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CNS neurons change their connectivity to accommodate a changing environment, form memories, or respond to injury. Plasticity in the adult mammalian retina after injury or disease was thought to be limited to restructuring resulting in abnormal retinal anatomy and function. Here we report that neurons in the mammalian retina change their connectivity and restore normal retinal anatomy and function after injury. Patches of photoreceptors in the rabbit retina were destroyed by selective laser photocoagulation, leaving retinal inner neurons (bipolar, amacrine, horizontal, ganglion cells) intact. Photoreceptors located outside of the damaged zone migrated to make new functional connections with deafferented bipolar cells located inside the lesion. The new connections restored ON and OFF responses in deafferented ganglion cells. This finding extends the previously perceived limits of restorative plasticity in the adult retina and allows for new approaches to retinal laser therapy free of current detrimental side effects such as scotomata and scarring. [ABSTRACT FROM AUTHOR]

Sensory neurons have been hypothesized to efficiently encode signals from the natural environment subject to resource constraints. The predictions of this efficient coding hypothesis regarding the spatial filtering properties of the visual system have been found consistent with human perception, but they have not been compared directly with neural responses. Here, we analyze the information that retinal ganglion cells transmit to the brain about the spatial information in natural images subject to three resource constraints: the number of retinal ganglion cells, their total response variances, and their total synaptic strengths. We derive a model that optimizes the transmitted information and compare it directly with measurements of complete functional connectivity between cone photoreceptors and the four major types of ganglion cells in the primate retina, obtained at single-cell resolution. We find that the ganglion cell population exhibited 80% efficiency in transmitting spatial information relative to the model. Both the retina and the model exhibited high redundancy (--30%) among ganglion cells of the same cell type. A novel and unique prediction of efficient coding, the relationships between projection patterns of individual cones to all ganglion cells, was consistent with the observed projection patterns in the retina. These results indicate a high level of efficiency with near-optimal redundancy in visual signaling by the retina. [ABSTRACT FROM AUTHOR]

Understanding how ensembles of neurons collectively interact will be a key step in developing a mechanistic theory of cognitive processes. Recent progress in multineuron recording and analysis techniques has generated tremendous excitement over the physiology of living neural networks. One of the key developments driving this interest is a new class of models based on the principle of maximum entropy. Maximum entropy models have been reported to account for spatial correlation structure in ensembles of neurons recorded from several different types of data. Importantly, these models require only information about the firing rates of individual neurons and their pairwise correlations. If this approach is generally applicable, it would drastically simplify the problem of understanding how neural networks behave. Given the interest in this method, several groups now have worked to extend maximum entropy models to account for temporal correlations. Here, we review how maximum entropy models have been applied to neuronal ensemble data to account for spatial and temporal correlations. We also discuss criticisms of the maximum entropy approach that argue that it is not generally applicable to larger ensembles of neurons. We conclude that future maximum entropy models will need to address three issues: temporal correlations, higher-order correlations, and larger ensemble sizes. Finally, we provide a brief list of topics for future research. [ABSTRACT FROM AUTHOR]

Synchronized firing among neurons has been proposed to constitute an elementary aspect of the neural code in sensory and motor systems. However, it remains unclear how synchronized firing affects the large-scale patterns of activity and redundancy of visual signals in a complete population of neurons. We recorded simultaneously from hundreds of retinal ganglion cells in primate retina, and examined synchronized firing in completely sampled populations of ~50 -100 ON-parasol cells, which form a major projection to the magnocellular layers of the lateral geniculate nucleus. Synchronized firing in pairs of cells was a subset of a much larger pattern of activity that exhibited local, isotropic spatial properties. However, a simple model based solely on interactions between adjacent cells reproduced 99% of the spatial structure and scale of synchronized firing. No more than 20% of the variability in firing of an individual cell was predictable from the activity of its neighbors. These results held both for spontaneous firing and in the presence of independent visual modulation of the firing of each cell. In sum, large-scale synchronized firing in the entire population of ON-parasol cells appears to reflect simple neighbor interactions, rather than a unique visual signal or a highly redundant coding scheme. [ABSTRACT FROM AUTHOR]

The collective representation of visual space in high resolution visual pathways was explored by simultaneously measuring the receptive fields of hundreds of ON and OFF midget and parasol ganglion cells in isolated primate retina. As expected, the receptive fields of all four cell types formed regular mosaics uniformly tiling the visual scene. Surprisingly, comparison of all four mosaics revealed that the overlap of neighboring receptive fields was nearly identical, for both the excitatory center and inhibitory surround components of the receptive field. These observations contrast sharply with the large differences in the dendritic overlap between the parasol and midget cell populations, revealing a surprising lack of correspondence between the anatomical and functional architecture in the dominant circuits of the primate retina. [ABSTRACT FROM AUTHOR]

Multineuron firing patterns are often observed, yet are predicted to be rare by models that assume independent firing. To explain these correlated network states, two groups recently applied a second-order maximum entropy model that used only observed firing rates and pairwise interactions as parameters (Schneidman et al., 2006; Shlens et al., 2006). Interestingly, with these minimal assumptions they predicted 90-99% of network correlations. If generally applicable, this approach could vastly simplify analyses of complex networks. However, this initial work was done largely on retinal tissue, and its applicability to cortical circuits is mostly unknown. This work also did not address the temporal evolution of correlated states. To investigate these issues, we applied the model to multielectrode data containing spontaneous spikes or local field potentials from cortical slices and cultures. The model worked slightly less well in cortex than in retina, accounting for 88 ±7% (mean ± SD) of network correlations. In addition, in 8 of 13 preparations, the observed sequences of correlated states were significantly longer than predicted by concatenating states from the model. This suggested that temporal dependencies are a common feature of cortical network activity, and should be considered in future models. We found a significant relationship between strong pairwise temporal correlations and observed sequence length, suggesting that pairwise temporal correlations may allow the model to be extended into the temporal domain. We conclude that although a second-order maximum entropy model successfully predicts correlated states in cortical networks, it should be extended to account for temporal correlations observed between states. [ABSTRACT FROM AUTHOR]

The primate visual system consists of parallel pathways initiated by distinct cell types in the retina that encode different features of the visual scene. Small bistratified cells (SBCs), which form a major projection to the thalamus, exhibit blue-ON/yellow-OFF [S-ON/ (L+M)-OFF] light responses thought to be important for high-acuity color vision. However, the spatial processing properties of individual SBCs and their spatial arrangement across the visual field are poorly understood. The present study of peripheral primate retina reveals that contrary to previous suggestions, SBCs exhibit center-surround spatial structure, with the (L+M)-OFF component of the receptive field ~50% larger in diameter than the S-ON component. Analysis of response kinetics shows that the (L+M)-OFF response in SBCs is slower than the S-ON response and significantly less transient than that of simultaneously recorded OFF-parasol cells. The (L+M)-OFF response in SBCs was eliminated by bath application of the metabotropic glutamate receptor agonist L-APB. These observations indicate that the (L+M)-OFF response of SBCs is not formed by OFF-bipolar cell input as has been suspected and suggest that it arises from horizontal cell feedback. Finally, the receptive fields of SBCs form orderly mosaics, with overlap and regularity similar to those of ON-parasol cells. Thus, despite their distinctive morphology and chromatic properties, SBCs exhibit two features of other retinal ganglion cell types: center-surround antagonism and regular mosaic sampling of visual space. [ABSTRACT FROM AUTHOR]

The primate retina communicates visual information to the brain via a set of parallel pathways that originate from at least 22 anatomically distinct types of retinal ganglion cells. Knowledge of the physiological properties of these ganglion cell types is of critical importance for understanding the functioning of the primate visual system. Nonetheless, the physiological properties of only a handful of retinal ganglion cell types have been studied in detail. Here we show, using a newly developed multielectrode array system for the large-scale recording of neural activity, the existence of a physiologically distinct population of ganglion cells in the primate retina with distinctive visual response properties. These cells, which we will refer to as upsilon cells, are characterized by large receptive fields, rapid and transient responses to light, and significant nonlinearities in their spatial summation. Based on the measured properties of these cells, we speculate that they correspond to the smooth/large radiate cells recently identified morphologically in the primate retina and may therefore provide visual input to both the lateral geniculate nucleus and the superior colliculus. We further speculate that the upsilon cells may be the primate retina's counterparts of the Y-cells observed in the cat and other mammalian species. [ABSTRACT FROM AUTHOR]

Retinal implants are intended to help patients with degenerative conditions by electrically stimulating surviving cells to produce artificial vision. However, little is known about how individual retinal ganglion cells respond to direct electrical stimulation in degenerating retina. Here we used a transgenic rat model to characterize ganglion cell responses to light and electrical stimulation during photoreceptor degeneration. Retinas from pigmented P23H-1 rats were compared with wild-type retinas between ages P37 and P752. During degeneration, retinal thickness declined by 50%, largely as a consequence of photoreceptor loss. Spontaneous electrical activity in retinal ganglion cells initially increased two- to threefold, but returned to nearly normal levels around P600. A profound decrease in the number of light-responsive ganglion cells was observed during degeneration, culminating in retinas without detectable light responses by P550. Ganglion cells from transgenic and wild-type animals were targeted for focal electrical stimulation using multielectrode arrays with electrode diameters of ∼10 microns. Ganglion cells were stimulated directly and the success rate of stimulation in both groups was 60–70% at all ages. Surprisingly, thresholds (∼0.05 mC/cm2) and latencies (∼0.25 ms) in P23H rat ganglion cells were comparable to those in wild-type ganglion cells at all ages and showed no change over time. Thus ganglion cells in P23H rats respond normally to direct electrical stimulation despite severe photoreceptor degeneration and complete loss of light responses. These findings suggest that high-resolution epiretinal prosthetic devices may be effective in treating vision loss resulting from photoreceptor degeneration. [ABSTRACT FROM AUTHOR]

Current understanding of many neural circuits is limited by our ability to explore the vast number of potential interactions between different cells. We present a new approach that dramatically reduces the complexity of this problem. Large-scale multi-electrode recordings were used to measure electrical activity in nearly complete, regularly spaced mosaics of several hundred ON and OFF parasol retinal ganglion cells in macaque monkey retina. Parasol cells exhibited substantial pairwise correlations, as has been observed in other species, indicating functional connectivity. However, pairwise measurements alone are insufficient to determine the prevalence of multi-neuron firing patterns, which would be predicted from widely diverging common inputs and have been hypothesized to convey distinct visual messages to the brain. The number of possible multi-neuron firing patterns is far too large to study exhaustively, but this problem may be circumvented if two simple rules of connectivity can be established: (1) multi-cell firing patterns arise from multiple pairwise interactions, and (2) interactions are limited to adjacent cells in the mosaic. Using maximum entropy methods from statistical mechanics, we show that pairwise and adjacent interactions accurately accounted for the structure and prevalence of multi-neuron firing patterns, explaining ∼98% of the departures from statistical independence in parasol cells and ∼99% of the departures that were reproducible in repeated measurements. This approach provides a way to define limits on the complexity of network interactions and thus may be relevant for probing the function of many neural circuits. [ABSTRACT FROM AUTHOR]

To achieve its precise neural connectivity, the developing mammalian nervous system undergoes extensive activity-dependent synapse remodeling. Recently microglial cells have been shown to be responsible for a portion of synaptic remodeling, but the remaining mechanisms remain mysterious. Here we report a new role for astrocytes in actively engulfing CNS synapses. This process helps to mediate synapse elimination, requires the Megf10 and Mertk phagocytic pathways, and is strongly dependent on neuronal activity. Developing mice deficient in both astrocyte pathways fail to normally refine their retinogeniculate connections and retain excess functional synapses. Lastly, we show that in the adult mouse brain, astrocytes continuously engulf both excitatory and inhibitory synapses. These studies reveal a novel role for astrocytes in mediating synapse elimination in the developing and adult brain, identify Megf10 and Mertk as critical players in the synapse remodeling underlying neural circuit refinement, and have important implications for understanding learning and memory as well as neurological disease processes.

Abstract: Q-Naturale® is a natural food-grade surfactant isolated from the bark of the Quillaja saponaria Molina tree. The major surface active components of Q-Naturale® are believed to be saponin-based amphiphilic molecules. In this study, we compared the effectiveness of this natural surfactant for forming and stabilizing emulsions with a synthetic surfactant (Tween 80) that is widely used in the food industry. We examined the influence of homogenization pressure, number of passes, and emulsifier concentration on the particle size produced. Q-Naturale® was capable of forming relatively small droplets (d < 200 nm) at low surfactant-to-oil ratios (SOR < 0.1) using high pressure homogenization (microfluidization), but the droplets were not as small as those produced using Tween 80 under similar conditions (d < 150 nm). Q-Naturale®-coated droplets were stable to droplet coalescence over a range of pH values (2–8), salt concentrations (0–500 mM NaCl) and temperatures (20–90 °C). However, some droplet flocculation was observed under highly acidic (pH 2) and high ionic strength (≥400 mM NaCl) conditions, which was attributed to screening of electrostatic repulsion. Indeed, Q-Naturale®-coated droplets had a relatively high negative charged at neutral pH that decreased in magnitude with decreasing pH. These results indicate that Q-Naturale® is an effective natural surfactant that may be able to replace synthetic surfactants in food and beverage products. [Copyright &y& Elsevier]

Objective: Neural interfaces are designed to evoke specific patterns of electrical activity in populations of neurons by stimulating with many electrodes. However, currents passed simultaneously through multiple electrodes often combine nonlinearly to drive neural responses, making evoked responses difficult to predict and control. This response nonlinearity could arise from the interaction of many excitable sites in each cell, any of which can produce a spike. However, this multi-site activation hypothesis is difficult to verify experimentally., Approach: We developed a biophysical model to study retinal ganglion cell (RGC) responses to multi-electrode stimulation and validated it using data collected from ex vivo preparations of the macaque retina using a microelectrode array (512 electrodes; 30µm pitch; 10µm diameter)., Results: First, the model was validated by using it to reproduce essential empirical findings from single-electrode recording and stimulation, including recorded spike voltage waveforms at multiple locations and sigmoidal responses to injected current. Then, stimulation with two electrodes was modeled to test how the positioning of the electrodes relative to the cell affected the degree of response nonlinearity. Currents passed through pairs of electrodes positioned near the cell body or far from the axon (>40 µm) exhibited approximately linear summation in evoking spikes. Currents passed through pairs of electrodes close to the axon summed linearly when their locations along the axon were similar, and nonlinearly otherwise. Over a range of electrode placements, several distinct, localized spike initiation sites were observed, and the number of these sites covaried with the degree of response nonlinearity. Similar trends were observed for three-electrode stimuli. All of these trends in the simulation were consistent with experimental observations. Significance . These findings support the multi-site activation hypothesis for nonlinear activation of neurons, providing a biophysical interpretation of previous experimental results and potentially enabling more efficient use of multi-electrode stimuli in future neural implants.

Fixational eye movements alter the number and timing of spikes transmitted from the retina to the brain, but whether these changes enhance or degrade the retinal signal is unclear. To quantify this, we developed a Bayesian method for reconstructing natural images from the recorded spikes of hundreds of retinal ganglion cells (RGCs) in the macaque retina (male), combining a likelihood model for RGC light responses with the natural image prior implicitly embedded in an artificial neural network optimized for denoising. The method matched or surpassed the performance of previous reconstruction algorithms, and provides an interpretable framework for characterizing the retinal signal. Reconstructions were improved with artificial stimulus jitter that emulated fixational eye movements, even when the eye movement trajectory was assumed to be unknown and had to be inferred from retinal spikes. Reconstructions were degraded by small artificial perturbations of spike times, revealing more precise temporal encoding than suggested by previous studies. Finally, reconstructions were substantially degraded when derived from a model that ignored cell-to-cell interactions, indicating the importance of stimulus-evoked correlations. Thus, fixational eye movements enhance the precision of the retinal representation., Competing Interests: 9Competing Interests Statement The authors declare no competing interests.