Publications

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    ABSTRACT: Both genetic and environmental factors likely contribute to the neuropathology of tauopathies, but it remains unclear how specific genetic backgrounds affect the susceptibility towards environmental toxins. Mutations in the tau gene have been associated with familial tauopathies, while annonacin, a plant-derived mitochondrial inhibitor, has been implicated in an environmental form of tauopathy. We therefore determined whether there was a pathogenic synergy between annonacin exposure and the expression of the R406W-tau mutation in transgenic mice. We found that annonacin exposure caused an increase in the number of neurons with phosphorylated tau in the somatodendritic compartment in several brain areas in R406W(+/+) mice as opposed to mice that had only the endogenous mouse tau (R406W(-/-)). Western blot analysis demonstrated a concomitant increase in total tau protein without increase in tau mRNA, but reduced proteasomal proteolytic activity in R406W(+/+), but not R406W(-/-) mice, upon annonacin-treatment. Phosphorylated tau levels exceeded the increase in total tau protein, along with increased levels of different tau kinases, foremost a striking increase in the p25/p35 ratio, known to activate the tau kinase Cdk5. In summary, we observed a synergistic interaction between annonacin exposure and the presence of the R406W-tau mutation, which resulted in reduced degradation, increased phosphorylation and redistribution of neuronal tau.
    Experimental Neurology 01/2014; · 4.65 Impact Factor
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    ABSTRACT: Five new flavonoids, 5,3'-dihydroxy-4'-methoxy-2'',2''-dimethylchromene-(5'',6'':6,7)dihydroflavonol (1), 5,3'-dihydroxy-7,4'-dimethoxy-6,8-dimethylallyl-dihydroflavonol (2), 5,3'-dihydroxy-4'-methoxy-8-allyl-2'',2''-dimethylchromene-(5'',6'':6,7) flavanone (3), 5,3'-dihydroxy-7,4'-dimethoxy-6,8-dimethylallyl-flavanone (4), 3,5,3'-trihydroxy-7,4'-dimethoxy6,8-dimethylallyl-flavanol (5), together with the stilbenes 4-methoxylonchocarpene (6) and lonchocarpene (7) were isolated from the leaves of Deguelia utilis. Their chemical structures were established on the basis of NMR (nuclear magnetic resonance) spectral data and HRESITOF-MS (electrospray ionization-high resolution time-of-flight mass spectrometry). Also, in order to investigate potential cytoprotective effects of these flavonoids, we used a fraction eluted with hexane:EtOAc containing all seven flavonoids, in an in vitro model of neurodegeneration, using hippocampal primary cultures from neonatal (PND2-P3) rats exposed to rotenone, a mitochondrial complex I inhibitor. There was a significant reduction in cell viability (19.4 ± 1.6%) when the cultures were exposed to 30 nmol L-1 rotenone for 72 h. Concomitant exposure of the cultures to the FR3 (5 µg mL-1) and 30 nmol L-1 rotenone resulted in values of cell viability similar to control groups (99.6 ± 4.8%), strongly suggesting a cytoprotective effect for this flavonoid-rich fraction.
    Journal of the Brazilian Chemical Society 10/2012; 23(10):1933-1939. · 1.28 Impact Factor
  • Basal Ganglia. 03/2011; 1(1):29.
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    ABSTRACT: The tyrant flycatchers represent a monophyletic radiation of predominantly insectivorous passerine birds that exhibit a plethora of stereotyped prey capture techniques. However, little is known about their retinal organization. Using retinal wholemounts, we estimated the total number and topography of neurons in the ganglion cell layer in the generalist yellow-bellied elaenia (Elaenia flavogaster) and the up-hover-gleaner mouse-colored tyrannulet (Phaeomyias murina) with the optical fractionator method. The mean estimated total number of neurons in the ganglion cell layer was 4,152,416 +/- 189,310 in E. flavogaster and 2,965,132 +/- 354,359 in P. murina. Topographic maps of isocounting lines revealed a similar distribution for both species: a central fovea and a temporal area surrounded by a poorly defined horizontal streak. In addition, both species had increased numbers of giant ganglion cells in the dorsotemporal retina forming an area giganto cellularis. In E. flavogaster, these giant ganglion cells were also distributed across the nasal and ventral retinal peripheries, which is in agreement with the generalist habits of this species. However, in P. murina these cells were rarely seen along the nasal and ventral peripheries, possibly reflecting a lesser need to perceive movement because this species captures stationary insects resting on foliage. Thus, we suggest that the retinas of the tyrant flycatchers in the present study show a general common pattern of neuron distribution in the ganglion cell layer irrespective of their foraging habits. We also suggest that the distribution of giant ganglion cells is indicative of the visual requirements of the species.
    The Journal of Comparative Neurology 06/2009; 514(1):66-73. · 3.66 Impact Factor
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    ABSTRACT: The clinical motor dysfunction in Parkinson's disease is primarily the consequence of a progressive degeneration of dopaminergic neurons in the substantia nigra of the nigrostriatal pathway. The degeneration of this tract provokes a depletion of dopamine in the striatum, where it is required as a permissive factor for normal motor function. Despite intense investigations, no effective therapy is available to prevent the onset or to halt the progression of the neuronal cell loss. Therefore, recent years have seen research into the mechanisms of endogenous repair processes occurring in the adult brain, particularly in the substantia nigra. Neurogenesis occurs in the adult brain in a constitutive manner under physiological circumstances within two regions: the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. In contrast to these two so-called neurogenic areas, the remainder of the brain is considered to be primarily nonneurogenic in nature, implying that no new neurons are produced there under normal conditions. The occurrence of adult neurogenesis in the substantia nigra under the pathological conditions of Parkinson's disease, however, remains controversial. Here, we review the published evidence of whether adult neurogenesis exists or not within the substantia nigra, where dopaminergic neurons are lost in Parkinson's disease.
    Journal of Neural Transmission 01/2009; · 3.05 Impact Factor
  • Planta Medica 07/2008; 74(09). · 2.35 Impact Factor
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    ABSTRACT: To better understand the evolution of spatial and color vision, the number and spatial distributions of cones, rods, and optic nerve axon numbers were assessed in seven New World primates (Cebus apella, Saimiri ustius, Saguinus midas niger, Alouatta caraya, Aotus azarae, Calllithrix jacchus, and Callicebus moloch). The spatial distribution and number of rods and cones was determined from counts of retinal whole mounts. Optic axon number was determined from optic nerve sections by electron microscopy. These data were amassed with existing data on retinal cell number and distribution in Old World primates, and the scaling of relative densities and numbers with respect to retinal area, eye and brain sizes, and foveal specializations were evaluated. Regular scaling of all cell types was observed, with the exceptionally large, rod-enriched retina of the nocturnal owl monkey Aotus azarae, and the unusually high cone density of the fovea of the trichromatic howler monkey Alouatta caraya presenting interesting variations on this basic plan. Over all species, the lawful scaling of rods, cones, and retinal ganglion cell number is hypothesized to result from a conserved sequence of cell generation that defends retinal acuity and sensitivity over a large range of eye sizes.
    Visual Neuroscience 01/2008; 25(3):289-99. · 1.48 Impact Factor
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    ABSTRACT: A neurodegenerative tauopathy endemic to the Caribbean island of Guadeloupe has been associated with the consumption of anonaceous plants that contain acetogenins, potent lipophilic inhibitors of complex I of the mitochondrial respiratory chain. To test the hypothesis that annonacin, a prototypical acetogenin, contributes to the etiology of the disease, we investigated whether annonacin affects the cellular distribution of the protein tau. In primary cultures of rat striatal neurons treated for 48 h with annonacin, there was a concentration-dependent decrease in ATP levels, a redistribution of tau from the axons to the cell body, and cell death. Annonacin induced the retrograde transport of mitochondria, some of which had tau attached to their outer membrane. Taxol, a drug that displaces tau from microtubules, prevented the somatic redistribution of both mitochondria and tau but not cell death. Antioxidants, which scavenged the reactive oxygen species produced by complex I inhibition, did not affect either the redistribution of tau or cell death. Both were prevented, however, by forced expression of the NDI1 nicotinamide adenine dinucleotide (NADH)-quinone-oxidoreductase of Saccharomyces cerevisiae, which can restore NADH oxidation in complex I-deficient mammalian cells and stimulation of energy production via anaerobic glycolysis. Consistently, other ATP-depleting neurotoxins (1-methyl-4-phenylpyridinium, 3-nitropropionic, and carbonyl cyanide m-chlorophenylhydrazone) reproduced the somatic redistribution of tau, whereas toxins that did not decrease ATP levels did not cause the redistribution of tau. Therefore, the annonacin-induced ATP depletion causes the retrograde transport of mitochondria to the cell soma and induces changes in the intracellular distribution of tau in a way that shares characteristics with some neurodegenerative diseases.
    Journal of Neuroscience 08/2007; 27(29):7827-37. · 6.91 Impact Factor
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    ABSTRACT: A Neurobiotin-injected OFF parasol cell from midperipheral macaque retina was studied by reconstruction of serial ultrathin sections and compared with ON parasol cells studied previously. In most respects, the synaptic inputs to the two subtypes were similar. Only a few of the amacrine cell processes that provided input to the labeled OFF parasol ganglion cell dendrites made or received inputs within the series, and none of these interactions were with the bipolar cells or other amacrine cells presynaptic to the OFF parasol cell. These findings suggest that the direct inhibitory input to OFF parasol cells originates from other areas of the retina. OFF parasol cells were known to receive inputs from two types of diffuse bipolar cells. To identify candidates for the presynaptic amacrine cells, OFF parasol cells were labeled with Lucifer yellow by using a juxtacellular labeling technique, and amacrine cells known to costratify with them were labeled via immunofluorescent methods. Appositions were observed with amacrine cells containing immunoreactive calretinin, parvalbumin, choline acetylatransferase, and G6-Gly, a cholecystokinin precursor. These findings suggest that the inhibitory input to parasol cells conveys information about several different attributes of visual stimuli and, particularly, about their global properties.
    The Journal of Comparative Neurology 10/2006; 498(1):46-57. · 3.66 Impact Factor
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    ABSTRACT: Tyrant flycatchers comprise the largest group of passerine birds of the Neotropical region but their retinal organization is unknown. The great kiskadee, Pitangus sulphuratus, is categorized as a supreme generalist and utilizes a variety of foraging strategies. The rusty margined flycatcher, Myiozetetes cayanensis, is partially frugivorous and captures insects in the air. Using retinal wholemounts, we described the topographic distribution of density and size of neurons lying in the retinal ganglion cell layer in those two species of tyrant flycatchers. Maps of neuron distribution showing isodensity contours revealed the presence of a pronounced central fovea and a temporal area in both species. Both retinal specializations were circumscribed by an inconspicuous horizontal visual streak. The highest foveal densities ranged from 48,000 to 55,000 cells/mm(2) for Pitangus sulphuratus and between 62,000 and 65,000 cells/mm(2) for Myiozetetes cayanensis. The peak density in the temporal area was around 40,000 cells/mm(2) for Pitangus sulphuratus and 46,000 cells/mm(2) for Myiozetetes cayanensis. At central, mid-peripheral and peripheral eccentricities, perikaryon size varied quite similarly in both species. A cohort of giant retinal ganglion cells with perikaryon size > 300 microm(2) was observed at the temporal periphery and defines an 'area giganto cellularis' described previously in procellariiform seabirds. This specialization is thought to be involved in movement detection and could aid the tyrant flycatchers to capture moving prey. Functionally, the presence of a fovea associated with a temporal area would allow high spatial resolution for capturing insects by the tyrant flycatchers. Nonetheless, even though both species exhibit different foraging strategies, they shared a similar topographic arrangement of neuronal density in the ganglion cell layer. This suggests that the retinal topography did not accompany changes in the foraging ecology throughout evolutionary history for these species of tyrant flycatchers.
    Brain Behavior and Evolution 01/2006; 68(1):15-25. · 2.89 Impact Factor
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    ABSTRACT: Fish of the genus Anableps (Anablepidae, Cyprinodontiformes) have eyes that are adapted for simultaneous aerial and aquatic vision. In this study we investigate some of the corresponding retinal specializations of the adult Anableps anableps eye using retinal transverse sections and wholemounts. The linear dimensions of the retina were found to be asymmetric with a greater representation of the dorsal compared to the ventral visual field. The total number of neurons in the ganglion cell layer of the ventral hemiretina was on average 3.6 times greater than the values obtained in the dorsal hemiretina. Isodensity contour maps revealed a prominent horizontal visual streak in the ventral hemiretina with an average peak cell density of 18,286 cells/mm(2). A second less-well-developed horizontal visual streak was also observed in the dorsal hemiretina. A sub-population of large cells with soma areas between 74 and 188 microm(2) was identified and found to be distributed evenly across both hemiretinas. Together, these results show that the sampling gain of the ventral retina is significantly greater than the dorsal segment, that retinal specializations important for mediating acute vision are present in the parts of the visual field immediately above and below the surface of the water, and that visual functions related with the large ganglion cells require more even sampling across the visual field. The relevance of these retinal specializations to the feeding and other behavioral strategies adopted by Anableps is discussed.
    Visual Neuroscience 01/2006; 23(6):879-86. · 1.48 Impact Factor
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    ABSTRACT: We performed a quantitative analysis of M and P cell mosaics of the common-marmoset retina. Ganglion cells were labeled retrogradely from optic nerve deposits of Biocytin. The labeling was visualized using horseradish peroxidase (HRP) histochemistry and 3-3'diaminobenzidine as chromogen. M and P cells were morphologically similar to those found in Old- and New-World primates. Measurements were performed on well-stained cells from 4 retinas of different animals. We analyzed separate mosaics for inner and outer M and P cells at increasing distances from the fovea (2.5-9 mm of eccentricity) to estimate cell density, proportion, and dendritic coverage. M cell density decreased towards the retinal periphery in all quadrants. M cell density was higher in the nasal quadrant than in other retinal regions at similar eccentricities, reaching about 740 cells/mm(2) at 2.5 mm of temporal eccentricity, and representing 8-14% of all ganglion cells. P cell density increased from peripheral to more central regions, reaching about 5540 cells/mm(2) at 2.5 mm of temporal eccentricity. P cells represented a smaller proportion of all ganglion cells in the nasal quadrant than in other quadrants, and their numbers increased towards central retinal regions. The M cell coverage factor ranged from 5 to 12 and the P cell coverage factor ranged from 1 to 3 in the nasal quadrant and from 5 to 12 in the other quadrants. These results show that central and peripheral retinal regions differ in terms of cell class proportions and dendritic coverage, and their properties do not result from simply scaling down cell density. Therefore, differences in functional properties between central and peripheral vision should take these distinct regional retinal characteristics into account.
    Brazilian Journal of Medical and Biological Research 07/2005; 38(6):915-24. · 1.14 Impact Factor
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    ABSTRACT: Rotenone is a heterocyclic compound widely used as an insecticide, acaricide and piscicide. Its toxicity is mainly caused by the inhibition of mitochondrial respiratory processes and ATP production, resulting in the generation of reactive oxygen species. Reactive oxygen species can interact with DNA, RNA and proteins, leading to cell damage, followed by death. We used the Comet assay, and we analyzed chromosome aberrations, in order to evaluate the genotoxic and clastogenic effects of rotenone on the different phases of the cell cycle. Cultured human lymphocytes were treated with 1.0, 1.5 and 2.0 microg/mL rotenone during the G1, G1/S, S (pulses of 1 and 6 h), and G2 phases of the cell cycle. Rotenone induced DNA damage and was clastogenic, but the clastogenicity was detected only with treatments conducted during the G1/S and S phases of the cell cycle. Rotenone also induced endoreduplication and polyploidy in treatments made during G1, while it significantly reduced the mitotic index in all phases of the cell cycle.
    Genetics and molecular research: GMR 02/2005; 4(4):822-31. · 0.99 Impact Factor
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    ABSTRACT: Neural systems are necessarily the adaptive products of natural selection, but a neural system, dedicated to any particular function in a complex brain, may be composed of components that covary with functionally unrelated systems, owing to constraints beyond immediate functional requirements. Some studies support a modular or mosaic organization of the brain, whereas others emphasize coordination and covariation. To contrast these views, we have analysed the retina, striate cortex (V1) and extrastriate cortex (V2, V3, MT, etc.) in 30 mammals, examining the area of the neocortex and individual neocortical areas and the relative numbers of rods and cones. Controlling for brain size and species relatedness, the sizes of visual cortical areas (striate, extrastriate) within the brains of nocturnal and diurnal mammals are not statistically different from one another. The relative sizes of all cortical areas, visual, somatosensory and auditory, are best predicted by the total size of the neocortex. In the sensory periphery, the retina is clearly specialized for niche. New data on rod and cone numbers in various New World primates confirm that rod and cone complements of the retina vary substantially between nocturnal and diurnal species. Although peripheral specializations or receptor surfaces may be highly susceptible to niche-specific selection pressures, the areal divisions of the cerebral cortex are considerably more conservative.
    Proceedings of the Royal Society B: Biological Sciences 02/2005; 272(1558):91-100. · 5.68 Impact Factor
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    Elizabeth S Yamada, Andrea S Bordt, David W Marshak
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    ABSTRACT: To describe the wide-field ganglion cells, they were injected intracellularly with Neurobiotin using an in vitro preparation of macaque retina and labeled with streptavidin-Cy3. The retinas were then labeled with antibodies to choline acetyltransferase and other markers to indicate the depth of the dendrites within the inner plexiform layer (IPL) and analyzed by confocal microscopy. There were eight different subtypes of narrowly unistratified cells that ramified in each of the 5 strata, S1-5, including narrow thorny, large sparse, large moderate, large dense, large radiate, narrow wavy, large very sparse, and fine very sparse. There were four types of broadly stratified cells with dendritic trees extending from S4 to S2. One type resembled the parvocellular giant cell and another the broad thorny type described previously in primates. Another broadly stratified cell was called multi-tufted based on its distinctive dendritic branching pattern. The fourth type had been described previously, but not named; we called it broad wavy. There was a bistratified type with its major arbor in S5, the same level as the blue cone bipolar cell; it resembled the large, bistratified cell with blue ON-yellow OFF responses described recently. Two wide-field ganglion cell types were classified as diffuse because they had dendrites throughout the IPL. One had many small branches and was named thorny diffuse. The second was named smooth diffuse because it had straighter dendrites that lacked these processes. Dendrites of the large moderate and multi-tufted cells cofasciculated with ON-starburst cell dendrites and were, therefore, candidates to be ON- and ON-OFF direction-selective ganglion cells, respectively. We concluded that there are at least 15 morphoplogical types of wide-field ganglion cells in macaque retinas.
    Visual Neuroscience 01/2005; 22(4):383-93. · 1.48 Impact Factor
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    ABSTRACT: Catarrhines and platyrrhines, the so-called Old- and New-World anthropoids, have different cone photopigments. Postreceptoral mechanisms must have co-evolved with the receptors to provide trichromatic color vision, and so it is important to compare postreceptoral processes in these two primate groups, both from anatomical and physiological perspectives. The morphology of ganglion cells has been studied in the retina of catarrhines such as the diurnal and trichromatic Macaca, as well as platyrrhines such as the diurnal, di- or trichromatic Cebus, and the nocturnal, monochromatic Aotus. Diurnal platyrrhines, both di- and trichromats, have ganglion cell classes very similar to those found in catarrhines: M (parasol), P (midget), small-field bistratified, and several classes of wide-field ganglion cells. In the fovea of all diurnal anthropoids, P-cell dendritic trees contact single midget bipolars, which contact single cones. The Aotus retina has far fewer cones than diurnal species, but M- and P-cells are similar to those in diurnal primates although of larger size. As in diurnal anthropoids, in the Aotus, the majority of midget bipolar cells, found in the central 2 mm of eccentricity, receive input from a single cone and the sizes of their axon terminals match the sizes of P-cell dendritic fields in the same region. The visual responses of retinal ganglion cells of these species have been studied using single-unit electrophysiological recordings. Recordings from retinal ganglion cells in Cebus and Aotus showed that they have very similar properties as those in the macaque, except that P-cells of mono- and dichromatic animals lack cone opponency. Whatever the original role of the M- and P-cells was, they are likely to have evolved prior to the divergence of catarrhines and platyrrhines. M- and P-cell systems thus appear to be strongly conserved in the various primate species. The reasons for this may lie in the roles of these systems for both achromatic and chromatic vision.
    Progress in brain research 02/2004; 144:21-46. · 4.19 Impact Factor
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    ABSTRACT: Starburst amacrine cells in the macaque retina were studied by electron microscopic immunohistochemistry. We found that these amacrine cells make a type of synapse not described previously; they are presynaptic to axon terminals of bipolar cells. We also confirmed that starburst amacrine cells are presynaptic to ganglion cell dendrites and amacrine cell processes. In order to determine the functions of these synapses, we localized acetylcholine receptors using a monoclonal antibody (mAb210) that recognizes human alpha3- and alpha5-containing nicotinic receptors and also antisera against the five known subtypes of muscarinic receptors. The majority of the mAb210-immunoreactive perikarya were amacrine cells and ganglion cells, but a subpopulation of bipolar cells was also labeled. A subset of bipolar cells and a subset of horizontal cells were labeled with antibodies to M3 muscarinic receptors. A subset of amacrine cells, including those that contain cholecystokinin, were labeled with antibodies to M2 receptors. Taken together, these results suggest that acetylcholine can modulate the activity of retinal ganglion cells by multiple pathways.
    The Journal of Comparative Neurology 07/2003; 461(1):76-90. · 3.66 Impact Factor
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    ABSTRACT: A labeled ON parasol ganglion cell from a macaque retina was analyzed in serial, ultrathin sections. It received 13% of its input from diffuse bipolar cells. These directed a large proportion of their output to amacrine cells but received a relatively small proportion of their amacrine cell input via feedback synapses. In these respects, they were similar to the DB3 bipolar cells that make synapses onto OFF parasol cells. Bipolar cell axons that contacted the ON parasol cell in stratum 4 of the inner plexiform layer always made synapses onto the dendrite, and therefore, the number of bipolar cell synapses onto these ganglion cells could be estimated reliably by light microscopy in the future. Amacrine cells provided the majority of inputs to the ON parasol cell. Only a few of the presynaptic amacrine cell processes received inputs from the same bipolar cells as the parasol cells, and most of the presynaptic amacrine cell processes did not receive any inputs at all within the series. These findings suggest that most of the inhibitory input to the ON parasol cell originates from other areas of the retina. Amacrine cells presynaptic to the parasol ganglion cell interacted very infrequently with other neurons in the circuit, and therefore, they would be expected to act independently, for the most part.
    Visual Neuroscience 01/2002; 19(3):299-305. · 1.48 Impact Factor
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    ABSTRACT: We have estimated photoreceptor convergence to M and P retinal ganglion cells of two closely related nocturnal (owl monkey, Aotus) and diurnal (capuchin monkey, Cebus) anthropoids. Rod convergence is higher in the owl monkey retina while cone convergence to both M and P cells are very similar in the retinas of the owl monkey and the capuchin monkey. These results indicate that during evolution, the owl monkey retina has undergone changes compatible with a more nocturnal lifestyle, but kept a cone to ganglion cell relation similar to that found in diurnal primates.
    Vision Research 02/2001; 41(2):119-31. · 2.14 Impact Factor

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