iPSC-derived cortical neurons to study sporadic Alzheimer disease: A transcriptome comparison with post-mortem brain samples.

Alzheimer's disease (AD) is the most common cause of dementia, characterized by the progressive impairment of cognition and memory loss. Sporadic AD (sAD) represents approximately 95 % of the AD cases and is induced by a complex interplay between genetic and environmental factors called "Alzheimerogens". Heavy metals (e.g. copper) and pesticides (e.g. fipronil) can affect many AD-related processes, including neuroinflammation (considered as AD-inducing factor). Research would benefit from in vitro models to investigate effects of Alzheimerogens. We compared transcriptomics changes in sAD induced pluripotent stem cell (iPSC) derived cortical neurons to differentially expressed genes (DEGs) identified in post-mortem AD brain tissue. These analyses showed that many AD-related processes could be identified in the sAD iPSC-derived neurons, and furthermore, could even identify more DEGs functioning in these processes than post-mortem AD-brain tissue. Thereafter, we exposed the iPSCs to AD-inducing factors (copper(II)chloride, fipronil sulfone and an inflammatory cytokine cocktail). Cytokine exposure induced expression of immune related genes while copper-exposure affected genes involved in lipid and cholesterol metabolism, which are known AD-related processes. Fipronil-exposure did not result in significant transcriptomic changes, although prolonged exposures or higher doses may be necessary. Overall, we show that iPSC-derived cortical neurons can be beneficial in vitro models to identify Alzheimerogens and AD-related molecular mechanisms.

Circulating microRNAs as potential biomarkers for psychiatric and neurodegenerative disorders.

Circulating microRNAs (cimiRNAs) are a class of non-encoding RNAs found in bodily fluids such as blood, cerebrospinal fluid (CSF) and tears. CimiRNAs have been implicated as promising biomarkers for central nervous system (CNS) disorders because they are actively secreted as messengers and are profoundly involved in fine-tuning of developmental and differentiation processes. Furthermore, they are attractive biomarkers because they are extremely stable, tissue enriched and can be determined in a quantitative manner. This review aims to provide a comprehensive assessment on the current progress regarding the potential value of cimiRNAs as CNS biomarkers. Within this framework five CNS disorders are explored which share a common pathological hallmark namely cognitive impairment. The CNS disorders include Major depression disorder (MDD), Bipolar disorder (BD), Schizophrenia (SZ), Alzheimer's disease (AD) and Parkinson disease (PD). The similarities and differences between altered cimiRNAs in the different disorders are described. The miR-29 family, miR-34a-5p and miR-132-3p are discussed as common dysregulated cimiRNAs found in the CNS disorders. Furthermore, it is shown that the type of bodily fluid used for measuring cimiRNAs is important as inconsistencies in cimiRNAs expression directions are found when comparing CSF, blood cell-free and blood cell-bound samples.

Information conveyed by onset transients in responses of striate cortical neurons.

Normal eye movements ensure that the visual world is seen episodically, as a series of often stationary images. In this paper we characterize the responses of neurons in striate cortex to stationary grating patterns presented with abrupt onset. These responses are distinctive. In most neurons the onset of a grating gives rise to a transient discharge that decays with a time constant of 100 msec or less. The early stages of response have higher contrast gain and higher response gain than later stages. Moreover, the variability of discharge during the onset transient is disproportionately low. These factors together make the onset transient an information-rich component of response, such that the detectability and discriminability of stationary gratings grows rapidly to an early peak, within 150 msec of the onset of the response in most neurons. The orientation selectivity of neurons estimated from the first 150 msec of discharge to a stationary grating is indistinguishable from the orientation selectivity estimated from longer segments of discharge to moving gratings. Moving gratings are ultimately more detectable than stationary ones, because responses to the former are continuously renewed. The principal characteristics of the response of a neuron to a stationary grating-the initial high discharge rate, which decays rapidly, and the change of contrast gain with time-are well captured by a model in which each excitatory synaptic event leads to an immediate reduction in synaptic gain, from which recovery is slow.

Relative number of long- and middle-wavelength-sensitive cones in the human fovea.

Flicker photometric measurements yield spectral sensitivity curves that are well fitted by sums of the spectral sensitivity curves of long-wavelength-sensitive (L) cones and middle-wavelength-sensitive (M) cones if the L cones are given twice the weight of the M cones. This result has been interpreted as implying that L cones are more numerous than M cones but is also consistent with a different numerical ratio, say, 1:1, and with the assignment of greater weight to the L cone input than to the M cone input by the mechanism subserving flicker photometry. Measurements of temporal sensitivity are presented for lights that modulate the inputs of either only the L cones or only the M cones. Sensitivity to modulation of the L cones is approximately twice that of modulation of the M cones at approximately 30 Hz, but that advantage disappears at approximately 2 Hz. Thus flicker sensitivity is equivocal with regard to cone numerosity. Electrophysiological, anatomical, and psychophysical evidence is reviewed, with particular weight placed on the statistics of color appearance of small, brief, monochromatic lights and on increment thresholds measured on the same observers. It is concluded that, in the central fovea, the ratio of L:M cone numbers is close to unity and may not be so variable as is usually supposed.

Rapid adaptation in visual cortex to the structure of images.

Complex cells in striate cortex of macaque showed a rapid pattern-specific adaptation. Adaptation made cells more sensitive to orientation change near the adapting orientation. It reduced correlations among the responses of populations of cells, thereby increasing the information transmitted by each action potential. These changes were brought about by brief exposures to stationary patterns, on the time scale of a single fixation. Thus, if successive fixations expose neurons' receptive fields to images with similar but not identical structure, adaptation will remove correlations and improve discriminability.

Effect of contrast on detection of motion of chromatic and luminance targets: retina-relative and object-relative movement.

It is now clear, contrary to previous conclusions, that motion may be conveyed by purely chromatic stimuli. The question considered here is how the mechanisms for assessing motion of luminance and chromatic stimuli differ. The dependence on contrast of amplitude thresholds for the perception of oscillatory motion was measured. The targets were Gabor patches modulated either chromatically along the L-M isoluminant axis or in luminance. When single targets were presented, the slope of the function relating log threshold amplitude to log contrast was approximately -0.50 for chromatic targets and 0.00 for luminance targets. When a reference target was present the slopes were approximately -0.50 for both types of target. The results imply that perception of motion of chromatic targets is based on the assessment of changes in relative position of target elements while motion of luminance targets may be signalled either by relative motion of target elements or by local motion of an image relative to the retina.

Distinctive characteristics of subclasses of red-green P-cells in LGN of macaque.

We characterized the chromatic and temporal properties of a sample of 177 red-green parvocellular neurons in the LGN of Macaca nemestrina, using large-field stimuli modulated along different directions through a white point in color space. We examined differences among the properties of the four subclasses of red-green P-cells (on- and off-center, red and green center). The responses of off-center cells lag the stimulus more than do those of on-center cells. At low temporal frequencies, this causes the phase difference between responses of the two kinds of cells to be considerably less than 180 deg. For isoluminant modulations the phases of on- and off-responses were more nearly 180 deg apart. A cell's temporal characteristics did not depend on the class of cone driving its center. Red center and green center cells have characteristically different chromatic properties, expressed either as preferred elevations in color space, or as weights with which cells combine inputs from L- and M-cones. Red center cells are relatively more responsive to achromatic modulation, and attach relatively more weight to input from the cones driving the center. Off-center cells also attach relatively more weight than do on-center cells to input from the class of cone driving the center.

Temporal-chromatic interactions in LGN P-cells.

We studied the interaction between the chromatic and temporal properties of parvocellular (P) neurons in the lateral geniculate nucleus (LGN) of macaque monkeys. We measured the amplitudes and phases of responses to stimulation by spatially uniform fields modulated sinusoidally about a white point in a three-dimensional color space, at a range of temporal frequencies between 1 and 25 Hz. Below about 4 Hz, temporal frequency had relatively little effect on chromatic tuning. At higher frequencies chromatic opponency was weakened in almost all cells. The complex interactions between temporal and chromatic properties are represented by a linear filter model that describes response amplitude and phase as a function of temporal frequency and direction in color space along which stimuli are modulated. The model stipulates the cone inputs to center and surround, their temporal properties, and the linear combination of center and surround signals. It predicts the amplitudes and phases of responses of P-cells, and the change of chromatic properties with temporal frequency. We used the model to investigate whether or not the chromatic signature of the surround in a red-green cell could be estimated from the change in the cell's chromatic properties with temporal frequency. Our findings could be equally well described by mixed cone surrounds as by pure cone surrounds, and we conclude that, with regard to temporal properties, there is no benefit to be gained by segregating cone classes in center and surround.

Coherence, cardinal directions and higher-order mechanisms.

Our initial purpose was to develop a quantitative method of estimating the cardinal directions of color space. The method is based on the finding that patterns consisting of pairs of drifting gratings modulated along different cardinal axes appear to slip with respect to one another, while the same patterns appear as a single coherent plaid if the modulation directions of the patterns are rotated by 45 deg in color space [Krauskopf & Farell (1990). Nature, 348,328-331]. A forced-choice procedure was used in which observers were asked to choose which of two successively presented patterns appeared less coherent. The patterns consisted of pairs of drifting gratings; the direction of modulation of one of the gratings was fixed and that of the other varied. For example, an estimate of an individual's isoluminant plane could be obtained by fixing the modulation of one grating in the luminance direction and finding the elevation of the modulation of the other grating that resulted in minimum perceived coherence. We found it important to take into consideration individual differences in the tilt of the isoluminant plane in color space and in the detectability of targets in the nominal cardinal directions. When this was done we found that reliable measurements could be made. The method effectively provided quantitative estimates of the cardinal directions. However, the most important result was the inadequacy of the generalization that patterns appear coherent when they share similar components along cardinal directions (Krauskopf & Farell, 1990) to account for the new results. The present results suggest that patterns appear not to cohere to the extent that they fail to stimulate common chromatic mechanisms, but the assumption that these mechanisms are tuned only along cardinal axes can be rejected. Along with other data the results point to the existence of higher-order mechanisms tuned to different isoluminant chromatic directions.

Proximity judgments in color space: tests of a Euclidean color geometry.

We describe two tests of the hypothesis that human judgments of the proximity of colors are consistent with a Euclidean geometry on color matching space. The first test uses proximity judgments to measure the angle between any two intersecting lines in color space. Pairwise estimates of the angles between three lines in a plane were made in order to test the additivity of angles. Three different color proximity tasks were considered. Additivity failed for each of the three proximity tasks. Secondly, we tested a prediction concerning the growth of the variability of judgments of similarity with the distance between the test and reference stimuli. The Euclidean hypothesis was also rejected by this test. The results concerning the growth of variability are consistent with the assumption that observers use a city-block metric when judging the proximity of colored lights.

Color discrimination and adaptation.

We have measured color discrimination in the isoluminant plane under rigorously controlled adaptation conditions. Two regimes were studied. Under the first regime the observer was adapted to the region of color space in which the discriminations were made. Thresholds for detecting changes along the S-(L + M) axis are a linearly increasing function of the excitation of the S cones. Thresholds for detecting changes along the L-M axis are independent of the locus of adaptation along this axis. The straightness of these functions is inconsistent with the theory that second stage mechanisms are more sensitive in the middle of their operating ranges. No convincing evidence of interactions in the effects of adaptation locus or test stimuli was observed. Under the second regime the observer was adapted to one point in color space and the stimuli to be discriminated were located in other places in color space. Discrimination seems to be limited primarily by mechanisms maximally sensitive to modulation along the isoluminant cardinal axes but evidence suggestive of the operation of higher order mechanisms was also found.

Vernier acuity: effects of chromatic content, blur and contrast.

Offset thresholds were measured for targets whose horizontal profiles were either Gaussian or odd-symmetric Gabor functions. The targets were defined either by variation along the constant B or the constant R & G axes of color space or by luminance variation. Blur was varied in the case of the Gaussian targets by varying the standard deviation of the distribution and in the case of the Gabor functions by varying the spatial frequency of the sinusoidal component. Detection thresholds for all the stimuli were measured. The contrast of the targets used in the measurement of offset thresholds was varied from just above detection threshold to the maximum that could be produced. The offset thresholds obtained with targets of different chromatic composition are nearly identical when blur and contrast relative to detection threshold are held constant. We attribute the slight advantage held by luminance targets over chromatic targets for narrow Gaussians to the detectability of low frequency components of the chromatic targets which are of little use in the assessment of offsets. This conjecture is supported by the complete absence of such an advantage in the case of Gabor targets.

Influence of colour on the perception of coherent motion.

We have colour vision because there are three types of cone photoreceptors which are maximally sensitive in the long (L), middle (M) and short (S) wavelength regions of the spectrum. Psychophysical experiments have, however, revealed mechanisms selectively responsive to light modulated in three 'cardinal directions' in colour space. The responses of these mechanisms are determined by algebraic sums of the excitations of the cones. One of these mechanisms is responsive to changes in luminance, its spectral sensitivity being that of the sum of the L and M cones. The other two respond best to isoluminant changes in light. The responses of one of these mechanisms are determined by the difference in the excitations of the L and M cones, and those of the other one determined by the difference between the excitation of the S cones on the one hand and the excitations of the L and M cones on the other. We have obtained quite surprising results concerning the role of these mechanisms in the perception of motion. Drifting gratings modulated along different cardinal directions appear to slip with respect to one another. In contrast, when the directions of the modulations are rotated by 45 degrees in colour space, the gratings cohere. Our results are consistent with the notion that information about movement is analysed within mechanisms maximally responsive along the cardinal directions.

Chromatic mechanisms in striate cortex of macaque.

We measured the responses of 305 neurons in striate cortex to moving sinusoidal gratings modulated in chromaticity and luminance about a fixed white point. Stimuli were represented in a 3-dimensional color space defined by 2 chromatic axes and a third along which luminance varied. With rare exceptions the chromatic properties of cortical neurons were well described by a linear model in which the response of a cell is proportional to the sum (for complex cells, the rectified sum) of the signals from the 3 classes of cones. For each cell there is a vector passing through the white point along which modulation gives rise to a maximal response. The elevation (theta m) and azimuth (phi m) of this vector fully describe the chromatic properties of the cell. The linear model also describes neurons in l.g.n. (Derrington et al., 1984), so most neurons in striate cortex have the same chromatic selectivity as do neurons in l.g.n. However, the distributions of preferred vectors differed in cortex and l.g.n.: Most cortical neurons preferred modulation along vectors lying close to the achromatic axis and those showing overt chromatic opponency did not fall into the clearly defined chromatic groups seen in l.g.n. The neurons most responsive to chromatic modulation (found mainly in layers IVA, IVC beta, and VI) had poor orientation selectivity, and responded to chromatic modulation of a spatially uniform field at least as well as they did to any grating. We encountered neurons with band-pass spatial selectivity for chromatically modulated stimuli in layers II/III and VI. Most had complex receptive fields. Neurons in layer II/III did not fall into distinct groups according to their chromatic sensitivities, and the chromatic properties of neurons known to lie within regions rich in cytochrome oxidase appeared no different from those of neurons in the interstices. Six neurons, all of which resembled simple cells, showed unusually sharp chromatic selectivity.

Mechanisms of simultaneous color induction.

A new method of measuring simultaneous contrast, or chromatic induction, is introduced and used to test the hypotheses that induction results from either multiplicative or subtractive interaction of either like receptors or like second-stage, opponent mechanisms. Predictions derived from these hypotheses do not predict the outcome of the experiments as well as the traditional notion that induced colors are in the direction complementary to the inducing color with respect to the test color. We conclude that simultaneous contrast is a consequence of interaction within higher-level chromatic mechanisms.

Higher order color mechanisms.

Evidence supporting the existence of higher order color mechanisms, that is, ones beyond the previously identified second stage mechanisms is presented. This evidence includes a reanalysis of the data of Krauskopf et al. [Vision Res. 20, 1123-1131 (1982)] on the desensitizing effects of viewing chromatically modulated fields, new experiments on a generalized version of the "transient tritanopia" experiment of Mollon and Polden [Phil. Trans. R. Soc. Lond. 278, 207-240 (1977)] and results on the relationship between discrimination and detection of brief color changes.

Induced desensitization.

Viewing of annuli modulated in color in a sawtooth fashion in time results in differential threshold elevations for the detection of color changes of inscribed disks. The elevations are of nearly the same magnitude as those resulting from viewing modulated disks. However, the differential effects on thresholds for complimentary colors are reversed. The differential effects, thus, are correlated with the variation in appearance of the test area.

Chromatic mechanisms in lateral geniculate nucleus of macaque.

This paper introduces a new technique for the analysis of the chromatic properties of neurones, and applies it to cells in the lateral geniculate nucleus (l.g.n.) of macaque. The method exploits the fact that for any cell that combines linearly the signals from cones there is a restricted set of lights to which it is equally sensitive, and whose members can be exchanged for one another without evoking a response. Stimuli are represented in a three-dimensional space defined by an axis along which only luminance varies, without change in chromaticity, a 'constant B' axis along which chromaticity varies without changing the excitation of blue-sensitive (B) cones, a 'constant R & G' axis along which chromaticity varies without change in the excitation of red-sensitive (R) or green-sensitive (G) cones. The orthogonal axes intersect at a white point. The isoluminant plane defined by the intersection of the 'constant B' and 'constant R & G' axes contains lights that vary only in chromaticity. In polar coordinates the constant B axis is assigned the azimuth 0-180 deg, and the constant R & G axis the azimuth 90-270 deg. Luminance is expressed as elevation above or below the isoluminant plane (-90 to +90 deg). For any cell that combines cone signals linearly, there is one plane in this space, passing through the white point, that contains all lights that can be exchanged silently. The position of this 'null plane' provides the 'signature' of the cell, and is specified by its azimuth (the direction in which it intersects the isoluminant plane of the stimulus space) and its elevation (its angle of inclination to the isoluminant plane). A colour television receiver was used to produce sinusoidal gratings whose chromaticity and luminance could be modulated along any vector passing through the white point in the space described. The spatial and temporal frequencies of modulation could be varied over a large range. When stimulated by patterns of low spatial and low temporal frequency, two groups of cells in the parvocellular laminae of the l.g.n. were distinguished by the locations of their null planes. The null planes of the larger group were narrowly distributed about an azimuth of 92.6 deg and more broadly about an elevation of 51.5 deg, which suggests that they receive opposed, but not equally balanced, inputs from only R and G cones. These we call R-G cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Selective loss of chromatic sensitivity in demyelinating disease.

Thresholds for detecting changes in color for isoluminant stimuli and for detecting changes in luminance were measured in patients with histories of demyelinating disease and in normal controls. Thresholds for detecting changes in color were higher for patients' affected eyes, that is, ones in which symptoms had been found previously, than in their unaffected eyes, or for eyes of control subjects. Thresholds for detecting changes in luminance were raised less than those for changes in color. The pattern of loss is different than that found in subjects with congenital color blindness. The results suggest that the impairment occurs at a level in the nervous system beyond which signals from more than one class of cone receptor are combined.

Cardinal directions of color space.

Thresholds for detecting changes in color are raised following viewing a field sinusoidally modulated in color over time. This effect is highly selective. For example, thresholds for detecting reddish and greenish changes from white are raised following viewing a field varying in a reddish-greenish direction, but not after viewing one varying in a yellowish-bluish direction. Similarly thresholds for yellowish and bluish changes from white are raised following viewing a field varying along a yellowish-bluish axis but not altered by exposure to reddish-greenish variation. Thresholds for chromatic changes are not raised following viewing a field varying in luminance. Thresholds for changes in luminance are raised following viewing a field varying in luminance but not altered by exposure to purely chromatic variation. Since this selectivity is found only for these directions and not intermediate directions in color space we conclude that these directions are cardinal, that is, signals varying along these directions are carried along separate, fatiguable, second stage pathways. The results conform to the expectations of opponent process theory with the important exception that the yellowish-bluish cardinal direction is a tritanopic confusion line and not a red-green equilibrium line.