape representation at intermediate stages in the pathway, such as area V4. We studied 109 V4 cells that appeared sensitive to complex shape in preliminary tests. To achieve a more complete picture of shape representation in V4, we tested each cell with a set of 366 stimuli, constructed by systematically combining convex and concave boundary elements into closed shapes. Using this large, diverse stimulus set, we found that all the cells in our sample responded to a wide variety of shapes and did not appear to encode any single type of global shape. However, for most cells the shapes evoking strongest responses were characterized by a consistent type of boundary conformation at a specific position within the stimulus. For example, a given cell might be tuned for shapes containing concave curvature at the right, with other parts of the shape having little or no effect on responses. Many cells were tuned for more complex boundary configurations (e.g., a convex angle adjacent to a concave curve). We quantified this kind of shape tuning with Gaussian functions on a curvature x position domain. These tuning functions fit the neural responses much better than tuning functions based on edge or axis orientation. Thus individual V4 cells appear to encode moderately complex boundary information at specific locations within larger shapes. This finding suggests that, at intermediate stages in the V1-IT transformation, complex objects are represented at least partly in terms of the configurations and positions of their contour components.

Animals↗

PubMed2000

Visual perception: monkeys see things our way.

Neural mechanisms of visual perception can be studied in detail only in non-human animals. But recent work in humans has revealed a striking functional homology between the human and monkey visual systems, confirming the relevance of animal data and establishing a paradigm for cross-species studies of brain function.

Animals↗

PubMed1999

Responses to contour features in macaque area V4.

The ventral pathway in visual cortex is responsible for the perception of shape. Area V4 is an important intermediate stage in this pathway, and provides the major input to the final stages in inferotemporal cortex. The role of V4 in processing shape information is not yet clear. We studied V4 responses to contour features (angles and curves), which many theorists have proposed as intermediate shape primitives. We used a large parametric set of contour features to test the responses of 152 V4 cells in two awake macaque monkeys. Most cells responded better to contour features than to edges or bars, and about one-third exhibited systematic tuning for contour features. In particular, many cells were selective for contour feature orientation, responding to angles and curves pointing in a particular direction. There was a strong bias toward convex (as opposed to concave) features, implying a neural basis for the well-known perceptual dominance of convexity. Our results suggest that V4 processes information about contour features as a step toward complex shape recognition.

Animals↗

PubMed1998

Neural activity in areas V1, V2 and V4 during free viewing of natural scenes compared to controlled viewing.

Under natural viewing conditions primates make frequent exploratory eye movements across complex scenes. We recorded neural activity of 62 cells in visual areas V1, V2 and V4 in an awake behaving monkey that freely viewed natural images. About half of the cells studied showed a modulation in firing rate following some of the eye movements made during free viewing, though the proportions showing a discernible modulation varied across areas. These cells were also examined under controlled viewing conditions in which gratings or natural image patches were flashed in and around the classical receptive field while the animal performed a fixation task. Activity rates were generally highest with flashed gratings and lowest during free viewing. Flashed natural image patches evoked responses between these two extremes, and the responses were higher when the patches were confined to the classical receptive field than when they extended into the non-classical surround. Thus the reduction of activity during free viewing relative to that obtained with flashed gratings is partly attributable to natural images being less effective stimuli and partly to suppressive spatio-temporal neural mechanisms that are important during natural vision.

Animals↗

PubMed1998

Neural activity in areas V1, V2 and V4 during free viewing of natural scenes compared to controlled viewing.

Under natural viewing conditions primates make frequent exploratory eye movements across complex scenes. We recorded neural activity of 62 cells in visual areas V1, V2 and V4 in an awake behaving monkey that freely viewed natural images. About half of the cells studied showed a modulation in firing rate following some of the eye movements made during free viewing, though the proportions showing a discernible modulation varied across areas. These cells were also examined under controlled viewing conditions in which gratings or natural image patches were flashed in and around the classical receptive field while the animal performed a fixation task. Activity rates were generally highest with flashed gratings and lowest during free viewing. Flashed natural image patches evoked responses between these two extremes, and the responses were higher when the patches were confined to the classical receptive field than when they extended into the non-classical surround. Thus the reduction of activity during free viewing relative to that obtained with flashed gratings is partly attributable to natural images being less effective stimuli and partly to suppressive spatio-temporal neural mechanisms that are important during natural vision.

Animals↗

PubMed1998

Neural activity in areas V1, V2 and V4 during free viewing of natural scenes compared to controlled viewing.

Under natural viewing conditions primates make frequent exploratory eye movements across complex scenes. We recorded neural activity of 62 cells in visual areas V1, V2 and V4 in an awake behaving monkey that freely viewed natural images. About half of the cells studied showed a modulation in firing rate following some of the eye movements made during free viewing, though the proportions showing a discernible modulation varied across areas. These cells were also examined under controlled viewing conditions in which gratings or natural image patches were flashed in and around the classical receptive field while the animal performed a fixation task. Activity rates were generally highest with flashed gratings and lowest during free viewing. Flashed natural image patches evoked responses between these two extremes, and the responses were higher when the patches were confined to the classical receptive field than when they extended into the non-classical surround. Thus the reduction of activity during free viewing relative to that obtained with flashed gratings is partly attributable to natural images being less effective stimuli and partly to suppressive spatio-temporal neural mechanisms that are important during natural vision.

Animals↗

PubMed1997

Spatial attention effects in macaque area V4.

Focal visual attention typically produces enhanced perceptual processing at the psychological level and relatively stronger neural responses at the physiological level. A longstanding mechanistic question is whether these attentional effects pertain specifically to the attended (target) object or to the region of space it occupies. We show here that attentional response enhancement in macaque area V4 extends to behaviorally irrelevant objects in the vicinity of the target object, indicating that focal attention has a strong spatial component at the physiological level. In addition, we find that spatial attention effects typically show a striking directional asymmetry. The direction of the asymmetry varies between cells, so that some cells respond best when attention is directed to the left of the stimulus, some when attention is directed to the right, etc. Thus, attention involves not only enhanced responses to behavioral targets but also a complex modulation of responses to other stimuli in the surrounding visual space.

Animals↗

PubMed1996

Responses in area V4 depend on the spatial relationship between stimulus and attention.

1. We studied the spatial interaction between stimulus and attention in macaque area V4. Monkeys were required to fixate a small spot while continuously attending to a ring-shaped target within a large array of identical rings. Meanwhile, the response of the V4 cell under study was tested by flashing behaviorally irrelevant bar stimuli in the cell's classical receptive field (CRF). The location of the attended ring was varied across four positions surrounding the CRF, and the location of the bar stimulus was varied across five positions spanning the CRF. 2. Response strength depended on two aspects of the spatial relationship between the stimulus driving the cell (the bar) and the position of attention (the target ring). First, for 49% of the cells studied, responses were greater for bar stimuli near the attended ring; i.e., the receptive field profile shifted toward the attentional focus. Second, for 84% of the cells, the overall response level depended on the direction in which attention lay relative to the stimulus in the CRF (e.g., to the left, right, above, or below). 3. This study confirms a key prediction of spatial models of attention, which postulate enhanced processing of all stimuli near the attentional focus. It also introduces the novel finding that responses are influenced by the relative direction of attention. This result indicates that area V4 carries information about the spatial relationship between visual stimuli and attention.

Animals↗

PubMed1996

Neural responses to polar, hyperbolic, and Cartesian gratings in area V4 of the macaque monkey.

1. We studied the responses of 103 neurons in visual area V4 of anesthetized macaque monkeys to two novel classes of visual stimuli, polar and hyperbolic sinusoidal gratings. We suspected on both theoretical and experimental grounds that these stimuli would be useful for characterizing cells involved in intermediate stages of form analysis. Responses were compared with those obtained with conventional Cartesian sinusoidal gratings. Five independent, quantitative analyses of neural responses were carried out on the entire population of cells. 2. For each cell, responses to the most effective Cartesian, polar, and hyperbolic grating were compared directly. In 18 of 103 cells, the peak response evoked by one stimulus class was significantly different from the peak response evoked by the remaining two classes. Of the remaining 85 cells, 74 had response peaks for the three stimulus classes that were all within a factor of 2 of one another. 3. An information-theoretic analysis of the trial-by-trial responses to each stimulus showed that all but two cells transmitted significant information about the stimulus set as a whole. Comparison of the information transmitted about each stimulus class showed that 23 of 103 cells transmitted a significantly different amount of information about one class than about the remaining two classes. Of the remaining 80 cells, 55 had information transmission rates for the three stimulus classes that were all within a factor of 2 of one another. 4. To identify cells that had orderly tuning profiles in the various stimulus spaces, responses to each stimulus class were fit with a simple Gaussian model. Tuning curves were successfully fit to the data from at least one stimulus class in 98 of 103 cells, and such fits were obtained for at least two classes in 87 cells. Individual neurons showed a wide range of tuning profiles, with response peaks scattered throughout the various stimulus spaces; there were no major differences in the distributions of the widths or positions of tuning curves obtained for the different stimulus classes. 5. Neurons were classified according to their response profiles across the stimulus set with two objective methods, hierarchical cluster analysis and multidimensional scaling. These two analyses produced qualitatively similar results. The most distinct group of cells was highly selective for hyperbolic gratings. The majority of cells fell into one of two groups that were selective for polar gratings: one selective for radial gratings and one selective for concentric or spiral gratings. There was no group whose primary selectivity was for Cartesian gratings. 6. To determine whether cells belonging to identified classes were anatomically clustered, we compared the distribution of classified cells across electrode penetrations with the distribution that would be expected if the cells were distributed randomly. Cells with similar response profiles were often anatomically clustered. 7. A position test was used to determine whether response profiles were sensitive to precise stimulus placement. A subset of Cartesian and non-Cartesian gratings was presented at several positions in and near the receptive field. The test was run on 13 cells from the present study and 28 cells from an earlier study. All cells showed a significant degree of invariance in their selectivity across changes in stimulus position of up to 0.5 classical receptive field diameters. 8. A length and width test was used to determine whether cells preferring non-Cartesian gratings were selective for Cartesian grating length or width. Responses to Cartesian gratings shorter or narrower than the classical receptive field were compared with those obtained with full-field Cartesian and non-Cartesian gratings in 29 cells. Of the four cells that had shown significant preferences for non-Cartesian gratings in the main test, none showed tuning for Cartesian grating length or width that would account for their non-Cartesian res

Animals↗

PubMed1994

Covert attention suppresses neuronal responses in area 7a of the posterior parietal cortex.

1. The effect of covert attention was studied in area 7a of the posterior parietal cortex of rhesus monkeys performing a spatial match-to-sample task. The task required the animals to fixate a central target light, to detect and remember the location of a transient spatial cue, and to respond when one of a series of stimuli appeared at the cued location. Neuronal responses evoked by the visual stimuli were recorded during each behavioral trial. 2. Thirty-eight percent of the neurons isolated and studied in these experiments responded to visual stimuli. The responses of 55% of the neurons tested were suppressed, and 5% enhanced for stimuli presented at the attended location. Responses in the remaining neurons (40%) were unaffected by shifts in attention. 3. Activity in 57% of the suppressed neurons was reduced to rates not significantly different from spontaneous activity. 4. The extent of suppression for individual neurons was often restricted to the attended portion of the receptive field. 5. These data suggest a potential role for these neurons in the redirection of visual attention.

Animals↗

PubMed1992

Neural coding of tactile texture: comparison of spatial and temporal mechanisms for roughness perception.

A previous study showed that roughness perception may depend on either temporal or spatial variations in firing rate among cutaneous mechanoreceptive afferents. The present study was designed to distinguish between these hypotheses. Plastic surfaces embossed with patterns of dots designed to produce predictable alterations in temporal and spatial firing rate variation were used as stimuli in psychophysical and neurophysiological experiments. Subjective roughness magnitudes obtained from psychophysical experiments fitted the predictions of the spatial but not the temporal hypothesis. In the neurophysiological experiments, the stimuli were scanned across the receptive fields of cutaneous mechanoreceptive afferents. Firing rate variation in the neural responses was measured using a range of temporal and spatial filters. Temporal variation was not correlated with roughness magnitude. Spatial variation, on a scale of 1-2 mm (one to two receptor spacings), was closely correlated with roughness.

Adult↗

PubMed1990

Tactile roughness: neural codes that account for psychophysical magnitude estimates.

Hypothetical neural codes underlying the sensation of tactile roughness were investigated in a combined psychophysical and neurophysiological study. The stimulus set consisted of plastic surfaces embossed with dot arrays of varying dot diameter and center-to-center spacing. Human subjects explored each surface with the pad of the index finger and reported their subjective sense of roughness magnitude. The same surfaces were scanned across the receptive fields of cutaneous mechanoreceptive afferents in monkeys while recording the evoked action potentials. Hypothetical neural codes for roughness magnitude were computed from the neural response patterns and tested for their ability to account for the psychophysical data. The psychophysical results showed that subjective roughness magnitude is an inverted U-shaped function of dot spacing that peaks near 3.0 mm spacing, and that increased dot diameter produces decreased roughness sensations at all dot spacings. Hypothetical neural codes that do not bear a consistent relationship to roughness magnitude across all of these stimulus conditions can be rejected as the code for roughness. Four types of neural codes were considered. They were based on (1) mean firing rate, (2) general variation in firing rate, (3) short-term temporal variation in firing rate, and (4) local spatial variation in firing rate. Mean firing rate failed to explain the psychophysical results: surfaces that evoked the same firing rate often evoked very different roughness judgments. In contrast, neural codes based on firing-rate variation, especially in slowly adapting afferents, account for the psychophysical results.

Action Potentials↗