Neuronal nonlinearity explains greater visual spatial resolution for darks than lights

Astronomers and physicists noticed centuries ago that visual spatial resolution is higher for dark than light stimuli, but the neuronal mechanisms for this perceptual asymmetry remain unknown. Here we demonstrate that the asymmetry is caused by a neuronal nonlinearity in the early visual pathway. We show that neurons driven by darks (OFF neurons) increase their responses roughly linearly with luminance decrements, independent of the background luminance. However, neurons driven by lights (ON neurons) saturate their responses with small increases in luminance and need bright backgrounds to approach the linearity of OFF neurons. We show that, as a consequence of this difference in linearity, receptive fields are larger in ON than OFF thalamic neurons, and cortical neurons are more strongly driven by darks than lights at low spatial frequencies. This ON/OFF asymmetry in linearity could be demonstrated in the visual cortex of cats, monkeys, and humans and in the cat visual thalamus. Furthermore, in the cat visual thalamus, we show that the neuronal nonlinearity is present at the ON receptive field center of ON-center neurons and ON receptive field surround of OFF-center neurons, suggesting an origin at the level of the photoreceptor. These results demonstrate a fundamental difference in visual processing between ON and OFF channels and reveal a competitive advantage for OFF neurons over ON neurons at low spatial frequencies, which could be important during cortical development when retinal images are blurred by immature optics in infant eyes.Light and dark stimuli are separately processed by ON and OFF channels in the retina and visual thalamus. Surprisingly, although most textbooks assume that ON and OFF visual responses are balanced throughout the visual system, recent studies have identified a pronounced overrepresentation of the OFF visual responses in primary visual cortex (area V1) (1–3). This recent discovery resonates with pioneering studies by Galilei (4) and von Helmholtz (5) who noticed that visual spatial resolution was higher for dark than light stimuli. Galilei (4) related the difference in resolution to the observation that a light patch on a dark background appears larger than the same sized dark patch on a light background, an illusion that von Helmholtz (5) named the “irradiation illusion.” Although this illusion has been studied in the past (6, 7), its underlying neuronal mechanisms remain unknown. It has been suggested that the perceived size differences could be caused by the light scatter in the optics of the eye followed by a neuronal nonlinearity (6, 7), but there are no neuronal measurements of a nonlinearity that fits the explanation. Previous studies revealed differences in response linearity between ON and OFF retinal ganglion cells (8, 9) and horizontal cells (10). However, a main conclusion from these studies was that ON retinal ganglion cells were roughly linear and less rectified than OFF retinal ganglion cells (8, 9), which is exactly the opposite of what would be needed to explain the irradiation illusion. Moreover, it remains unclear if ON/OFF retinal differences in response linearity and response gain propagate from retina to visual cortex. To investigate the neuronal mechanisms of the irradiation illusion, we recorded neuronal activity in the visual thalamus and cortex of anesthetized cats, local field potentials in awake monkeys, and visually evoked potentials in humans. We show that OFF neurons in thalamus and cortex increase their responses roughly linearly with luminance contrast, independently of the background luminance. In contrast, ON neurons saturate their responses with small increases in luminance, and approach the linearity of the OFF neurons only on bright backgrounds that make ON responses weaker. We also show that a simple model that uses an early retinal nonlinearity can explain several seemingly unrelated ON/OFF spatial asymmetries, including the difference in spatial resolution between darks and lights, the spatial frequency dependence of OFF dominance in visual cortex, and the difference in receptive field size between ON and OFF retinal ganglion cells. Moreover, because the asymmetry between ON and OFF neurons is present both at the receptive field center and surround of thalamic neurons, our results strongly suggest that it originates at the level of photoreceptors.     

Scene statistics and noise determine the relative arrangement of receptive field mosaics

Many sensory systems utilize parallel ON and OFF pathways that signal stimulus increments and decrements, respectively. These pathways consist of ensembles or grids of ON and OFF detectors spanning sensory space. Yet, encoding by opponent pathways raises a question: How should grids of ON and OFF detectors be arranged to optimally encode natural stimuli? We investigated this question using a model of the retina guided by efficient coding theory. Specifically, we optimized spatial receptive fields and contrast response functions to encode natural images given noise and constrained firing rates. We find that the optimal arrangement of ON and OFF receptive fields exhibits a transition between aligned and antialigned grids. The preferred phase depends on detector noise and the statistical structure of the natural stimuli. These results reveal that noise and stimulus statistics produce qualitative shifts in neural coding strategies and provide theoretical predictions for the configuration of opponent pathways in the nervous system.

Across many sensory systems, neurons encode information about either increments or decrements of stimuli in the environment, so-called ON and OFF signals. This division between ON and OFF signaling has been observed in visual (1, 2), thermosensory (3), auditory (4), olfactory (5), and electrosensory (6) systems. This organization has the advantage that neurons can be tasked with signaling increments or decrements in steady-state stimulus levels with fewer spikes, thereby resulting in more efficient neural codes (7, 8). Moreover, when the number of potential stimuli is large, neurons often specialize; for example, they only respond to a small region of visual space or a narrow auditory frequency band. The combination of these coding strategies raises two questions. First, how should a particular set of detectors, either the ON or OFF cells, arrange themselves most efficiently to cover stimulus space? Second, what is the optimal relative arrangement of ON and OFF detector grids? For one system, the retina, the answer to the first question is clear from previous work: Detectors of a particular type tile stimulus space and exhibit overlap near the 1-sigma boundary of a Gaussian receptive field (9–13). The answer to the second question, what might be called the “sensor alignment problem,” has received comparatively little attention and is the focus of this study.Conceptually, there are three general possibilities for how the sensor alignment problem could be solved. One possibility is that the grids of sensors are statistically independent, meaning the locations of receptive fields in one grid provide no information about the receptive field locations in the other grid. A second possibility is that the two grids are aligned, meaning the receptive field centers in one grid are closer than expected by chance. The third possibility is that the two grids are antialigned, meaning the receptive field centers in the two grids are further apart than expected by chance. On general information theory grounds, the optimal solution is likely to depend on noise in the encoding process and the statistics of the encoded stimuli (14, 15).While most anatomical studies of retinal mosaics indicate they are statistically independent (16–18, but see ref. 19), we have recently shown that grids of ON and OFF receptive field (henceforth called “mosaics”) formed by retinal ganglion cells (RGCs) are antialigned when those cells encode similar visual features (20). Here, we show how these results can be explained through the lens of efficient coding theory (7). This theory argues that sensory systems should aim to reduce the redundancy present in sensory input while minimizing metabolic costs, thereby reliably encoding natural stimuli with fewer spikes. Efficient coding theory has been successful at explaining many aspects of sensory processing and retinal physiology, including center-surround receptive fields, the formation of mosaics, and a greater proportion of OFF than ON cells (7, 11, 15, 21, 22). Thus, we asked whether efficient coding theory might predict the optimal spatial arrangement of ON and OFF receptive field mosaics within the retina. Our approach to this question involved optimizing a model that approximates the processing performed by many RGCs (21). By maximizing the mutual information between an (input) library of natural images and (output) spike rates, we examined the effects of image statistics and encoding noise on the optimal arrangement of ON and OFF mosaics.In this model, we found that the optimal spatial arrangement was a pair of approximately hexagonal mosaics of ON and OFF receptive fields. However, surprisingly, the relative alignment of these mosaics depended on the input noise, output noise, and the statistics of the natural image set. When output noise was low, the mosaics were aligned, with ON and OFF receptive fields centered at nearby locations more often than expected by chance. When output noise was relatively high, antialignment became the favored arrangement. Surprisingly, the content of the image set also strongly influenced the transition between aligned and antialigned mosaics. In particular, when image sets contained more “outlier” images with particularly large luminance or contrast values, antialignment became the favored state for fixed input and output noise. We demonstrate analytically and confirm computationally that as noise parameters or stimulus statistics vary, mutual information changes smoothly, while the optimal mosaic arrangements undergo a sudden, qualitative shift. Finally, we confirm these predictions by showing that systematic manipulations of the training dataset change the phase boundary in a manner predicted by an analytical model. These findings underscore the crucial role played by both noise and the statistics of natural stimuli for understanding specialization and coordination in sensory processing.     

Gating currents of the cloned delayed-rectifier K+ channel DRK1.

Gating currents of the cloned delayed-rectifier K+ channel DRK1 expressed in Xenopus oocytes were measured with the open-oocyte Vaseline-gap voltage-clamp technique. DRK1 gating charge had the following salient properties: (i) gating-charge amplitude correlated positively with size of the expressed ionic K+ currents; (ii) the time integral of ON and OFF gating currents was similar, indicating charge conservation and lack of charge immobilization; (iii) the gating-charge activation curve was shallower and had a half-activation potential 15 mV more negative than the activation curve for K+ conductance; (iv) effective valence for the gating current was about two electronic charges per gating subunit; (v) for large depolarizations (to > 0 mV) prominent rising phases were observed during the ON and OFF gating charge, which appeared as shoulders in unsubtracted traces; (vi) for small depolarizing pulses (to < 0 mV) ionic-current activation and deactivation had time constants similar to ON and OFF gating-current decay, respectively; (vii) negative prepulses made more prominent the ON rising phase and delayed ionic and gating currents. The results are consistent with a model for K+ channel activation that has an early slow and/or weakly voltage-dependent transition between early closed states followed by more voltage-dependent transitions between later closed states and a final voltage-independent closed-open transition.     

Calix[4]arene-based conical-shaped ligands for voltage-dependent potassium channels

Potassium channels are among the core functional elements of life because they underpin essential cellular functions including excitability, homeostasis, and secretion. We present here a series of multivalent calix[4]arene ligands that bind to the surface of voltage-dependent potassium channels (K_v1.x) in a reversible manner. Molecular modeling correctly predicts the best candidates with a conical C₄ symmetry for optimal binding, and the effects on channel function are assessed electrophysiologically. Reversible inhibition was observed, without noticeable damage of the oocytes, for tetraacylguanidinium or tetraarginine members of the series with small lower rim O-substituents. Apparent binding constants were in the low micromolar range and had Hill coefficients of 1, consistent with a single site of binding. Suppression of current amplitude was accompanied by a positive shift in the voltage dependence of gating and slowing of both voltage sensor motion and channel opening. These effects are in keeping with expectations for docking in the central pore and interaction with the pore domain “turret.”     

Retina is structured to process an excess of darkness in natural scenes

Retinal ganglion cells that respond selectively to a dark spot on a brighter background (OFF cells) have smaller dendritic fields than their ON counterparts and are more numerous. OFF cells also branch more densely, and thus collect more synapses per visual angle. That the retina devotes more resources to processing dark contrasts predicts that natural images contain more dark information. We confirm this across a range of spatial scales and trace the origin of this phenomenon to the statistical structure of natural scenes. We show that the optimal mosaics for encoding natural images are also asymmetric, with OFF elements smaller and more numerous, matching retinal structure. Finally, the concentration of synapses within a dendritic field matches the information content, suggesting a simple principle to connect a concrete fact of neuroanatomy with the abstract concept of information: equal synapses for equal bits.     

OFF ganglion cells cannot drive the optokinetic reflex in zebrafish

Whereas the zebrafish retina has long been an important model system for developmental and genetic studies, little is known about the responses of the inner retinal neurons. Here we report single-unit ganglion cell recordings from 5- to 6-day-old zebrafish larvae. In wild-type larvae we identify at least five subtypes of ganglion cell responses to full-field illumination, with ON-OFF and ON-type cells predominating. In the nrc mutant retina, in which the photoreceptor terminals develop abnormally, we observe normal OFF responses but abnormal ON-OFF responses and no ON responses. Previously characterized as blind, these mutants lack an optokinetic reflex (OKR), but in another behavioral assay nrc mutant fish have near-normal responses to the offset of light and slow and sluggish responses to the onset of light. Pharmacological block of the ON pathway mimics most of the nrc visual defects. We conclude that the abnormal photoreceptor terminals in nrc mutants predominantly perturb the ON pathway and that the ON pathway is necessary to drive the OKR in larval zebrafish.     

Glutamate and 2-amino-4-phosphonobutyrate evoke an increase in potassium conductance in retinal bipolar cells.

Although there is general agreement that L-glutamate can produce a depolarizing inward current to account for the hyperpolarizing (OFF) bipolar cell response, the conductance mechanism underlying the depolarizing (ON) response has been difficult to establish satisfactorily. To investigate the ionic bases of the center responses, we studied the whole-cell currents controlled by L-glutamate and its analogues in solitary bipolar cells from salamander retina. We report here two groups of isolated bipolar cells: one group responded to L-glutamate with the previously described inward current [Attwell, D., Mobbs, P., Tessier-Lavigne, M. & Wilson, M. (1987) J. Physiol. (London) 387, 125-161] and a second group showed an outward current that reversed at about -70 mV. Both were associated with an increase in membrane conductance. In addition, DL-2-amino-4-phosphonobutyrate, a compound diagnostic for ON-bipolar cell activity [Slaughter, M. M. & Miller, R. F. (1981) Science 211, 182-185], elicited outward currents that closely resembled those seen in response to L-glutamate and, furthermore, that were shown to arise from an increase in conductance to potassium ions. Thus the presence of two distinct conductances controlled by L-glutamate in solitary cells would provide one mechanism for generating the ON and OFF light responses at the bipolar cell level in the intact retina.     

From the Cover: Generic theory for channel sinuosity

Sinuous patterns traced by fluid flows are a ubiquitous feature of physical landscapes on Earth, Mars, the volcanic floodplains of the Moon and Venus, and other planetary bodies. Typically discussed as a consequence of migration processes in meandering rivers, sinuosity is also expressed in channel types that show little or no indication of meandering. Sinuosity is sometimes described as “inherited” from a preexisting morphology, which still does not explain where the inherited sinuosity came from. For a phenomenon so universal as sinuosity, existing models of channelized flows do not explain the occurrence of sinuosity in the full variety of settings in which it manifests, or how sinuosity may originate. Here we present a generic theory for sinuous flow patterns in landscapes. Using observations from nature and a numerical model of flow routing, we propose that flow resistance (representing landscape roughness attributable to topography or vegetation density) relative to surface slope exerts a fundamental control on channel sinuosity that is effectively independent of internal flow dynamics. Resistance-dominated surfaces produce channels with higher sinuosity than those of slope-dominated surfaces because increased resistance impedes downslope flow. Not limited to rivers, the hypothesis we explore pertains to sinuosity as a geomorphic pattern. The explanation we propose is inclusive enough to account for a wide variety of sinuous channel types in nature, and can serve as an analytical tool for determining the sinuosity a landscape might support.     

State-dependent FRET reports calcium- and voltage-dependent gating-ring motions in BK channels

Large-conductance voltage- and calcium-dependent potassium channels (BK, “Big K+”) are important controllers of cell excitability. In the BK channel, a large C-terminal intracellular region containing a “gating-ring” structure has been proposed to transduce Ca²⁺ binding into channel opening. Using patch-clamp fluorometry, we have investigated the calcium and voltage dependence of conformational changes of the gating-ring region of BK channels, while simultaneously monitoring channel conductance. Fluorescence resonance energy transfer (FRET) between fluorescent protein inserts indicates that Ca²⁺ binding produces structural changes of the gating ring that are much larger than those predicted by current X-ray crystal structures of isolated gating rings.     

Dynamic hybrid materials for constitutional self-instructed membranes

Constitutional self-instructed membranes were developed and used for mimicking the adaptive structural functionality of natural ion-channel systems. These membranes are based on dynamic hybrid materials in which the functional self-organized macrocycles are reversibly connected with the inorganic silica through hydrophobic noncovalent interactions. Supramolecular columnar ion-channel architectures can be generated by reversible confinement within scaffolding hydrophobic silica mesopores. They can be structurally determined by using X-ray diffraction and morphologically tuned by alkali-salts templating. From the conceptual point of view, these membranes express a synergistic adaptive behavior: the simultaneous binding of the fittest cation and its anion would be a case of “homotropic allosteric interactions,” because in time it increases the transport efficiency of the pore-contained superstructures by a selective evolving process toward the fittest ion channel. The hybrid membranes presented here represent dynamic constitutional systems evolving over time to form the fittest ion channels from a library of molecular and supramolecular components, or selecting the fittest ion pairs from a mixture of salts demonstrating flexible adaptation.     

Filter gate closure inhibits ion but not water transport through potassium channels

The selectivity filter of K⁺ channels is conserved throughout all kingdoms of life. Carbonyl groups of highly conserved amino acids point toward the lumen to act as surrogates for the water molecules of K⁺ hydration. Ion conductivity is abrogated if some of these carbonyl groups flip out of the lumen, which happens (i) in the process of C-type inactivation or (ii) during filter collapse in the absence of K⁺. Here, we show that K⁺ channels remain permeable to water, even after entering such an electrically silent conformation. We reconstituted fluorescently labeled and constitutively open mutants of the bacterial K⁺ channel KcsA into lipid vesicles that were either C-type inactivating or noninactivating. Fluorescence correlation spectroscopy allowed us to count both the number of proteoliposomes and the number of protein-containing micelles after solubilization, providing the number of reconstituted channels per proteoliposome. Quantification of the per-channel increment in proteoliposome water permeability with the aid of stopped-flow experiments yielded a unitary water permeability p_f of (6.9 ± 0.6) × 10⁻¹³ cm³⋅s⁻¹ for both mutants. “Collapse” of the selectivity filter upon K⁺ removal did not alter p_f and was fully reversible, as demonstrated by current measurements through planar bilayers in a K⁺-containing medium to which K⁺-free proteoliposomes were fused. Water flow through KcsA is halved by 200 mM K⁺ in the aqueous solution, which indicates an effective K⁺ dissociation constant in that range for a singly occupied channel. This questions the widely accepted hypothesis that multiple K⁺ ions in the selectivity filter act to mutually destabilize binding.     

Effects of self-motion on auditory scene analysis

Auditory scene analysis requires the listener to parse the incoming flow of acoustic information into perceptual "streams," such as sentences from a single talker in the midst of background noise. Behavioral and neural data show that the formation of streams is not instantaneous; rather, streaming builds up over time and can be reset by sudden changes in the acoustics of the scene. Here, we investigated the effect of changes induced by voluntary head motion on streaming. We used a telepresence robot in a virtual reality setup to disentangle all potential consequences of head motion: changes in acoustic cues at the ears, changes in apparent source location, and changes in motor or attentional processes. The results showed that self-motion influenced streaming in at least two ways. Right after the onset of movement, self-motion always induced some resetting of perceptual organization to one stream, even when the acoustic scene itself had not changed. Then, after the motion, the prevalent organization was rapidly biased by the binaural cues discovered through motion. Auditory scene analysis thus appears to be a dynamic process that is affected by the active sensing of the environment.     

Structure of the C-terminal region of an ERG channel and functional implications

The human ether-à-go-go–related gene (hERG) encodes a K⁺ channel crucial for repolarization of the cardiac action potential. EAG-related gene (ERG) channels contain a C-terminal cyclic nucleotide-binding homology domain coupled to the pore of the channel by a C-linker. Here, we report the structure of the C-linker/cyclic nucleotide-binding homology domain of a mosquito ERG channel at 2.5-Å resolution. The structure reveals that the region expected to form the cyclic nucleotide-binding pocket is negatively charged and is occupied by a short β-strand, referred to as the intrinsic ligand, explaining the lack of direct regulation of ERG channels by cyclic nucleotides. In hERG channels, the intrinsic ligand harbors hereditary mutations associated with long-QT syndrome (LQTS), a potentially lethal cardiac arrhythmia. Mutations in the intrinsic ligand affected hERG channel gating and LQTS mutations abolished hERG currents and altered trafficking of hERG channels, which explains the LQT phenotype. The structure also reveals a dramatically different conformation of the C-linker compared with the structures of the related ether-à-go-go–like K⁺ and hyperpolarization-activated cyclic nucleotide-modulated channels, suggesting that the C-linker region may be highly dynamic in the KCNH, hyperpolarization-activated cyclic nucleotide-modulated, and cyclic nucleotide-gated channels.     

Hierarchical model of natural images and the origin of scale invariance

The study of natural images and how our brain processes them has been an area of intense research in neuroscience, psychology, and computer science. We introduced a unique approach to studying natural images by decomposing images into a hierarchy of layers at different logarithmic intensity scales and mapping them to a quasi-2D magnet. The layers were in different phases: “cold” and ordered at large-intensity scales, “hot” and disordered at small-intensity scales, and going through a second-order phase transition at intermediate scales. There was a single “critical” layer in the hierarchy that exhibited long-range correlation similar to that found in the 2D Ising model of ferromagnetism at the critical temperature. We also determined the interactions between layers mapped from natural images and found mutual inhibition that generated locally “frustrated” antiferromagnetic states. Almost all information in natural images was concentrated in a few layers near the phase transition, which has biological implications and also points to the hierarchical origin of scale invariance in natural images.     

The roles of the two proton input channels in cytochrome c oxidase from Rhodobacter sphaeroides probed by the effects of site-directed mutations on time-resolved electrogenic intraprotein proton transfer

The crystal structures of cytochrome c oxidase from both bovine and Paracoccus denitrificans reveal two putative proton input channels that connect the heme-copper center, where dioxygen is reduced, to the internal aqueous phase. In this work we have examined the role of these two channels, looking at the effects of site-directed mutations of residues observed in each of the channels of the cytochrome c oxidase from Rhodobacter sphaeroides. A photoelectric technique was used to monitor the time-resolved electrogenic proton transfer steps associated with the photo-induced reduction of the ferryl-oxo form of heme a₃ (Fe⁴⁺ = O²⁻) to the oxidized form (Fe³⁺OH⁻). This redox step requires the delivery of a “chemical” H⁺ to protonate the reduced oxygen atom and is also coupled to proton pumping. It is found that mutations in the K channel (K362M and T359A) have virtually no effect on the ferryl-oxo-to-oxidized (F-to-Ox) transition, although steady-state turnover is severely limited. In contrast, electrogenic proton transfer at this step is strongly suppressed by mutations in the D channel. The results strongly suggest that the functional roles of the two channels are not the separate delivery of chemical or pumped protons, as proposed recently [Iwata, S., Ostermeier, C., Ludwig, B. & Michel, H. (1995) Nature (London) 376, 660–669]. The D channel is likely to be involved in the uptake of both “chemical” and “pumped” protons in the F-to-Ox transition, whereas the K channel is probably idle at this partial reaction and is likely to be used for loading the enzyme with protons at some earlier steps of the catalytic cycle. This conclusion agrees with different redox states of heme a₃ in the K362M and E286Q mutants under aerobic steady-state turnover conditions.     

Regulated and aberrant glycosylation modulate cardiac electrical signaling

Millions afflicted with Chagas disease and other disorders of aberrant glycosylation suffer symptoms consistent with altered electrical signaling such as arrhythmias, decreased neuronal conduction velocity, and hyporeflexia. Cardiac, neuronal, and muscle electrical signaling is controlled and modulated by changes in voltage-gated ion channel activity that occur through physiological and pathological processes such as development, epilepsy, and cardiomyopathy. Glycans attached to ion channels alter channel activity through isoform-specific mechanisms. Here we show that regulated and aberrant glycosylation modulate cardiac ion channel activity and electrical signaling through a cell-specific mechanism. Data show that nearly half of 239 glycosylation-associated genes (glycogenes) were significantly differentially expressed among neonatal and adult atrial and ventricular myocytes. The N-glycan structures produced among cardiomyocyte types were markedly variable. Thus, the cardiac glycome, defined as the complete set of glycan structures produced in the heart, is remodeled. One glycogene, ST8sia2, a polysialyltransferase, is expressed only in the neonatal atrium. Cardiomyocyte electrical signaling was compared in control and ST8sia2^(−/−) neonatal atrial and ventricular myocytes. Action potential waveforms and gating of less sialylated voltage-gated Na⁺ channels were altered consistently in ST8sia2^(−/−) atrial myocytes. ST8sia2 expression had no effect on ventricular myocyte excitability. Thus, the regulated (between atrium and ventricle) and aberrant (knockout in the neonatal atrium) expression of a single glycogene was sufficient to modulate cardiomyocyte excitability. A mechanism is described by which cardiac function is controlled and modulated through physiological and pathological processes that involve regulated and aberrant glycosylation.     

A theory of direction selectivity for macaque primary visual cortex

This paper offers a theory for the origin of direction selectivity (DS) in the macaque primary visual cortex, V1. DS is essential for the perception of motion and control of pursuit eye movements. In the macaque visual pathway, neurons with DS first appear in V1, in the Simple cell population of the Magnocellular input layer 4Cα. The lateral geniculate nucleus (LGN) cells that project to these cortical neurons, however, are not direction selective. We hypothesize that DS is initiated in feed-forward LGN input, in the summed responses of LGN cells afferent to a cortical cell, and it is achieved through the interplay of 1) different visual response dynamics of ON and OFF LGN cells and 2) the wiring of ON and OFF LGN neurons to cortex. We identify specific temporal differences in the ON/OFF pathways that, together with item 2, produce distinct response time courses in separated subregions; analysis and simulations confirm the efficacy of the mechanisms proposed. To constrain the theory, we present data on Simple cells in layer 4Cα in response to drifting gratings. About half of the cells were found to have high DS, and the DS was broadband in spatial and temporal frequency (SF and TF). The proposed theory includes a complete analysis of how stimulus features such as SF and TF interact with ON/OFF dynamics and LGN-to-cortex wiring to determine the preferred direction and magnitude of DS.

This paper proposes a solution to a longstanding question in visual neuroscience, namely, the origin of direction selectivity (DS) in the visual cortex of macaque monkeys. Motion perception is a vital visual capability well developed in primates. As perceiving motion requires perceiving the direction in which a target moves, DS, the ability of visual neurons to sense the direction of movement, is essential for motion perception (1) and for the control of pursuit eye movements (2). For these reasons, understanding DS is an important first step toward understanding how the cortex processes motion signals.DS in cortical neurons was first documented in the cat (3). Since then, it has been found in neurons all along the visual dorsal stream (an area associated with motion processing) in primates like macaque monkeys (4–7), whose vision is like that of humans. Neurons with DS are, in fact, present across species; they are widespread among visual mammals, an experimental fact that testifies to their biological significance.In the visual pathway of macaques, DS appears first in the primary visual cortex (V1), in the Simple cell population of the input layer 4Cα (8). These neurons provide feed-forward direction-selective signals to subsequent cortical layers and brain regions in the dorsal pathway. Thus, to discover the origin of DS, one is led to examining how neurons in layer 4Cα acquire their DS—and that is where it gets interesting: The neurons that provide visual signals to layer 4Cα, the Magnocellular cells in the lateral geniculate nucleus (LGN), are not direction selective (9–12). Yet many of the cells in the input layer of V1 to which they project are direction selective. A fundamental scientific question, therefore, is how 4Cα neurons acquire their DS. That is the question we would like to answer in this paper.Although many papers have been written on DS since its discovery over half a century ago, and there is continued interest in the subject (13–16), no satisfactory mechanistic explanation for the origin of DS in primate cortex has been proposed before now: Early conceptual models of how DS may arise, such as the Reichardt multiplier (17) or the motion energy model (18), were not concerned with biological mechanisms. Later work proposed neural mechanisms for the motion energy model (19), but they are not sufficient for explaining DS in primate cortex. See Discussion for comparisons of different model mechanisms.It is widely accepted that the DS computation requires spatiotemporal inseparability (STI); that is, different subregions of the receptive field have different time courses of response (18, 20, 21). What were lacking were biological mechanisms that could produce STI, and a clear understanding of how DS depends on the interaction between STI and the spatial and temporal character of the visual stimulus. These are the issues we address in this paper.We hypothesize that a plausible biological mechanism is the interplay between 1) the different dynamics of ON and OFF LGN cells and 2) the specific wiring that connects ON and OFF cells to V1. Item 2 refers here to the well-known fact that OFF and ON LGN cells are wired to segregated V1 receptive field subregions (3, 22, 23). Our main contribution is item 1: We identify, in Results, dynamic differences in the ON/OFF pathways that, together with item 2, produce distinct response time courses in separated receptive-field subregions. The mechanisms we propose are biologically grounded, and, as we show, they are sufficient for initiating DS in the feed-forward LGN input to cortical cells.To constrain our theory, we present experimental results on the responses of macaque 4Cα Simple cells to drifting gratings. Most Simple cells we recorded in 4Cα were unambiguously direction selective, preferring, consistently, the same direction over their entire visible ranges of spatial frequency (SF) and temporal frequency (TF); about half of the cells had high DS. Our data reveal also an important characteristic of neurons with DS, namely, the approximate invariance of DS with SF and TF. Explaining the broadband character of DS (in TF and SF) is a challenge for all previous theories. Our theory includes a complete analysis of how stimulus features like SF and TF interact with ON/OFF dynamics and LGN-to-cortex wiring to explain the broadband character of DS. The theoretical predictions are in good agreement with data.With regard to broader implications, although the theory as described in this paper is specifically about DS, an important message is that, when combining information from multiple channels, slight biases in their temporal filters can greatly enhance the capability of a system. Thus, it may be possible to exploit the temporal axis further in the processing of biological and nonbiological signals, especially in the neural processing of sensory inputs and, possibly, in computer vision.     

The US Department of Justice stumbles on visual perception

A large and highly valuable category of forensic evidence consists of patterned impressions created during the perpetration of a crime. These crime scene artifacts, such as fingerprints or tire tracks, offer visual sensory information that is assessed by trained human observers and compared to sensory experiences elicited by model patterns that would have been produced under a hypothesized set of conditions. By means of this “forensic feature comparison,” the observer makes a judgment about whether the evidence and the model are sufficiently similar to support common origin. In light of documented failures of this approach, significant concerns have been raised about its scientific validity. In response to these concerns, the US Department of Justice has made assertions about how forensic examiners perform feature comparison tasks that are not consistent with modern scientific understanding of the processes of sensation and perception. Clarification of these processes highlights new ways of thinking about and improving the accuracy of forensic feature comparison and underscores the vital role of science in achieving justice.     

TRPM1 is required for the depolarizing light response in retinal ON-bipolar cells

The ON pathway of the visual system, which detects increases in light intensity, is established at the first retinal synapse between photoreceptors and ON-bipolar cells. Photoreceptors hyperpolarize in response to light and reduce the rate of glutamate release, which in turn causes the depolarization of ON-bipolar cells. This ON-bipolar cell response is mediated by the metabotropic glutamate receptor, mGluR6, which controls the activity of a depolarizing current. Despite intensive research over the past two decades, the molecular identity of the channel that generates this depolarizing current has remained elusive. Here, we present evidence indicating that TRPM1 is necessary for the depolarizing light response of ON-bipolar cells, and further that TRPM1 is a component of the channel that generates this light response. Gene expression profiling revealed that TRPM1 is highly enriched in ON-bipolar cells. In situ hybridization experiments confirmed that TRPM1 mRNA is found in cells of the retinal inner nuclear layer, and immunofluorescent confocal microscopy showed that TRPM1 is localized in the dendrites of ON-bipolar cells in both mouse and macaque retina. The electroretinogram (ERG) of TRPM1-deficient (TRPM1^−/−) mice had a normal a-wave, but no b-wave, indicating a loss of bipolar cell response. Finally, whole-cell patch-clamp recording from ON-bipolar cells in mouse retinal slices demonstrated that genetic deletion of TRPM1 abolished chemically simulated light responses from rod bipolar cells and dramatically altered the responses of cone ON-bipolar cells. Identification of TRPM1 as a mGluR6-coupled cation channel reveals a key step in vision, expands the role of the TRP channel family in sensory perception, and presents insights into the evolution of vertebrate vision.