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Time is largely a hidden variable in vision. It is the condition for seeing interesting things such as spatial forms and patterns, colours and movements in the external world, and yet is not meant to be noticed in itself. Temporal aspects of visual processing have received comparatively little attention in research. Temporal properties have been made explicit mainly in measurements of resolution and integration in simple tasks such as detection of spatially homogeneous flicker or light pulses of varying duration. Only through a mechanistic understanding of their basis in retinal photoreceptors and circuits can such measures guide modelling of natural vision in different species and illuminate functional and evolutionary trade-offs. Temporal vision research would benefit from bridging traditions that speak different languages. Towards that goal, I here review studies from the fields of human psychophysics, retinal physiology and neuroethology, with a focus on fundamental constraints set by early vision.

Neuroinflammation has been put forward as a mechanism triggering axonal regrowth in the mammalian central nervous system (CNS), yet little is known about the underlying cellular and molecular players connecting these two processes. In this study, we provide evidence that MMP2 is an essential factor linking inflammation to axonal regeneration by using an in vivo mouse model of inflammation-induced axonal regeneration in the optic nerve. We show that infiltrating myeloid cells abundantly express MMP2 and that MMP2 deficiency results in reduced long-distance axonal regeneration. However, this phenotype can be rescued by restoring MMP2 expression in myeloid cells via a heterologous bone marrow transplantation. Furthermore, while MMP2 deficiency does not affect the number of infiltrating myeloid cells, it does determine the coordinated expression of pro- and anti-inflammatory molecules. Altogether, in addition to its role in axonal regeneration via resolution of the glial scar, here, we reveal a new mechanism via which MMP2 facilitates axonal regeneration, namely orchestrating the expression of pro- and anti-inflammatory molecules by infiltrating innate immune cells. ispartof: Cells vol:10 issue:7 pages:1-19 ispartof: location:Switzerland status: Published online

The establishment of neuronal circuits requires neurons to develop and maintain appropriate connections with cellular partners in and out the central nervous system. These phenomena include elaboration of dendritic arborization and formation of synaptic contacts, initially made in excess. Subsequently, refinement occurs, and pruning takes places both at axonal and synaptic level, defining a homeostatic balance maintained throughout the lifespan. All these events require genetic regulations which happens cell-autonomously and are strongly influenced by environmental factors. This review aims to discuss the involvement of guidance cues from the Semaphorin family.

From the mid-19th century until the 1980's, frogs and toads provided important research models for many fundamental questions in visual neuroscience. In the present century, they have been largely neglected. Yet they are animals with highly developed vision, a complex retina built on the basic vertebrate plan, an accessible brain, and an experimentally useful behavioural repertoire. They also offer a rich diversity of species and life histories on a reasonably restricted physiological and evolutionary background. We suggest that important insights may be gained from revisiting classical questions in anurans with state-of-the-art methods. At the input to the system, this especially concerns the molecular evolution of visual pigments and photoreceptors, at the output, the relation between retinal signals, brain processing and behavioural decision-making.

Significance Human retinas contain five light-responsive cell types: rods; short (S)-, mid (M)-, and long (L)-wavelength–sensitive cones; and melanopsin-expressing ganglion cells. Intrinsically light-sensitive retinal ganglion cells (RGCs) also relay rod and cone information to brain areas involved in nonvisual responses, such as pupil constriction. Cones allow for visual color discrimination. How cone-dependent color discrimination affects nonvisual responses is poorly understood. We show that selectively activating L-cones or melanopsin constricts the pupil whereas S- or M-cone activation paradoxically dilates the pupil. Intrinsically photosensitive RGCs therefore appear to signal color on yellow/blue and red/green scales, with blue and green cone shifts being processed as brightness decrements. These findings are crucial in understanding brightness coding for visual and nonvisual responses such as circadian entrainment and alerting effects of light., The human retina contains five photoreceptor types: rods; short (S)-, mid (M)-, and long (L)-wavelength–sensitive cones; and melanopsin-expressing ganglion cells. Recently, it has been shown that selective increments in M-cone activation are paradoxically perceived as brightness decrements, as opposed to L-cone increments. Here we show that similar effects are also observed in the pupillary light response, whereby M-cone or S-cone increments lead to pupil dilation whereas L-cone or melanopic illuminance increments resulted in pupil constriction. Additionally, intermittent photoreceptor activation increased pupil constriction over a 30-min interval. Modulation of L-cone or melanopic illuminance within the 0.25–4-Hz frequency range resulted in more sustained pupillary constriction than light of constant intensity. Opposite results were found for S-cone and M-cone modulations (2 Hz), mirroring the dichotomy observed in the transient responses. The transient and sustained pupillary light responses therefore suggest that S- and M-cones provide inhibitory input to the pupillary control system when selectively activated, whereas L-cones and melanopsin response fulfill an excitatory role. These findings provide insight into functional networks in the human retina and the effect of color-coding in nonvisual responses to light, and imply that nonvisual and visual brightness discrimination may share a common pathway that starts in the retina.

Genetic engineering by viral infection of single cells is useful to study complex systems such as the brain. However, available methods for infecting single cells have drawbacks that limit their applications. Here we describe 'virus stamping', in which viruses are reversibly bound to a delivery vehicle - a functionalized glass pipette tip or magnetic nanoparticles in a pipette - that is brought into physical contact with the target cell on a surface or in tissue, using mechanical or magnetic forces. Different single cells in the same tissue can be infected with different viruses and an individual cell can be simultaneously infected with different viruses. We use rabies, lenti, herpes simplex, and adeno-associated viruses to drive expression of fluorescent markers or a calcium indicator in target cells in cell culture, mouse retina, human brain organoid, and the brains of live mice. Virus stamping provides a versatile solution for targeted single-cell infection of diverse cell types, both in vitro and in vivo.

There is great individual variation in response to general anesthetics (GAs) leading to difficulties in optimal dosing and sometimes even accidental awareness during general anesthesia (AAGA). AAGA is a rare, but potentially devastating, complication affecting between 0.1% and 2% of patients undergoing surgery. The development of novel personalized screening techniques to accurately predict a patient’s response to GAs and the risk of AAGA remains an unmet clinical need. In the present study, we demonstrate the principle of using a fluorescent reporter of the membrane dipole potential, di-8-ANEPPs, as a novel method to monitor anesthetic activity using a well-described inducer/noninducer pair. The membrane dipole potential has previously been suggested to contribute a novel mechanism of anesthetic action. We show that the fluorescence ratio of di-8-ANEPPs changed in response to physiological concentrations of the anesthetic, 1-chloro-1,2,2-trifluorocyclobutane (F3), but not the structurally similar noninducer, 1,2-dichlorohexafluorocyclobutane (F6), to artificial membranes and in vitro retinal cell systems. Modulation of the membrane dipole provides an explanation to overcome the limitations associated with the alternative membrane-mediated mechanisms of GA action. Furthermore, by combining this technique with noninvasive retinal imaging technologies, we propose that this technique could provide a novel and noninvasive technique to monitor GA susceptibility and identify patients at risk of AAGA.

See Herms and Schön (doi:10.1093/brain/awx100) for a scientific commentary on this article. Glaucoma is often diagnosed late when vision loss has already occurred. Cordeiro et al. report a new fluorescent marker for retinal imaging that can safely visualise real-time in vivo neuronal apoptosis in patients. Increased labelling is observed in patients with progressive neurodegenerative disease compared to healthy controls., See Herms and Schön (doi:10.1093/brain/awx100) for a scientific commentary on this article. Retinal cell apoptosis occurs in many ocular neurodegenerative conditions including glaucoma—the major cause of irreversible blindness worldwide. Using a new imaging technique that we have called DARC (detection of apoptosing retinal cells), which until now has only been demonstrated in animal models, we assessed if annexin 5 labelled with fluorescent dye DY-776 (ANX776) could be used safely in humans to identify retinal cell apoptosis. Eight patients with glaucomatous neurodegeneration and evidence of progressive disease, and eight healthy subjects were randomly assigned to intravenous ANX776 doses of 0.1, 0.2, 0.4 and 0.5 mg in an open-label, phase 1 clinical trial. In addition to assessing the safety, tolerability and pharmacokinetics of ANX776, the study aimed to explore whether DARC could successfully visualize individual retinal cell apoptosis in vivo in humans, with the DARC count defined as the total number of unique ANX776-labelled spots. DARC enabled retinal cell apoptosis to be identified in the human retina using ANX776. Single ANX776-labelled cells were visualized in a dose-dependent pattern (P < 0.001) up to 6 h after injection. The DARC count was significantly higher (2.37-fold, 95% confidence interval: 1.4–4.03, P = 0.003) in glaucoma patients compared to healthy controls, and was significantly (P = 0.045) greater in patients who later showed increasing rates of disease progression, based on either optic disc, retinal nerve fibre layer or visual field parameters. Additionally, the DARC count significantly correlated with decreased central corneal thickness (Spearman’s R = −0.68, P = 0.006) and increased cup-disc ratios (Spearman’s R = 0.47, P = 0.038) in glaucoma patients and with increased age (Spearman’s R = 0.77, P = 0.001) in healthy controls. Finally, ANX776 was found to be safe and well-tolerated with no serious adverse events, and a short half-life (10–36 min). This proof-of-concept study demonstrates that retinal cell apoptosis can be identified in the human retina with increased levels of activity in glaucomatous neurodegenerative disease. To our knowledge, this is the first time individual neuronal apoptosis has been visualized in vivo in humans and is the first demonstration of detection of individual apoptotic cells in a neurodegenerative disease. Furthermore, our results suggest the level of apoptosis (‘DARC count’) is predictive of disease activity, indicating the potential of DARC as a surrogate marker. Although further trials are clearly needed, this study validates experimental findings supporting the use of DARC as a method of detection and monitoring of patients with glaucomatous neurodegeneration, where retinal ganglion cell apoptosis is an established process and where there is a real need for tools to non-invasively assess treatment efficacy.

Circadian clocks predictively adjust the physiology of organisms to the day/night cycle. The retina has its own clock, and many diurnal changes in its physiology have been reported. However, their implications for retinal functions and visually guided behavior are largely unresolved. Here, we study the impact of diurnal rhythm on the sensitivity limit of mouse vision. A simple photon detection task allowed us to link well-defined retinal output signals directly to visually guided behavior. We show that visually guided behavior at its sensitivity limit is strongly under diurnal control, reaching the highest sensitivity and stability at night. The diurnal differences in visual sensitivity did not arise in the retina, as assessed by spike recordings from the most sensitive retinal ganglion cell types: ON sustained, OFF sustained, and OFF transient alpha ganglion cells. Instead, we found that mice, as nocturnal animals, use a more efficient search strategy for visual cues at night. Intriguingly, they can switch to the more efficient night strategy even at their subjective day after first having performed the task at night. Our results exemplify that the shape of visual psychometric functions depends robustly on the diurnal state of the animal, its search strategy, and even its diurnal history of performing the task. The results highlight the impact of the day/night cycle on high-level sensory processing, demonstrating a direct diurnal impact on the behavioral strategy of the animal.

Using sensory information to trigger different behaviours relies on circuits that pass-through brain regions. However, the rules by which parallel inputs are routed to different downstream targets is poorly understood. The superior colliculus mediates a set of innate behaviours, receiving input from ~30 retinal ganglion cell types and projecting to behaviourally important targets including the pulvinar and parabigeminal nucleus. Combining transsynaptic circuit tracing with in-vivo and ex-vivo electrophysiological recordings we observed a projection specific logic where each collicular output pathway sampled a distinct set of retinal inputs. Neurons projecting to the pulvinar or parabigeminal nucleus uniquely sampled 4 and 7 cell types, respectively. Four others innervated both pathways. The visual response properties of retinal ganglion cells correlated well with those of their disynaptic targets. These findings suggest that projection specific sampling of retinal inputs forms a mechanistic basis for the selective triggering of visually guided behaviours by the superior colliculus.

Glaucoma is a major eye disease characterized by a progressive loss of retinal ganglion cells (RGCs). Biomechanical forces as a result of hydrostatic pressure and strain play a role in this disease. Decreasing intraocular pressure is the only available therapy so far, but is not always effective and does not prevent blindness in many cases. There is a need for drugs that protect RGCs from dying in glaucoma; to develop these, we need valid glaucoma and drug screening models. Since in vivo models are unsuitable for screening purposes, we focus on in vitro and ex vivo models in this review. Many groups have studied pressure and strain model systems to mimic glaucoma, to investigate the molecular and cellular events leading to mechanically induced RGC death. Therefore, the focus of this review is on the different mechanical model systems used to mimic the biomechanical forces in glaucoma. Most models use either cell or tissue strain, or fluid- or gas-controlled hydrostatic pressure application and apply it to the relevant cell types such as trabecular meshwork cells, optic nerve head astrocytes, and RGCs, but also to entire eyes. New model systems are warranted to study concepts and test experimental compounds for the development of new drugs to protect vision in glaucoma patients. Impact Statement The outcome of currently developed models to investigate mechanically induced retinal ganglion cell death by applying different mechanical strains varies widely. This suggests that a robust glaucoma model has not been developed yet. However, a comprehensive overview of current developments is not available. In this review, we have therefore assessed what has been done before and summarized the available knowledge in the field, which can be used to develop improved models for glaucoma research.

In many international studies, rates of completed suicide and suicide attempts have a seasonal pattern that peaks in spring or summer. This exploratory study investigated the association between solar insolation and a history of suicide attempt in patients with bipolar I disorder. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area on Earth. Data were collected previously from 5536 patients with bipolar I disorder at 50 collection sites in 32 countries at a wide range of latitudes in both hemispheres. Suicide related data were available for 3365 patients from 310 onset locations in 51 countries. 1047 (31.1%) had a history of suicide attempt. There was a significant inverse association between a history of suicide attempt and the ratio of mean winter solar insolation/mean summer solar insolation. This ratio is smallest near the poles where the winter insolation is very small compared to the summer insolation. This ratio is largest near the equator where there is relatively little variation in the insolation over the year. Other variables in the model that were positively associated with suicide attempt were being female, a history of alcohol or substance abuse, and being in a younger birth cohort. Living in a country with a state-sponsored religion decreased the association. (All estimated coefficients p

Adult postmitotic mammalian cells, including neurons and cardiomyocytes, have a limited capacity to regenerate after injury. Therefore, an understanding of the molecular mechanisms underlying their regenerative ability is critical to advance tissue repair therapies. Recent studies highlight how redox signalling via paracrine cell-to-cell communication may act as a central mechanism coupling tissue injury with regeneration. Post-injury redox paracrine signalling can act by diffusion to nearby cells, through mitochondria or within extracellular vesicles, affecting specific intracellular targets such as kinases, phosphatases, and transcription factors, which in turn trigger a regenerative response. Here, we review redox paracrine signalling mechanisms in postmitotic tissue regeneration and discuss current challenges and future directions.

The human pupillary light response is driven by all classes of photoreceptors in the human eye-the three classes of cones, the rods, and the intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment melanopsin. These photoreceptor classes have distinct but overlapping spectral tuning, and even a monochromatic light with a wavelength matched to the peak spectral sensitivity of a given photoreceptor will stimulate all photoreceptors. The method of silent substitution uses pairs of lights ("metamers") to selectively stimulate a given class of photoreceptors while keeping the activation of all others constant. In this primer, we describe the method of silent substitution and provide an overview of studies that have used it to examine inputs to the human pupillary light response.

The human pupillary light response is driven by all classes of photoreceptors in the human eye—the three classes of cones, the rods, and the intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment melanopsin. These photoreceptor classes have distinct but overlapping spectral tuning, and even a monochromatic light with a wavelength matched to the peak spectral sensitivity of a given photoreceptor will stimulate all photoreceptors. The method of silent substitution uses pairs of lights (“metamers”) to selectively stimulate a given class of photoreceptors while keeping the activation of all others constant. In this primer, we describe the method of silent substitution and provide an overview of studies that have used it to examine inputs to the human pupillary light response.

Recently, we showed that matrix metalloproteinase-12 (MMP-12) is highly expressed in microglia and myeloid infiltrates, which are presumably involved in blood&ndash, brain barrier (BBB) leakage and subsequent neuronal cell death that follows status epilepticus (SE). Here, we assessed the effects of a hydroxypyrone-based inhibitor selective for MMP-12 in the pilocarpine-induced SE rat model to determine hippocampal cell survival. In the hippocampus of rats treated with pilocarpine, intra-hippocampal injections of the MMP-12 inhibitor protected Cornu Ammonis 3 (CA3) and hilus of dentate gyrus neurons against cell death and limited the development of the ischemic-like lesion that typically develops in the CA3 stratum lacunosum-moleculare of the hippocampus. Furthermore, we showed that MMP-12 inhibition limited immunoglobulin G and albumin extravasation after SE, suggesting a reduction in BBB leakage. Finally, to rule out any possible involvement of seizure modulation in the neuroprotective effects of MMP-12 inhibition, neuroprotection was also observed in the retina of treated animals after optic nerve crush. Overall, these results support the hypothesis that MMP-12 inhibition can directly counteract neuronal cell death and that the specific hydroxypyrone-based inhibitor used in this study could be a potential therapeutic agent against neurological diseases/disorders characterized by an important inflammatory response and/or neuronal cell loss.

Kailin Tian,1,2 Shannon Shibata-Germanos,1 Milena Pahlitzsch,1 M Francesca Cordeiro1,3 1Glaucoma and Retinal Neurodegeneration Research Group, UCL Institute of Ophthalmology, London, UK; 2Eye Centre, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 3Western Eye Hospital, ICORG, Imperial College NHS Trust, London, UK Abstract: Glaucoma is the second leading cause of blindness worldwide and is most notably characterized by progressive optic nerve atrophy and advancing loss of retinal ganglion cells (RGCs). The main concomitant factor is the elevated intraocular pressure (IOP). Existing treatments are focused generally on lowering IOP. However, both RGC loss and optic nerve atrophy can independently occur with IOP at normal levels. In recent years, there has been substantial progress in the development of neuroprotective therapies for glaucoma in order to restore vital visual function. The present review intends to offer a brief insight into conventional glaucoma treatments and discuss exciting current developments of mostly preclinical data in novel neuroprotective strategies for glaucoma that include recent advances in noninvasive diagnostics going beyond IOP maintenance for an enhanced global view. Such strategies now target RGC loss and optic nerve damage, opening a critical therapeutic window for preventative monitoring and treatment. Keywords: glaucoma, retinal ganglion cell, neuroprotection

Injury to the adult central nervous systems (CNS) can result in severe long-term disability because damaged CNS connections fail to regenerate after trauma. Identification of regulators that enhance the intrinsic growth capacity of severed axons is a first step to restore function. Here, we conducted a gain-of-function genetic screen in Drosophila to identify strong inducers of axonal growth after injury. We focus on a novel axis the Down Syndrome Cell Adhesion Molecule (Dscam1), the de-ubiquitinating enzyme Fat Facets (Faf)/Usp9x and the Jun N-Terminal Kinase (JNK) pathway transcription factor Kayak (Kay)/Fos. Genetic and biochemical analyses link these genes in a common signaling pathway whereby Faf stabilizes Dscam1 protein levels, by acting on the 3'-UTR of its mRNA, and Dscam1 acts upstream of the growth-promoting JNK signal. The mammalian homolog of Faf, Usp9x/FAM, shares both the regenerative and Dscam1 stabilizing activities, suggesting a conserved mechanism. ispartof: FRONTIERS IN CELLULAR NEUROSCIENCE vol:11 ispartof: location:Switzerland status: published

The visual system is composed of diverse cell types that encode distinct aspects of the visual scene and may form separate processing channels. Here we present further evidence for that hypothesis whereby functional cell groups in the dorsal lateral geniculate nucleus (dLGN) are differentially modulated during behavior. Using simultaneous multi-electrode recordings in dLGN and primary visual cortex (V1) of behaving mice, we characterized the impact of locomotor activity on response amplitude, variability, correlation and spatiotemporal tuning. Locomotion strongly impacts the amplitudes of dLGN and V1 responses but the effects on variability and correlations are relatively minor. With regards to tunings, locomotion enhances dLGN responses to high temporal frequencies, preferentially affecting ON transient cells and neurons with nonlinear responses to high spatial frequencies. Channel specific modulations may serve to highlight particular visual inputs during active behaviors., Locomotion is known to modulate neuronal firing in both the visual thalamus (LGN) and V1. Here, the authors characterize the LGN modulation in detail and report that neurons with transient ON responses for high spatial frequency stimuli show the strongest gain modulation.

Study objectives To determine the effect of light exposure on subsequent sleep characteristics under ambulatory field conditions. Methods Twenty healthy participants were fitted with ambulatory polysomnography (PSG) and wrist-actigraphs to assess light exposure, rest–activity, sleep quality, timing, and architecture. Laboratory salivary dim-light melatonin onset was analyzed to determine endogenous circadian phase. Results Later circadian clock phase was associated with lower intensity (R2 = 0.34, χ2(1) = 7.19, p < .01), later light exposure (quadratic, controlling for daylength, R2 = 0.47, χ2(3) = 32.38, p < .0001), and to later sleep timing (R2 = 0.71, χ2(1) = 20.39, p < .0001). Those with later first exposure to more than 10 lux of light had more awakenings during subsequent sleep (controlled for daylength, R2 = 0.36, χ2(2) = 8.66, p < .05). Those with later light exposure subsequently had a shorter latency to first rapid eye movement (REM) sleep episode (R2 = 0.21, χ2(1) = 5.77, p < .05). Those with less light exposure subsequently had a higher percentage of REM sleep (R2 = 0.43, χ2(2) = 13.90, p < .001) in a clock phase modulated manner. Slow-wave sleep accumulation was observed to be larger after preceding exposure to high maximal intensity and early first light exposure (p < .05). Conclusions The quality and architecture of sleep is associated with preceding light exposure. We propose that light exposure timing and intensity do not only modulate circadian-driven aspects of sleep but also homeostatic sleep pressure. These novel ambulatory PSG findings are the first to highlight the direct relationship between light and subsequent sleep, combining knowledge of homeostatic and circadian regulation of sleep by light. Upon confirmation by interventional studies, this hypothesis could change current understanding of sleep regulation and its relationship to prior light exposure. Clinical trial details This study was not a clinical trial. The study was ethically approved and nationally registered (NL48468.042.14).

Coenzyme Q10 (CoQ10) is a mitochondrial-targeted antioxidant with known neuroprotective activity. Its ocular effects when co-solubilised with α–tocopherol polyethylene glycol succinate (TPGS) were evaluated. In vitro studies confirmed that CoQ10 was significantly protective in different retinal ganglion cell (RGC) models. In vivo studies in Adult Dark Agouti (DA) rats with unilateral surgically-induced ocular hypertension (OHT) treated with either CoQ10/TPGS micelles or TPGS vehicle twice daily for three weeks were performed, following which retinal cell health was assessed in vivo using DARC (Detection of Apoptotic Retinal Cells) and post-mortem with Brn3a histological assessment on whole retinal mounts. CoQ10/TPGS showed a significant neuroprotective effect compared to control with DARC (p

Microglia play an important role in the pathology of CNS disorders, however, there remains significant uncertainty about the neuroprotective/degenerative role of these cells due to a lack of techniques to adequately assess their complex behaviour in response to injury. Advancing microscopy techniques, transgenic lines and well-characterized molecular markers, have made histological assessment of microglia populations more accessible. However, there is a distinct lack of tools to adequately extract information from these images to fully characterise microglia behaviour. This, combined with growing economic pressures and the ethical need to minimise the use of laboratory animals, led us to develop tools to maximise the amount of information obtained. This study describes a novel approach, combining image analysis with spatial statistical techniques. In addition to monitoring morphological parameters and global changes in microglia density, nearest neighbour distance, and regularity index, we used cluster analyses based on changes in soma size and roundness to yield novel insights into the behaviour of different microglia phenotypes in a murine optic nerve injury model. These methods should be considered a generic tool to quantitatively assess microglia activation, to profile phenotypic changes into microglia subpopulations, and to map spatial distributions in virtually every CNS region and disease state. ispartof: Scientific Reports vol:7 issue:1 ispartof: location:England status: published

openaire: EC/H2020/713645/EU//BioMEP All sensory information is encoded in neural spike trains. It is unknown how the brain utilizes this neural code to drive behavior. Here, we unravel the decoding rules of the brain at the most elementary level by linking behavioral decisions to retinal output signals in a single-photon detection task. A transgenic mouse line allowed us to separate the two primary retinal outputs, ON and OFF pathways, carrying information about photon absorptions as increases and decreases in spiking, respectively. We measured the sensitivity limit of rods and the most sensitive ON and OFF ganglion cells and correlated these results with visually guided behavior using markerless head and eye tracking. We show that behavior relies only on the ON pathway even when the OFF pathway would allow higher sensitivity. Paradoxically, behavior does not rely on the spike code with maximal information but instead relies on a decoding strategy based on increases in spiking. Smeds et al. combine retinal ganglion cell recordings with markerless tracking of mouse behavior in photon detection. They show that behavior relies on information presented as increased spiking activity rather than the spike code carrying the maximal information.

Primary open angle glaucoma (POAG) is a complex progressive optic nerve neuropathy triggered by both environmental and genetic risk factors. Several ocular tissues, including the ciliary body, trabecular meshwork and optic nerve head, and perhaps even brain tissues, are involved in a chain of pathological events leading to POAG.Genetic risk evidence for POAG came from family linkage-studies implicating a small number of disease genes (MYOC, OPEN, WDR36). Recent Genome Wide Association Studies (GWAS) identified a large number of new POAG loci and disease genes, such as CAV1, CDKN2B and GAS7. In the current study, we reviewed over 120 family and GWA studies. We selected in total 65 (candidate) POAG disease genes and proceeded to assess their function, mRNA expression in POAG relevant eye tissues and possible changes in disease state. We found that the proteins corresponding to these 65 (candidate) POAG disease genes take part in as few as four common functional molecular networks. Functions attributed to these 4 networks were developmental (dys)function, lipid metabolism, and inflammatory processes. For the 65 POAG disease genes, we reviewed the available (transgenic) mouse models of POAG, which may be useful for future functional studies. Finally, we showed that the 65 (candidate) POAG genes substantially increased the specificity and sensitivity of a discriminative POAG risk test. This suggests that personal risk assessment and personalized medicine for POAG are on the horizon. Taken together, the data presented are essential to comprehend the role of genetic variation in POAG, and may provide leads to understand the pathophysiology of POAG as well as other neurodegenerative disorders, such as Alzheimer's disease. (C) 2013 Elsevier Ltd. All rights reserved.

The amyloid beta (Aβ) pathway is strongly implicated in neurodegenerative conditions such as Alzheimer’s disease and more recently, glaucoma. Here, we identify the α2 adrenergic receptor agonists (α2ARA) used to lower intraocular pressure can prevent retinal ganglion cell (RGC) death via the non-amyloidogenic Aβ-pathway. Neuroprotective effects were confirmed in vivo and in vitro in different glaucoma-related models using α2ARAs brimonidine (BMD), clonidine (Clo) and dexmedetomidine. α2ARA treatment significantly reduced RGC apoptosis in experimental-glaucoma models by 97.7% and 92.8% (BMD, P

The regenerative ability of CNS axons decreases with age however this ability remains largely intact in PNS axons throughout adulthood. These differences are likely to correspond with age-related silencing of proteins necessary for axon growth and elongation. In previous studies, it has been shown that reintroduction of the alpha9 integrin subunit (tenascin-C receptor, ?9) that is downregulated in adult CNS can improve neurite outgrowth and sensory axon regeneration after a dorsal rhizotomy or a dorsal column crush spinal cord lesion. In the current study, we demonstrate that virally-expressed integrins (?9, ?6, or ?1 integrin) in the adult rat sensorimotor cortex and adult red nucleus are excluded from axons following neuronal transduction. Attempts to stimulate transport by inclusion of a cervical spinal injury and thus an upregulation of extracellular matrix molecules at the lesion site, or co-transduction with its binding partner, ?1 integrin, did not induce integrin localization within axons. In contrast, virally-expressed ?9 integrin in developing rat cortex (postnatal day 5 or 10) demonstrated clear localization of integrins in cortical axons revealed by the presence of integrin in the axons of the corpus callosum and internal capsule as well as in the neuronal cell body. Furthermore, examination of dorsal root ganglia neurons and retinal ganglion cells demonstrated integrin localization both within peripheral nerve as well as dorsal root axons and within optic nerve axons, respectively. Together, our results suggest a differential ability for in vivo axonal transport of transmembrane proteins dependent on neuronal age and subtype.Significance Statement: Most CNS neurons have an intrinsically low ability to regenerate their axons. This study has asked whether the transport into axons of integrins, the receptors that mediate growth through extracellular matrix, might reveal reasons for the poor regenerative ability of CNS axons. Tagged integrins were expressed in sensory, retinal ganglion cell, cortical and red nucleus neurons. The integrins were transported down the axons of sensory and retinal ganglion cell axons, but not down the axons of adult cortical or red nucleus neurons. However, during the postnatal period of corticospinal axon growth, cortical neurons admitted integrins into their axons. The findings suggest that exclusion of integrins and other receptors from CNS axons may be a cause for their poor regenerative ability.

Sirtuins, comprised of seven members, protect cells from injury, possibly through different roles. In this study, we used two young rat optic nerve injury models to analyze the changes in Sirts 1-7 at different time points to better understand the role of sirtuins during optic nerve injury. Twelve-week-old adult male F344 rats (total n=42) were divided randomly into two groups. One group was subjected to optic nerve cut (ON-cut) and the other group was subjected to a peripheral nerve-optic nerve graft (PN-ON graft) on the left eye. At 1 and 3 days and 1, 2, and 4 weeks, rats were euthanized and retinas of both eyes were removed. Total RNA was extracted and first-strand cDNA was synthesized. Sirts 1-7 and housekeeping -actin quantitative real-time PCR were performed. The quantitative real-time PCR profile showed that sirtuin mRNAs in both groups increased following optic nerve injury with and without peripheral nerve grafting. Sirt1 mRNA increased rapidly, reaching its peak at 3 days after surgery. Sirts 2-7 showed an increasing trend and remained high through 4 weeks after surgery. Sirts 4 and 6 were the only Sirts that increased in number in the PN-graft group at 4 weeks after surgery, where neuronal survival should be higher. Our data indicate that Sirt1 and Sirts 2-7 may play different or complementary roles in optic nerve injury and that Sirts 4 and 6 may play a greater role than the remaining Sirts in axon regeneration.

Besides a beneficial cardiovascular effect, it was recently suggested that statins can also exert neuroprotective actions. In a previous study, we provided in vitro evidence that lovastatin treatment abates excitotoxic cell death in primary cortical neurons. Here, we investigated the neuroprotective effect of lovastatin in an in vivo mouse model. We found that administration of lovastatin (20 mg/kg) significantly protects cholinergic neurons and their cortical projections against N-methyl-D-aspartate (60 nmol)-induced cell death in the magnocellular nucleus basalis, a neuronal cell group that is characteristically affected in Alzheimer's disease. Furthermore, lovastatin-mediated neuroprotection was shown to be dependent on protein kinase B (PKB)/Akt signaling since treatment with the PKB/Akt inhibitor LY294002 blocked the lovastatin-induced neuroprotective effect. The loss of cholinergic neurons after the lesion in the magnocellular nucleus basalis resulted in memory impairment as tested in a passive avoidance paradigm. This was reverted by pre-lesion lovastatin treatment. From these studies we conclude that treatment with lovastatin may provide protection against neuronal injury in excitotoxic conditions associated with neurodegenerative diseases including Alzheimer's disease.

Studies in humans and mice revealed that circadian phase shifting effects of light are larger at the beginning of a light exposure interval than during subsequent exposure. Little is known about the dynamics of this response reduction phenomenon. Here the authors propose a method to obtain information on the progression of phase during light exposure. Phase response curves to intervals of light exposure over a wide range in duration are available for flesh flies, mice, and humans. By comparing the phase shifts induced by pulses of various durations but starting at the same circadian phase, the progression of phase during a long interval (hours) of light exposure is reconstructed for each of these 3 species. For flies, the phase progression curves show that light pulses—if long enough— eventually make the pacemaker stabilize around InT18 (near subjective dusk), as is typical for strong resetting. The progression of phase toward the final value never shows advances larger than 7 h, while delays can be as large as 18 h. By applying the phase progression curve method presented in this study, differences between advances and delays in type-0 phase response curves can be distinguished clearly. In flesh flies ( Sarcophaga) this bifurcation between delays and advance occurs when light exposure starts at InT0 (subjective midnight). The present study confirms earlier findings in mice showing that the beginning of the light pulse generates stronger phase shifts than subsequent hours of light. Response reduction is complete within 1 h of exposure. It is argued that the variation is not so much due to light adaptation processes, but rather to response saturation. In contrast to light adaptation, response saturation is fundamental to proper functioning of the circadian pacemaker during natural entrainment. For understanding entrainment of the pacemaker to natural light, phase progression curves in which naturalistic light profiles are applied could be an important tool.

Mammalian retinal photoreceptors form an irradiance detection system that drives many nonvisual responses to light such as pupil reflex and resetting of the circadian clock. To understand the role of pupil size in circadian light responses, pupil diameter was pharmacologically manipulated and the effect on behavioral phase shifts at different irradiance levels was studied in the Syrian hamster. Dose-response curves for steady-state pupil size and for behavioral phase shifts were constructed for 3 pupil conditions (dilated, constricted, and control). Retinal irradiance was calculated from corneal irradiance, pupil size, retinal surface area, and absorption of ocular media. The sensitivity of photic responses to retinal irradiance is approximately 1.5 log units higher than to corneal irradiance. When plotted against corneal irradiance, pharmacological pupil constriction reduces the light sensitivity of the circadian system, but pupil dilation has no effect. As expected, when plotted against retinal irradiance all dose-response curves superimposed, confirming that the circadian system responds to photon flux on the retina. Pupil dilation does not increase the circadian response to increasing irradiance, since the response of the circadian system attains saturation at irradiance levels lower than those required to induce pupil constriction. The main finding shows that due to the different response sensitivities, the effect of pupil constriction on the light sensitivity of the circadian system in the hamster under natural conditions is virtually negligible. We further suggest the existence of distinct modulating mechanisms for the differential retinal irradiance sensitivity of the pupil system and the circadian system, which enables the different responses to be tuned to their specific tasks while using similar photoreceptive input.

Background The discovery of a novel photoreceptor in the retinal ganglion cells with a highest sensitivity of 470-490 nm blue light has led to research on the effects of short-wavelength light in humans. Several studies have explored the efficacy of monochromatic blue or blue-enriched light in the treatment of SAD. In this study, a comparison has been made between the effects of broad-wavelength light without ultraviolet (UV) wavelengths compared to narrow-band blue light in the treatment of sub-syndromal seasonal affective disorder (Sub-SAD). Method In a 15-day design, 48 participants suffering from Sub-SAD completed 20-minute sessions of light treatment on five consecutive days. 22 participants were given bright white-light treatment (BLT, broad-wavelength light without UV 10 000 lux, irradiance 31.7 Watt/m2) and 26 participants received narrow-band blue light (BLUE, 100 lux, irradiance 1.0 Watt/m2). All participants completed daily and weekly questionnaires concerning mood, activation, sleep quality, sleepiness and energy. Also, mood and energy levels were assessed by means of the SIGH-SAD, the primary outcome measure. Results On day 15, SIGH-SAD ratings were significantly lower than on day 1 (BLT 54.8 %, effect size 1.7 and BLUE 50.7 %, effect size 1.9). No statistically significant differences were found on the main outcome measures. Conclusion Light treatment is an effective treatment for Sub-SAD. The use of narrow-band blue-light treatment is equally effective as bright white-light treatment. Trial registration This study was registered in the Dutch Trial Register (Nederlands Trial Register TC = 4342) (20-12-2013).

The molecular diversification of cell surface molecules has long been postulated to impart specific surface identities on neuronal cell types. The existence of unique cell surface identities would allow neurons to distinguish one another and connect with their appropriate target cells. Although progress has been made in identifying cell type-specific surface molecule repertoires and in characterizing their extracellular interactions, determining how this molecular diversity contributes to the precise wiring of neural circuitry has proven challenging. Here, we review the role of the cadherin, neurexin, immunoglobulin and leucine-rich repeat protein superfamilies in the specification of connectivity. The emerging evidence suggests that the concerted actions of these proteins may critically contribute to the assembly of neural circuits. ispartof: Nature Reviews. Neuroscience vol:17 issue:4 pages:22-35 ispartof: location:England status: published

It is beyond doubt that the timing of sleep is under control of the circadian pacemaker. Humans are a diurnal species; they sleep mostly at night, and they do so at approximately 24-h intervals. If they do not adhere to this general pattern, for instance when working night shifts or when travelling across time zones, they experience the stubborn influence of their circadian clock. In recent years much has been discovered about the organisation of the circadian clock. New photoreceptor cells in the retina have been found to influence the input to the clock, and much of the molecular machinery of the clock has been unravelled. It is now known that the circadian rhythm of sleep and wakefulness is only loosely coupled to the circadian rhythm of the pacemaker. New theories have been proposed for the functions of sleep and the sites at which those functions are executed. In spite of this rapid increase in knowledge of the circadian clock and of sleep regulatory processes, much remains to be discovered concerning the precise interaction between the biological clock and sleep timing. This is particularly unfortunate in view of the 24-h demands of our society for 7 days a week. Too little is known about the negative consequences of the societal pressures on well-being and performance. (c) 2006 Elsevier Inc. All rights reserved.

Characterizing the functional phenotypes of neurons is essential for understanding how genotypes can be related to the neural basis of behaviour. Traditional classifications of neurons by single features (such as morphology or firing behaviour) are increasingly inadequate for reflecting functional phenotypes, as they do not integrate functions across different neuronal types. Here, we describe a set of rules for identifying and predicting functional phenotypes that combine morphology, intrinsic ion channel species and their distributions in dendrites, and functional properties. This more comprehensive neuronal classification should be an improvement on traditional classifications for relating genotype to functional phenotype.

We measured human psychophysical detection thresholds for test pulses which are superimposed on spatially homogeneous backgrounds that have abrupt onsets and offsets of high-contrast 25 Hz flicker. After the onset of the background flicker, test thresholds reach their steady-state levels within 20-60 ms. After the offset of the background flicker, test thresholds remain elevated above their steady-state level for much longer durations. Adaptation after onsets and offsets of background flicker is modeled with a divisive gain control that is activated by temporal contrast. We show that a feedback structure for the gain control can explain the asymmetric dynamics observed after onsets and offsets of the background contrast. Finally, we measure detection thresholds for tests presented on steadily flickering backgrounds as a function of the contrast of the background flicker. We show that the divisive feedback model for contrast gain control can describe these results as well.

Recovery from contrast adaptation was studied in psychophysical experiments. We measured detection thresholds for a test pulse presented on a photopic background as a function of the time after the offset of a high-contrast flicker of the background. The decrease of thresholds with time is well described by a power-law function. Thresholds for tests presented at 640 ms after the offset of the background contrast are still significantly elevated above the threshold measured when the observers have completely adapted to a steady background. We compare the psychophysical data with contrast estimates of ideal-observer models. A match between the results for human and ideal observers can be obtained when the ideal observer is limited by noise. For a quantitative match, we assume that the ideal observer performs a Bayesian calculation on its noise-perturbed input, sampled every 10–20 ms. For the Bayesian calculation we assume a prior probability distribution function for the input contrast that has a lower cutoff at the standard deviation of the noise.

Computational analyses have begun to elucidate which components of somatosensory cortical population activity may encode basic stimulus features. Recent results from rat barrel cortex suggest that the essence of this code is not synergistic spike patterns, but rather the precise timing of single neuron's first post-stimulus spikes. This may form the basis for a fast, robust population code.

The presence of two spectrally different kinds of rod photoreceptors in amphibians has been hypothesized to enable purely rod-based colour vision at very low light levels. The hypothesis has never been properly tested, so we performed three behavioural experiments at different light intensities with toads (Bufo) and frogs (Rana) to determine the thresholds for colour discrimination. The thresholds of toads were different in mate choice and prey-catching tasks, suggesting that the differential sensitivities of different spectral cone types as well as task-specific factors set limits for the use of colour in these behavioural contexts. In neither task was there any indication of rod-based colour discrimination. By contrast, frogs performing phototactic jumping were able to distinguish blue from green light down to the absolute visual threshold, where vision relies only on rod signals. The remarkable sensitivity of this mechanism comparing signals from the two spectrally different rod types approaches theoretical limits set by photon fluctuations and intrinsic noise. Together, the results indicate that different pathways are involved in processing colour cues depending on the ecological relevance of this information for each task.This article is part of the themed issue ‘Vision in dim light’.

A model is presented for the early (retinal) stages of temporal processing of light inputs in the visual system. The model consists of a sequence of three adaptation processes, with two instantaneous nonlinearities in between. The three adaptation processes are, in order of processing of the light input: a divisive light adaptation, a subtractive light adaptation, and a contrast gain control. Divisive light adaptation is modeled by two gain controls. The first of these is a fast feedback loop with square-root behavior, the second a slow feedback loop with logarithm-like behavior. This can explain several aspects of the temporal behavior of photoreceptor outputs. Subtractive light adaptation is modeled by a high-pass filter equivalent to a fractional differentiation, and it can explain the attenuation of low frequencies observed in ganglion cell responses. Contrast gain control in the model is fast, and can explain the decreased detectability of test signals that are superimposed on dynamic backgrounds. We determine psychophysical detection thresholds for brief test pulses that are presented on flickering backgrounds, for a wide range of temporal modulation frequencies of these backgrounds. The model can explain the psychophysical data for the full range of modulation frequencies tested, as well as detection thresholds obtained for test pulses on backgrounds with increment and decrement steps in intensity.

Comparative modeling and ab initio multiconfigurational quantum chemistry are combined to investigate the reactivity of the human nonvisual photoreceptor melanopsin. It is found that both the thermal and photochemical isomerization of the melanopsin 11-cis retinal chromophore occur via a space-saving mechanism involving the unidirectional, counterclockwise twisting of the =C11H-C12H= moiety with respect to its Lys340-linked frame as proposed by Warshel for visual pigments [Warshel A (1976) Nature 260(5553):679-683]. A comparison with the mechanisms documented for vertebrate (bovine) and invertebrate (squid) visual photoreceptors shows that such a mechanism is not affected by the diversity of the three chromophore cavities. Despite such invariance, trajectory computations indicate that although all receptors display less than 100 fs excited state dynamics, human melanopsin decays from the excited state ∼40 fs earlier than bovine rhodopsin. Some diversity is also found in the energy barriers controlling thermal isomerization. Human melanopsin features the highest computed barrier which appears to be ∼2.5 kcal mol(-1) higher than that of bovine rhodopsin. When assuming the validity of both the reaction speed/quantum yield correlation discussed by Warshel, Mathies and coworkers [Weiss RM, Warshel A (1979) J Am Chem Soc 101:6131-6133; Schoenlein RW, Peteanu LA, Mathies RA, Shank CV (1991) Science 254(5030):412-415] and of a relationship between thermal isomerization rate and thermal activation of the photocycle, melanopsin turns out to be a highly sensitive pigment consistent with the low number of melanopsin-containing cells found in the retina and with the extraretina location of melanopsin in nonmammalian vertebrates.

Background: Retinal ganglion cells (RGCs), the output neurons of the retina, project to over 20 distinct brain nuclei, including the lateral geniculate nucleus (LGN), a thalamic region comprised of three functionally distinct subnuclei: the ventral LGN (vLGN), the dorsal LGN (dLGN) and the intergeniculate leaflet (IGL). We previously identified reelin, an extracellular glycoprotein, as a critical factor that directs class-specific targeting of these subnuclei. Reelin is known to bind to two receptors: very-low-density lipoprotein receptor (VLDLR) and low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2). Here we examined the roles of these canonical reelin receptors in retinogeniculate targeting. Results: To assess the roles of VLDLR and LRP8 in retinogeniculate targeting, we used intraocular injections of fluorescently conjugated cholera toxin B subunit (CTB) to label all RGC axons in vivo. Retinogeniculate projections in mutant mice lacking either VLDLR or LRP8 appeared similar to controls; however, deletion of both receptors resulted in dramatic defects in the pattern of retinal innervation in LGN. Surprisingly, defects in vldlr(-/-); lrp8(-/-) double mutant mice were remarkably different than those observed in mice lacking reelin. First, we failed to observe retinal axons exiting the medial border of the vLGN and IGL to invade distant regions of non-retino-recipient thalamus. Second, an ectopic region of binocular innervation emerged in the dorsomedial pole of vldlr(-/-); lrp8(-/-) mutant dLGN. Analysis of retinal projection development, retinal terminal sizes and LGN cytoarchitecture in vldlr(-/-); lrp8(-/-) mutants, all suggest that a subset of retinal axons destined for the IGL are misrouted to the dorsomedial pole of dLGN in the absence of VLDLR and LRP8. Such mistargeting is likely the result of abnormal migration of IGL neurons into the dorsomedial pole of dLGN in vldlr(-/-); lrp8(-/-) mutants. Conclusions: In contrast to our expectations, the development of both the LGN and retinogeniculate projections appeared dramatically different in mutants lacking either reelin or both canonical reelin receptors. These results suggest that there are reelin-independent functions of VLDLR and LRP8 in LGN development, and VLDLR- and LRP8-independent functions of reelin in class-specific axonal targeting. NIH EY021222, NS047463 Thomas F Jeffress and Kate Miller Jeffress Memorial Trust VCU Presidential Research Incentive Program (PRIP)