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.     

Aging of human short-wave cone pathways

The retinal image is sampled concurrently, and largely independently, by three physiologically and anatomically distinct pathways, each with separate ON and OFF subdivisions. The retinal circuitry giving rise to an ON pathway receiving input from the short-wave-sensitive (S) cones is well understood, but the S-cone OFF circuitry is more controversial. Here, we characterize the temporal properties of putative S-cone ON and OFF pathways in younger and older observers by measuring thresholds for stimuli that produce increases or decreases in S-cone stimulation, while the middle- and long-wave-sensitive cones are unmodulated. We characterize the data in terms of an impulse response function, the theoretical response to a flash of infinitely short duration, from which the response to any temporally varying stimulus may be predicted. Results show that the S-cone response to increments is faster than to decrements, but this difference is significantly greater for older individuals. The impulse response function amplitudes for increment and decrement responses are highly correlated across individuals, whereas the timing is not. This strongly suggests that the amplitude is controlled by neural circuitry that is common to S-cone ON and OFF responses (photoreceptors), whereas the timing is controlled by separate postreceptoral pathways. The slower response of the putative OFF pathway is ascribed to different retinal circuitry, possibly attributable to a sign-inverting amacrine cell not present in the ON pathway. It is significant that this pathway is affected selectively in the elderly by becoming slower, whereas the temporal properties of the S-cone ON response are stable across the life span of an individual.     

TRPM1 is a component of the retinal ON bipolar cell transduction channel in the mGluR6 cascade

An essential step in intricate visual processing is the segregation of visual signals into ON and OFF pathways by retinal bipolar cells (BCs). Glutamate released from photoreceptors modulates the photoresponse of ON BCs via metabotropic glutamate receptor 6 (mGluR6) and G protein (Go) that regulates a cation channel. However, the cation channel has not yet been unequivocally identified. Here, we report a mouse TRPM1 long form (TRPM1-L) as the cation channel. We found that TRPM1-L localization is developmentally restricted to the dendritic tips of ON BCs in colocalization with mGluR6. TRPM1 null mutant mice completely lose the photoresponse of ON BCs but not that of OFF BCs. In the TRPM1-L-expressing cells, TRPM1-L functions as a constitutively active nonselective cation channel and its activity is negatively regulated by Go in the mGluR6 cascade. These results demonstrate that TRPM1-L is a component of the ON BC transduction channel downstream of mGluR6 in ON BCs.     

Innervation patterns of single physiologically identified geniculocortical axons in the striate cortex of the tree shrew.

We examined the termination patterns of single geniculocortical axons in the striate cortex of the tree shrew by using intracellular recording and horseradish peroxidase staining methods. Axons were classified by whether they responded to light onset (ON center) or light offset (OFF center) and whether they were driven by the ipsi- or contralateral eye. Afferents with ON-center responses end in the upper part of layer IV (IVa) whereas afferents with OFF-center responses end in the lower part of layer IV (IVb). Within each tier, axons driven by the ipsilateral and contralateral eye overlap. These results suggest that binocular convergence occurs within layer IV without mixing the information from the ON- and OFF-center pathways and we consider the significance of this arrangement for visual cortical function.     

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.     

Visual electrophysiological responses in persons with type 1 diabetes

Persons with type 1 diabetes show electrophysiological abnormalities of the visual system which are revealed by methods such as flash electroretinogram (FERG), oscillatory potentials (OPs), pattern electroretinogram (PERG), focal electroretinogram (focal ERG), visual evoked potentials (VEP) in basal condition and after photostress. This review reports the changes in electrophysiological responses of the different structures composing the visual system observed in persons with type 1 diabetes before the development of the overt clinical retinopathy. In persons with type 1 diabetes without retinopathy (IDD), the earlier abnormal electrophysiological responses are recorded from the innermost retinal layers and postretinal visual pathways, as suggested by impaired PERGs and delayed retinocortical time (RCT). These are observed in IDD persons with a disease duration shorter than 6 months. Further electrophysiological changes are recorded from the macula (abnormal focal ERG and VEP after photostress) in IDD persons with disease duration greater than 1 year. Additional electrophysiological changes are recorded from the middle and outer retinal layers (impaired FERG and OPs) in IDD persons with a disease duration greater than 10 years. All the electrophysiological tests show a greater degree of abnormal responses in persons with type 1 diabetes when a background retinopathy is present.     

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.     

Statistics of lateral geniculate nucleus (LGN) activity determine the segregation of ON/OFF subfields for simple cells in visual cortex

The receptive fields for simple cells in visual cortex show a strong preference for edges of a particular orientation and display adjacent excitatory and inhibitory subfields. These subfields are projections from ON-center and OFF-center lateral geniculate nucleus cells, respectively. Here we present a single-cell model using ON and OFF channels, a natural scene environment, and synaptic modification according to the Bienenstock, Cooper, and Munro (BCM) theory. Our results indicate that lateral geniculate nucleus cells must act predominantly in the linear region around the level of spontaneous activity, to lead to the observed segregation of ON/OFF subfields.     

The glutamate analog 2-amino-4-phosphonobutyrate antagonizes synaptic transmission from cones to horizontal cells in the goldfish retina

In the retina, the glutamate analog 2-amino-4-phosphonobutyrate (APB) distinguishes a class of glutamate receptors that is thought to be found only on depolarizing bipolar cells (DBCs). We now report that APB is a potent antagonist of cone-driven horizontal cells in the goldfish retina. APB hyperpolarized the membrane to the same potential as cobalt Ringer's and blocked the light responses. APB acted specifically on the cone pathway, as it had no effect on rod-driven horizontal cells. The lowest effective APB concentration for antagonistic action on the horizontal cells (approximately 2 microM) was similar to the concentration for agonist action on DBCs. APB was not able to block the actions of exogenous glutamate or kainate on horizontal cells. We propose that the action of APB on the cone-horizontal cell synapse is mediated at a site that is distinct from the glutamate and kainate binding site. Therefore, APB is most probably acting at a different locus on the synaptic glutamatergic receptors of the horizontal cells or at presynaptic receptors located on the cones themselves.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Parallel information processing channels created in the retina

In the retina, several parallel channels originate that extract different attributes from the visual scene. This review describes how these channels arise and what their functions are. Following the introduction four sections deal with these channels. The first discusses the “ON” and “OFF” channels that have arisen for the purpose of rapidly processing images in the visual scene that become visible by virtue of either light increment or light decrement; the ON channel processes images that become visible by virtue of light increment and the OFF channel processes images that become visible by virtue of light decrement. The second section examines the midget and parasol channels. The midget channel processes fine detail, wavelength information, and stereoscopic depth cues; the parasol channel plays a central role in processing motion and flicker as well as motion parallax cues for depth perception. Both these channels have ON and OFF subdivisions. The third section describes the accessory optic system that receives input from the retinal ganglion cells of Dogiel; these cells play a central role, in concert with the vestibular system, in stabilizing images on the retina to prevent the blurring of images that would otherwise occur when an organism is in motion. The last section provides a brief overview of several additional channels that originate in the retina.     

Neuroprotective effect of melatonin in experimental optic neuritis in rats

Optic neuritis (ON) is an inflammatory, demyelinating, and neurodegenerative condition of the optic nerve, which might induce permanent vision loss. Currently, there are no effective therapies for this disorder. We have developed an experimental model of primary ON in rats through a single microinjection of 4.5 μg of bacterial lipopolysaccharide (LPS) into the optic nerve. Since melatonin acts as a pleiotropic therapeutic agent in various neurodegenerative diseases, we analyzed the effect of melatonin on LPS‐induced ON. For this purpose, LPS or vehicle were injected into the optic nerve from adult male Wistar rats. One group of animals received a subcutaneous pellet of 20 mg melatonin at 24 hr before vehicle or LPS injection, and another group was submitted to a sham procedure. Melatonin completely prevented the decrease in visual evoked potentials (VEPs), and pupil light reflex (PLR), and preserved anterograde transport of cholera toxin β‐subunit from the retina to the superior colliculus. Moreover, melatonin prevented microglial reactivity (ED1‐immunoreactivity, P < 0.01), astrocytosis (glial fibrillary acid protein‐immunostaining, P < 0.05), demyelination (luxol fast blue staining, P < 0.01), and axon (toluidine blue staining, P < 0.01) and retinal ganglion cell (Brn3a‐immunoreactivity, P < 0.01) loss, induced by LPS. Melatonin completely prevented the increase in nitric oxide synthase 2, cyclooxygenase‐2 levels (Western blot) and TNFα levels, and partly prevented lipid peroxidation induced by experimental ON. When the pellet of melatonin was implanted at 4 days postinjection of LPS, it completely reversed the decrease in VEPs and PLR. These data suggest that melatonin could be a promising candidate for ON treatment.     

Breathing pattern in patients with Parkinson's disease

The improvement in motor performance resulting from levodopa administration in patients with Parkinson's disease (PD) provides the opportunity to investigate ventilatory changes brought about by the disease. The aim of this study has been to investigate these changes in order to specify the mechanisms of the impairment in breathing in PD. Breathing patterns at rest were investigated in 11 patients with idiopathic PD both before (OFF) and after (ON) administration of levodopa at a dose improving their motor performance by at least 30%. Airflow (Fleisch head mounted on a mask), rib cage and abdomen movements (inductance plethysmography) were recorded in the OFF condition 1 h after subjects woke up. Subjects then received levodopa and a new set of recordings was obtained 1 h later, in the ON condition. Breath-by-breath processing of recordings was carried out, and tidal volume (VT), inspiratory (TI) and expiratory (TE) durations were measured. The main finding was a lengthening of TI resulting in a decrease in ventilation and in VT/TI, and an increase in TI/TTOT in the ON compared to the OFF condition. In the ON condition abnormal rib cage-abdomen plots patterns were found in four out of six subjects. A hypothesis on the effect of PD on breathing is proposed on grounds of normal diaphragmatic activity but impaired activity of the other respiratory muscles and more specifically the intercostal muscles.     

A review of primary hereditary optic neuropathies

Summary: The primary inherited optic neuropathies are a heterogeneous group of disorders that result in loss of retinal ganglion cells, leading to the clinical appearance of optic atrophy. They affect between 1:10 000 to 1:50 000 people. The main clinical features are a reduction in visual acuity, colour vision abnormalities, centro-caecal visual field defects and pallor of the optic nerve head. Electrophysiological testing shows a normal flash electroretinogram, absentor delayed pattern visually evoked potentials suggestive of a conduction deficit and N95 waveform reduction on the pattern electroretinogram, consistent with a primary ganglion cell pathology. The primary inherited optic neuropathies may be sporadic or familial. The mode of inheritance may be autosomal dominant, autosomal recessive, X-linked recessive or mitochondrial. Within each of these groups, the phenotypic characteristics vary in such features as the mode and age of onset, the severity of the visual loss, the colour deficit and the overall prognosis. A number of different genes (most as yet unidentified) in both nuclear and mitochondrial genomes, underlie these disorders. The elucidation of the role of the encoded proteins will improve our understanding of basic mechanisms of ganglion cell development, physiology and metabolism and further our understanding of the pathophysiology of optic nerve disease. It will also improve diagnosis, counselling and management of patients, and eventually lead to the development of new therapeutic modalities. This revised version was published online in August 2006 with corrections to the Cover Date.     

Sensory suppression during feeding

Feeding is essential for survival, whereas withdrawal and escape reactions are fundamentally protective. These critical behaviors can compete for an animal's resources when an acutely painful stimulus affects the animal during feeding. One solution to the feeding-withdrawal conflict is to optimize feeding by suppressing pain. We examined whether rats continue to feed when challenged with a painful stimulus. During feeding, motor withdrawal responses to noxious paw heat either did not occur or were greatly delayed. To investigate the neural basis of sensory suppression accompanying feeding, we recorded from brainstem pain-modulatory neurons involved in the descending control of pain transmission. During feeding, pain-facilitatory ON cells were inhibited and pain-inhibitory OFF cells were excited. When a nonpainful somatosensory stimulus preactivated ON cells and preinhibited OFF cells, rats interrupted eating to react to painful stimuli. Inactivation of the brainstem region containing ON and OFF cells also blocked pain suppression during eating, demonstrating that brainstem pain-modulatory neurons suppress motor reactions to external stimulation during homeostatic behaviors.     

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.     

Perioperative Outcomes after On- and Off-Pump Coronary Artery Bypass Grafting

Although numerous reports describe the results of off-pump coronary artery bypass grafting (CABG) at specialized centers and in select patient populations, it remains unclear how off-pump CABG affects real-world patient outcomes. We conducted a large, multicenter observational cohort study of perioperative death and morbidity in on-pump (ON) versus off-pump (OFF) CABG.We reviewed Veterans Affairs Surgical Quality Improvement Program data for all patients (N=65,097) who underwent isolated CABG from October 1997 through April 2011 (intention-to-treat data were available from 2005 onward). The primary outcome was perioperative (30-day or in-hospital) death; the secondary outcomes were perioperative stroke, dialysis dependence, reoperation for bleeding, mechanical circulatory support, myocardial infarction, ventilator support ≥48 hr, and mediastinitis. Propensity scores calculated from age, 17 preoperative risk factors, and year of surgery were used to match 8,911 OFF with 26,733 ON patients.In the complete cohort, compared with the ON patients (n=53,468), the OFF patients (n=11,629) had less perioperative death (2.02% vs 2.53%, P=0.0012) and lower incidences of all morbidities except perioperative myocardial infarction. In the matched cohort, perioperative death did not differ significantly between OFF and ON patients (1.94% vs 2.28%, P=0.06), but the OFF group had lower incidences of all morbidities except for perioperative myocardial infarction and mediastinitis. A subgroup intention-to-treat analysis yielded similar but smaller outcome differences between the ON and OFF groups.Off-pump CABG might be associated with decreased operative morbidity but did not affect operative death, compared with on-pump CABG. Future studies should examine the effect of off-pump CABG on long-term outcomes.     

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.     

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.     

Prospective randomized study of mode switching in a clinical trial of pacemaker therapy for sinus node dysfunction

INTRODUCTION: Atrial fibrillation (AF) is common in pacemaker patients with sinus node dysfunction (SND) and may result in rapid ventricular pacing (RVP) in the DDDR mode. Mode switching (MS) reduces RVP, but its clinical benefit in patients with SND is unknown. METHODS AND RESULTS: Two hundred two patients in the Mode Selection Trial (MOST; 2,010-patient, 6-year trial of DDDR vs VVIR pacing in SND) randomized to DDDR pacemakers with atrial high-rate episode (AHRE) storage capabilities were subrandomized to MS ON (N = 96) or MS OFF (N = 106). Cardiovascular symptoms, quality of life (QOL), reprogramming due to RVP, death, stroke, and heart failure hospitalization (HFH) were compared between groups. The treatment groups were similar with regard to AF history (59% MS ON vs 57% MS OFF). AHREs occurred in 49% patients during median follow-up of 2.2 years. Median AHRE duration (in min; MS ON 116 vs MS OFF 58, P = 0.29), frequency AHREs/week (MS ON 3.5 vs MS OFF 6.4, P = 0.23), and time spent in AHRE (min/week) (MS ON 450, MS OFF 268) were similar. Reprogramming due to any RVP during AHREs occurred more in MS OFF vs MS ON (13.2% vs 3.1%, P = 0.011) and marginally more for symptomatic RVP (8.5% vs 2.1%, P = 0.062). Cardiovascular symptoms occurred in 93.6% MS ON vs 90.2% MS OFF (P = 0.38). Median number of symptoms reported per visit was similar (MS ON 1.3 vs MS OFF 1.5, P = 0.62). Median symptom frequency/severity, summed and averaged over visits, was similar (MS ON 4.3 vs MS OFF 4.5, P = 0.74). QOL was not different between groups. Death, stroke, and HFH were not different between groups. CONCLUSION: MS reduces pacemaker reprogramming due to RVP during AHREs in a small number of patients but does not improve QOL or cardiovascular symptoms overall among patients with SND.