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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.