Adenosine is a neuromodulator present in various areas of the central nervous system, including the retina. Adenosine may serve a neuroprotective role in the retina, based on electroretinogram (ERG) recordings from the rat retina. Our purpose was to assess the role of A2A and A3 adenosine receptors in the generation and modulation of the rat ERG. The flash ERG was recorded with corneal electrodes from Sprague Dawley rats. Agonists and antagonists for A2A and A3 receptors, and adenosine were injected (5 µl) into the vitreous. The effects on the components of the single flash scotopic and photopic ERGs were examined, and ERG flicker. Adenosine (0.5 mM) increased the mean amplitudes of the scotopic ERG a-waves (68 ± 8 to 97 ± 14 µV, P = 0.042), and b-waves (236 ± 38 µV to 305 ± 42 µV). A2A agonist CGS21680 (2 mM) reduced the mean amplitude of the ERG b-wave, from 298 ± 21 µV in response to the brightest stimulus to 212 ± 19 µV (P = 0.005), and mean scotopic oscillatory potentials (OPs) from 100 ± 9 µV to 47 ± 11 µV (P = 0.023). ZM241385 [4 mM], an A2A antagonist, decreased the scotopic b-wave of the ERG. A3 agonist 2-CI-IB-MECA (0.5 mM) increased the a-wave, while decreasing the scotopic and photopic ERG b-waves, and the scotopic OPs. A3 antagonist VUF5574 (1 mM) increased the mean amplitude of the scotopic a-wave (66 ± 8 to 140 ± 29 µV, P = 0.046) and b-wave (224 ± 20 to 312 ± 39 µV, P = 0.0037). No significant effects on ERG flicker were found. We conclude that retinal neurons containing A2A and/or A3 adenosine receptors contribute to the generation of the ERG a- and b-waves and OPs.

Retinal bipolar cells spread their dendritic arbors to tile the retinal surface, extending them to the tips of the dendritic fields of their homotypic neighbors, minimizing dendritic overlap. Such uniform nonredundant dendritic coverage of these populations would suggest a degree of spatial order in the properties of their somal distributions, yet few studies have examined the patterning in retinal bipolar cell mosaics. The present study examined the organization of two types of cone bipolar cells in the mouse retina, the Type 2 cells and the Type 4 cells, and compared their spatial statistical properties with those of the horizontal cells and the cholinergic amacrine cells, as well as to random simulations of cells matched in density and constrained by soma size. The Delauney tessellation of each field was computed, from which nearest neighbor distances and Voronoi domain areas were extracted, permitting a calculation of their respective regularity indexes (RIs). The spatial autocorrelation of the field was also computed, from which the effective radius and packing factor (PF) were determined. Both cone bipolar cell types were found to be less regular and less efficiently packed than either the horizontal cells or cholinergic amacrine cells. Furthermore, while the latter two cell types had RIs and PFs in excess of those for their matched random simulations, the two types of cone bipolar cells had spatial statistical properties comparable to random distributions. An analysis of single labeled cone bipolar cells revealed dendritic arbors frequently skewed to one side of the soma, as would be expected from a randomly distributed population of cells with dendrites that tile. Taken together, these results suggest that, unlike the horizontal cells or cholinergic amacrine cells which minimize proximity to one another, cone bipolar cell types are constrained only by their physical size.

We examined the effect of intravitreal injections of D1-like and D2-like dopamine receptor agonists and antagonists and D4 receptor drugs on form-deprivation myopia (FDM) in tree shrews, mammals closely related to primates. In eleven groups (n = 7 per group), we measured the amount of FDM produced by monocular form deprivation (FD) over an 11-day treatment period. The untreated fellow eye served as a control. Animals also received daily 5 µL intravitreal injections in the FD eye. The reference group received 0.85% NaCl vehicle. Four groups received a higher, or lower, dose of a D1-like receptor agonist (SKF38393) or antagonist (SCH23390). Four groups received a higher, or lower, dose of a D2-like receptor agonist (quinpirole) or antagonist (spiperone). Two groups received the D4 receptor agonist (PD168077) or antagonist (PD168568). Refractions were measured daily; axial component dimensions were measured on day 1 (before treatment) and day 12. We found that in groups receiving the D1-like receptor agonist or antagonist, the development of FDM and altered ocular component dimensions did not differ from the NaCl group. Groups receiving the D2-like receptor agonist or antagonist at the higher dose developed significantly less FDM and had shorter vitreous chambers than the NaCl group. The D4 receptor agonist, but not the antagonist, was nearly as effective as the D2-like agonist in reducing FDM. Thus, using intravitreally-administered agents, we did not find evidence supporting a role for the D1-like receptor pathway in reducing FDM in tree shrews. The reduction of FDM by the dopamine D2-like agonist supported a role for the D2-like receptor pathway in the control of FDM. The reduction of FDM by the D4 receptor agonist, but not the D4 antagonist, suggests an important role for activation of the dopamine D4 receptor in the control of axial elongation and refractive development.

Vertebrate rod and cone photoreceptors require continuous supply of chromophore for regenerating their visual pigments after photoactivation. Cones, which mediate our daytime vision, demand a particularly rapid supply of 11-cis retinal chromophore in order to maintain their function in bright light. An important contribution to this process is thought to be the chromophore precursor 11-cis retinol, which is supplied to cones from Müller cells in the retina and subsequently oxidized to 11-cis retinal as part of the retina visual cycle. However, the molecular identity of the cis retinol oxidase in cones remains unclear. Here, as a first step in characterizing this enzymatic reaction, we sought to determine the subcellular localization of this activity in salamander red cones. We found that the onset of dark adaptation of isolated salamander red cones was substantially faster when exposing directly their outer vs. their inner segment to 9-cis retinol, an analogue of 11-cis retinol. In contrast, this difference was not observed when treating the outer vs. inner segment with 9-cis retinal, a chromophore analogue which can directly support pigment regeneration. These results suggest, surprisingly, that the cis-retinol oxidation occurs in the outer segments of cone photoreceptors. Confirming this notion, pigment regeneration with exogenously added 9-cis retinol was directly observed in the truncated outer segments of cones, but not in rods. We conclude that the enzymatic machinery required for the oxidation of recycled cis retinol as part of the retina visual cycle is present in the outer segments of cones.

Rod-cone gap junctions mediate the so-called “secondary rod pathway”, one of three routes that convey rod photoreceptor signals across the retina. Connexin 36 (Cx36) is expressed at these gap junctions, but an unidentified connexin protein also seems to be expressed. Cx36 knockout mice have been used extensively in the quest to dissect the roles in vision of all three pathways, with the assumption, never directly tested, that rod-cone electrical coupling is abolished by deletion of this connexin isoform. We previously showed that when wild type mouse cones couple to rods, their apparent dynamic range is extended toward lower light intensities, with the appearance of large responses to dim flashes (up to several mV) originating in rods. Here we recorded from the cones of Cx36del[LacZ]/del[LacZ] mice and found that dim flashes of the same intensity evoked at most small sub-millivolt responses. Moreover, these residual responses originated in the cones themselves, since: (i) their spectral preference matched that of the recorded cone and not of rods, (ii) their time-to-peak was shorter than in coupled wild type cones, (iii) a pharmacological block of gap junctions did not reduce their amplitude. Taken together, our data show that rod signals are indeed absent in the cones of Cx36 knockout mice. This study is the first direct demonstration that Cx36 is crucial for the assembly of functional rod-cone gap junctional channels, implying that its genetic deletion is a reliable experimental approach to eliminate rod-cone coupling.

Visual information reaches the cerebral cortex through a major thalamocortical pathway that connects the lateral geniculate nucleus (LGN) of the thalamus with the primary visual area of the cortex (area V1). In humans, ∼3.4 million afferents from the LGN are distributed within a V1 surface of ∼2400 mm2, an afferent number that is reduced by half in the macaque and by more than two orders of magnitude in the mouse. Thalamocortical afferents are sorted in visual cortex based on the spatial position of their receptive fields to form a map of visual space. The visual resolution within this map is strongly correlated with total number of thalamic afferents that V1 receives and the area available to sort them. The ∼20,000 afferents of the mouse are only sorted by spatial position because they have to cover a large visual field (∼300 deg) within just 4 mm2 of V1 area. By contrast, the ∼500,000 afferents of the cat are also sorted by eye input and light/dark polarity because they cover a smaller visual field (∼200 deg) within a much larger V1 area (∼400 mm2), a sorting principle that is likely to apply also to macaques and humans. The increased precision of thalamic sorting allows building multiple copies of the V1 visual map for left/right eyes and light/dark polarities, which become interlaced to keep neurons representing the same visual point close together. In turn, this interlaced arrangement makes cortical neurons with different preferences for stimulus orientation to rotate around single cortical points forming a pinwheel pattern that allows more efficient processing of objects and visual textures.

The dorsal lateral geniculate nucleus (dLGN) of the thalamus is the principal conduit for visual information from retina to visual cortex. Viewed initially as a simple relay, recent studies in the mouse reveal far greater complexity in the way input from the retina is combined, transmitted, and processed in dLGN. Here we consider the structural and functional organization of the mouse retinogeniculate pathway by examining the patterns of retinal projections to dLGN and how they converge onto thalamocortical neurons to shape the flow of visual information to visual cortex.

Chronic low grade inflammation is considered to contribute to the development of experimental diabetic retinopathy (DR). We recently demonstrated that lack of CD40 in mice ameliorates the upregulation of inflammatory molecules in the diabetic retina and prevented capillary degeneration, a hallmark of experimental diabetic retinopathy. Herein, we investigated the contribution of CD40 to diabetes-induced reductions in retinal function via the electroretinogram (ERG) to determine if inflammation plays a role in the development of ERG defects associated with diabetes. We demonstrate that diabetic CD40−/− mice are not protected from reduction to the ERG b-wave despite failing to upregulate inflammatory molecules in the retina. Our data therefore supports the hypothesis that retinal dysfunction found in diabetics occurs independent of the induction of inflammatory processes.

Previous psychophysical evidence suggests that motion and orientation processing systems interact asymmetrically in the human visual system, with orientation information having a stronger influence on the perceived motion direction than vice versa. To investigate the mechanisms underlying this motion-form interaction we used moving and oriented Glass patterns (GPs), which consist of randomly distributed dot pairs (dipoles) that induce the percept of an oriented texture. In Experiment 1 we varied the angle between dipole orientation and motion direction (conflict angle). In separate sessions participants either judged the orientation or motion direction of the GP. In addition, the spatiotemporal characteristics of dipole motion were manipulated as a way to limit (Experiment 1) or favor (Experiment 2) the availability of orientation signals from motion (motion streaks). The results of Experiment 1 showed that apparent GP motion direction is attracted toward dipole orientation, and apparent GP orientation is repulsed from GP motion. The results of Experiment 2 showed stronger repulsion effects when judging the GP orientation, but stronger motion streaks from the GP motion can dominate over the signals provided by conflicting dipole orientation. These results are consistent with the proposal that two separate mechanisms contribute to our perception of stimuli which contain conflicting orientation and motion information: (i) perceived GP motion is mediated by spatial motion-direction sensors, in which signals from motion sensors are combined with excitatory input from orientation-tuned sensors tuned to orientations parallel to the axis of GP motion, (ii) perceived GP orientation is mediated by orientation-tuned sensors which mutually inhibit each other. The two mechanisms are revealed by the different effects of conflict angle and dipole lifetime on perceived orientation and motion direction.

Comparative studies have greatly contributed to our understanding of the organization and function of visual pathways of the brain, including that of humans. This comparative approach is a particularly useful tactic for studying the pulvinar nucleus, an enigmatic structure which comprises the largest territory of the human thalamus. This review focuses on the regions of the mouse pulvinar that receive input from the superior colliculus, and highlights similarities of the tectorecipient pulvinar identified across species. Open questions are discussed, as well as the potential contributions of the mouse model for endeavors to elucidate the function of the pulvinar nucleus.

Often mislabeled as a simple relay of sensory information, the thalamus is a complicated structure with diverse functions. This diversity is exemplified by roles visual thalamus plays in processing and transmitting light-derived stimuli. Such light-derived signals are transmitted to the thalamus by retinal ganglion cells (RGCs), the sole projection neurons of the retina. Axons from RGCs innervate more than ten distinct nuclei within thalamus, including those of the lateral geniculate complex. Nuclei within the lateral geniculate complex of nocturnal rodents, which include the dorsal lateral geniculate nucleus (dLGN), ventral lateral geniculate nucleus (vLGN), and intergeniculate leaflet (IGL), are each densely innervated by retinal projections, yet, exhibit distinct cytoarchitecture and connectivity. These features suggest that each nucleus within this complex plays a unique role in processing and transmitting light-derived signals. Here, we review the diverse cytoarchitecture and connectivity of these nuclei in nocturnal rodents, in an effort to highlight roles for dLGN in vision and for vLGN and IGL in visuomotor, vestibular, ocular, and circadian function.

The thalamocortical (TC) relay neuron of the dorsoLateral Geniculate Nucleus (dLGN) has borne its imprecise label for many decades in spite of strong evidence that its role in visual processing transcends the implied simplicity of the term “relay”. The retinogeniculate synapse is the site of communication between a retinal ganglion cell and a TC neuron of the dLGN. Activation of retinal fibers in the optic tract causes reliable, rapid, and robust postsynaptic potentials that drive postsynaptics spikes in a TC neuron. Cortical and subcortical modulatory systems have been known for decades to regulate retinogeniculate transmission. The dynamic properties that the retinogeniculate synapse itself exhibits during and after developmental refinement further enrich the role of the dLGN in the transmission of the retinal signal. Here we consider the structural and functional substrates for retinogeniculate synaptic transmission and plasticity, and reflect on how the complexity of the retinogeniculate synapse imparts a novel dynamic and influential capacity to subcortical processing of visual information.

Although the core functions and structure of the lateral geniculate nucleus (LGN) are well understood, this core is surrounded by questions about the integration of feedforward and feedback connections, interactions between different channels of information, and how activity dependent development restructures synaptic networks. Our understanding of the organization of the mouse LGN is particularly limited given how important it has become as a model system. Advances in circuit scale electron microscopy (cellular connectomics) have made it possible to reconstruct the synaptic connectivity of hundreds of neurons within in a circuit the size of the mouse LGN. These circuit reconstructions can reveal cell type-to-cell type canonical wiring diagrams as well as the higher order wiring motifs that are only visible in reconstructions of intact networks. Connectomic analysis of the LGN therefore not only can answer longstanding questions about the organization of the visual thalamus but also presents unique opportunities for investigating fundamental properties of mammalian circuit formation.

The contribution of the purinergic receptors P2X7 (P2X7Rs) to the electroretinographic (ERG) responses was studied by testing the effects of the selective P2X7R antagonist A438079 and the selective P2X7R agonist Bz-ATP on the electroretinograms obtained in perfused frog (Rana ridibunda) eyecup preparations under a variety of stimulation conditions. The P2X7R blockade by 200 µM A438079 diminished the amplitude of the photoreceptor components: the a-wave and the pharmacologically isolated mass receptor potential. In the pure rod-driven and pure cone-driven responses, the amplitude of the postreceptoral ON (b-wave) and OFF (d-wave) components was also diminished. The OFF responses were affected to a greater extent compared to the ON responses. In the mixed rod- and cone-driven responses, obtained in the mesopic intensity range, the b-wave amplitude was increased, while the d-wave amplitude was decreased. The amplitude of the oscillatory potentials was diminished. The relative amplitude changes produced by the P2X7R blockade were greater in the dark-adapted compared to the light-adapted eyes. The application of 100 µM Bz-ATP produced small effects opposite to those of the antagonist, while a prolonged (>20 min) treatment with 1 mM Bz-ATP resulted in a significant amplitude reduction or even abolishment of b- and d-waves. Our results show that endogenous ATP through its P2X7Rs exerts significant, mostly potentiating effects on the ERG photoreceptor and postreceptoral responses. There is a clear ON/OFF asymmetry of the effects on the ERG postreceptoral responses favoring OFF responses: they are always strongly potentiated, while the ON responses are either less potentiated (in the rod-driven and most of the cone-driven responses) or even inhibited (in the mixed rod- and cone-driven responses). The overstimulation of P2X7Rs can produce acute pathological changes, that is, a decrease or abolishment of the ERG responses.

The corticogeniculate circuit is an evolutionarily conserved pathway linking the primary visual cortex with the visual thalamus in the feedback direction. While the corticogeniculate circuit is anatomically robust, the impact of corticogeniculate feedback on the visual response properties of visual thalamic neurons is subtle. Accordingly, discovering the function of corticogeniculate feedback in vision has been a particularly challenging task. In this review, the morphology, organization, physiology, and function of corticogeniculate feedback is compared across mammals commonly studied in visual neuroscience: primates, carnivores, rabbits, and rodents. Common structural and organizational motifs are present across species, including the organization of corticogeniculate feedback into parallel processing streams in highly visual mammals.

Intrinsic interneurons within the dorsal lateral geniculate nucleus (dLGN) provide a feed-forward inhibitory pathway for afferent visual information originating from the retina. These interneurons are unique because in addition to traditional axodendritic output onto thalamocortical neurons, these interneurons have presynaptic dendrites that form dendrodendritic synapses onto thalamocortical neurons as well. These presynaptic dendrites, termed F2 terminals, are tightly coupled to the retinogeniculate afferents that synapse onto thalamocortical relay neurons. Retinogeniculate stimulation of F2 terminals can occur through the activation of ionotropic and/or metabotropic glutamate receptors. The stimulation of ionotropic glutamate receptors can occur with single stimuli and produces a short-lasting inhibition of the thalamocortical neuron. By contrast, activation of metabotropic glutamate receptors requires tetanic activation and results in longer-lasting inhibition in the thalamocortical neuron. The F2 terminals are predominantly localized to the distal dendrites of interneurons, and the excitation and output of F2 terminals can occur independent of somatic activity within the interneuron thereby allowing these F2 terminals to serve as independent processors, giving rise to focal inhibition. By contrast, strong transient depolarizations at the soma can initiate a backpropagating calcium-mediated potential that invades the dendritic arbor activating F2 terminals and leading to a global form of inhibition. These distinct types of output, focal versus global, could play an important role in the temporal and spatial roles of inhibition that in turn impacts thalamocortical information processing.