The optic nerve in two species of subterranean mole-rats (Spalacidae) has been examined at the ultrastructural level. The axial length of the eye and the diameter of the optic nerve are 1.9 mm and 52.5 μm in Spalax leucodon, and 0.7 mm and 80.8 μm in Spalax ehrenbergi, respectively. An anti-glial fibrillary acidic protein postembedding procedure was used to distinguish glial cell processes from axons. In both species, the optic nerve is composed exclusively of unmyelinated axons and a spatial distribution gradient according to the size or the density of fibers is lacking. The optic nerve of S. leucodon contains 1790 fibers ranging in diameter from 0.07–2.30 μm (mean = 0.57 μm), whereas in S. ehrenbergi, only 928 fibers, with diameters of 0.04–1.77 μm (mean = 0.53 μm) are observed. In S. ehrenbergi, a higher proportion of glial tissue is present and the fascicular organization of optic fibers is less obvious. Distribution gradients according to size frequency or density of fibers in the optic nerve are absent in both species. Comparison with other mammals suggests that although ocular regression in microphthalmic species is correlated with a significant decrease in the total number of optic fibers and the relative proportion of myelinated fibers, no difference in the absolute size range of unmyelinated axons is observed. The total absence of myelinated fibers in Spalax may be related to the subcutaneous location of the eyes. The unique presence of unmyelinated fibers in the optic nerve is discussed in relation to the possible conservation of a single class of W-like ganglion cells in the retina, in relation to photoperiodic perception.

The development of synaptic ribbons in rod and cone photoreceptor terminals of the cat retina was studied using quantitative electron microscopy. At the region of the area centralis, synaptic ribbon profiles are initially recognized at PCD (postconception day) 59. Synaptic ribbon density increases rapidly, reaching a peak of 0.55 ribbons/μm3 at PCD 68 (postnatal day 3) and maintains approximately that value for an additional 8 d. Following PCD 76, ribbon density begins to decrease, to 0.37 ribbons/μm3 at PCD 82 and 0.25 ribbons/μm3 at PCD 102. Although ribbon density drops by approximately 50% during this 39-d period, the outer plexiform layer (OPL) volume at the area centralis increases by about 20%. Ribbon density continues to decrease gradually over a protracted period to reach a final adult value of 0.11–0.14 ribbons/μm3. During the period of high ribbon density, rod spherules with two, or even three ribbon profiles, were routinely observed. In contrast, in the adult, spherules with more than one ribbon profile are only rarely encountered. During development, the length of synaptic ribbon profiles increases from a mean of 0.22 μm at PCD 62 to the 0.47 μm mean length found in the adult.

Immunocytochemical methods were used to examine neuropeptide Y (NPY) immunoreactive neurons and fibers in area 17 of rhesus monkeys during the first year of life. NPY-immunoreactive (+) neurons are nonpyramidal cells which are either multipolar, bipolar, or bitufted in shape. They occur most frequently in layer 6 and the subjacent white matter, are sparser in the supragranular layers, and absent from layer 4C. Labeled somata in the supragranular layers are smaller compared to those in layer 6 and the white matter. A typical axon originates from the NPY+ soma or from a primary dendrite and frequently is varicose. Distribution and morphologies of NPY+ neurons in area 17 of infants are similar to those of adult monkeys. Thus, it seems that NPY+ neurons in rhesus monkeys are mature from birth. NPY+ fibers occur in area 17 from birth; however, they differ in density and distribution from those of older infant and adult monkeys. At birth, a prominent fiber plexus is found in the deepest part of layer 1, and another in the white matter. Immunoreactive processes are sparse in the remaining cortical gray, except for some vertical fibers extending from pia to white matter. By 4 months of age, labeled fibers form a coarse network in layers 2, 3, 5, and 6. In addition, a distinct plexus extends through layers 4B, 4A, and the lowest aspect of layer 3. Also, a thin immunoreactive fiber band is found at the bottom of layer 4C. In the remainder of layer 4C, NPY+ fibers are scant. The supragranular layers also exhibit a unique immunoreactive “snarl” of fibers. Increases in density of NPY+ processes in the older infants are gradual so that between 7 and 13 months of age, NPY+ fibers appear to have achieved adultlike densities. These observations indicate that NPY+ fibers in area 17 of newborn rhesus monkeys undergo postnatal maturation which reaches a plateau around 4 months of age. After monocular visual deprivation from birth to 4 months of age, either by eyelid suture or by occlusion with an opaque contact lens, density and distribution of NPY+ neurons and fibers, including snarls, appear similar to those of age-matched undeprived infants. Thus, disruption of the normal binocular input does not seem to arrest the maturation of the NPY system in area 17 of rhesus monkeys during a sensitive period of early postnatal development.

The endogenous cannabinoid system plays important roles in the retina of mice and monkeys via their classic CB1 and CB2 receptors. We have previously reported that the G protein-coupled receptor 55 (GPR55), a putative cannabinoid receptor, is exclusively expressed in rod photoreceptors in the monkey retina, suggesting its possible role in scotopic vision. To test this hypothesis, we recorded full-field electroretinograms (ERGs) after the intravitreal injection of the GPR55 agonist lysophosphatidylglucoside (LPG) or the selective GPR55 antagonist CID16020046 (CID), under light- and dark-adapted conditions. Thirteen vervet monkeys (Chlorocebus sabaeus) were used in this study: four controls (injected with the vehicle dimethyl sulfoxide, DMSO), four injected with LPG and five with CID. We analyzed amplitudes and latencies of the a-wave (photoreceptor responses) and the b-wave (rod and cone system responses) of the ERG. Our results showed that after injection of LPG, the amplitude of the scotopic b-wave was significantly higher, whereas after the injection of CID, it was significantly decreased, compared to the vehicle (DMSO). On the other hand, the a-wave amplitude, and the a-wave and b-wave latencies, of the scotopic ERG responses were not significantly affected by the injection of either compound. Furthermore, the photopic ERG waveforms were not affected by either drug. These results support the hypothesis that GPR55 plays an instrumental role in mediating scotopic vision.

Recent work has revealed multiple pathways for cross-orientation suppression in cat and human vision. In particular, ipsiocular and interocular pathways appear to assert their influence before binocular summation in human but have different (1) spatial tuning, (2) temporal dependencies, and (3) adaptation after-effects. Here we use mask components that fall outside the excitatory passband of the detecting mechanism to investigate the rules for pooling multiple mask components within these pathways. We measured psychophysical contrast masking functions for vertical 1 cycle/deg sine-wave gratings in the presence of left or right oblique (±45 deg) 3 cycles/deg mask gratings with contrast C%, or a plaid made from their sum, where each component (i) had contrast 0.5Ci%. Masks and targets were presented to two eyes (binocular), one eye (monoptic), or different eyes (dichoptic). Binocular-masking functions superimposed when plotted against C, but in the monoptic and dichoptic conditions, the grating produced slightly more suppression than the plaid when Ci ≥ 16%. We tested contrast gain control models involving two types of contrast combination on the denominator: (1) spatial pooling of the mask after a local nonlinearity (to calculate either root mean square contrast or energy) and (2) “linear suppression” (Holmes & Meese, 2004, Journal of Vision4, 1080–1089), involving the linear sum of the mask component contrasts. Monoptic and dichoptic masking were typically better fit by the spatial pooling models, but binocular masking was not: it demanded strict linear summation of the Michelson contrast across mask orientation. Another scheme, in which suppressive pooling followed compressive contrast responses to the mask components (e.g., oriented cortical cells), was ruled out by all of our data. We conclude that the different processes that underlie monoptic and dichoptic masking use the same type of contrast pooling within their respective suppressive fields, but the effects do not sum to predict the binocular case.

The trajectory of retinal projections and the location of retinorecipient nuclei in the quail brain was examined after application of horseradish peroxidase (HRP) either to the cut end of the optic nerve or following intraocular injection of HRP. Retinal projections to the hypothalamus, dorsalateral anterior thalamus (rostralateral part, magnocellular part, and lateral part), lateral anterior thalamus, lateroventral geniculate nucleus, lateral geniculate intercalated nuclei (rostral and caudal parts), ventrolateral thalamus, superficial synencephalic nucleus, external nucleus, tectal gray, diffuse pretectal area, pretectal optic area, ectomammillary nucleus, and optic tectum were revealed. Retinal projections observed in quail were compared with results obtained in other avian species and considered in relation to possible anatomic pathways underlying photoperiodism and circadian rhythms.

One subpopulation of amacrine in the turtle retina was shown to contain met-enkephalin by means of immunocytochemistry, and another was demonstrated to have a high-affinity uptake system for [3H]-dopamine by means of tutoradiography. Although the amacrine soma size, density, and distribution of their neurites in IPL substrata was similar in retinas in which met-enkephalin and dopamine were localized, combined light microscope immuncytochemistry-autoradiography demonstrated that these two neurotransmitter systems did not coexist in the same cells. Because the two amacrine cell subtypes ramify in the same IPL substrata, neuronal interaction between them is possible. Release experiments showed that the potassium-induced release of [3H]-dopamine from the superfused turtle retina was reduced by 40% when enkephlian was added to the superfusate. The inhibition of [3H]-dopamine release could be blocked by the addition of naloxone. The addition of enkephalin had no effect of the potassium-induced release of [3H]-GABA from the superfused retina. These findings suggest that an enkephalinergic modulation of the dopaminergic amacrine cell system exits in the turtle retina.

Endogenous opioid systems (i.e. opioid peptides and opioid receptors) modulate developmental events in the neonatal mammalian retina. In the present study, the mRNA encoding preproenkephalin A (PPE), the prohormone for the opioid growth factor (OGF), [Met5]-enkephalin, was studied in the developing and the adult retinas of rats. Northern analysis indicated the presence of a 1.4-kb message in the developing and adult retinas corresponding to rat PPE mRNA. Quantitation showed that PPE message was present on postnatal day 1 at 5% of the adult level, and increased during development until the adult quantity was reached by postnatal day 27. In situ hybridization experiments first detected the presence of PPE mRNA in retinal tissues during late gestation. In late prenatal and neonatal retinas, PPE message was associated with areas of the developing retina containing proliferating neuroblasts and postmitotic cells. Later in development, message appeared to be located primarily within the inner retina, with abundant PPE mRNA associated with putative horizontal cells of the inner nuclear layer (INL). The adult retina showed a similar pattern of PPE gene expression in the cells of the INL. These findings document that the gene expression in the retina for PPE begins in the fetus, continues during retinal development, and coincides with the presence of a PPE mRNA derivative ([Met5]-enkephalin) that regulates DNA synthesis during retinal ontogeny. Our results are also the first to show the presence of PPE message in the adult mammalian retina, suggesting transcription of an opioid gene in the mature visual system.

An investigation of retinal specializations was carried out in larval and juvenile dhufish, Glaucosoma hebraicum (Glaucosomidae, Teleostei). The development of photoreceptors and formation of the retinal mosaic was followed by light and electron microscopy. At hatching the eye was undifferentiated. Cone photoreceptors were present by day 3 posthatch (dph), when exogenous feeding began. Single and multiple cones were present in a row arrangement from 3 dph to 20 dph, when the first rod nuclei were observed. Between 20 dph and approximately 3 months posthatch (mph), the row arrangement was replaced by a square mosaic of four double cones surrounding a single cone, and the cones increased in size, with the outer segments reaching up to 30 μm in length. During the period of spatial rearrangement, triple cones were often observed. From their first appearance, rod photoreceptors were added rapidly. Investigation of ganglion cell topography in 3-mph fish that had attained the adult-like square photoreceptor mosaic was carried out using retinal wholemounts. The highest densities of neurones in the ganglion cell layer were in temporal retina but no well-defined area centralis was observed. Microspectrophotometric measurements of the visual pigments within the outer segments of the photoreceptors of 3-mph fish revealed double cones with identical absorption spectra in each member of the outer segment, and the wavelength of maximum absorption (λmax) located at 522 nm. Single cones were found to possess a visual pigment with λmax at 460 nm and rods with a λmax of 498 nm. The results imply that the larvae and juveniles are adapted for survival in coastal waters and may be active in relatively low light levels from early stages of development.

Recent results indicate that astrocytic β-adrenergic receptors (βAR) participate in noradrenergic modulation of synaptic activity. In this study, we sought to examine whether neural activity can, in turn, regulate astrocytic βAR. To address this question, an antiserum that recognizes β-adrenergic receptors (βAR) specifically in astrocytes was used to assess the distribution of the receptors across ocular dominance columns in VI of two monocular and four visually intact adult monkeys. Cytochrome oxidase histochemistry (CO) was used to identify the position of the cortical laminae and of the ocular dominance columns receiving visual inputs from the intact and enucleated eyes. This stain revealed the expected pattern within V1 of monocular monkeys–i.e. darker and lighter bands of equal widths (ca. 500μm) spanning laminae 4–6, each associated with larger and smaller blobs, respectively, in lamina 2/3;. Alignment of CO sections with adjacent sections stained for astrocytic βAR by the immunoperoxidase method revealed intense βAR-like immunoreactivity (βAR-li) in the superficial laminae, a slightly weaker staining in the infragranular laminae and weakest staining in lamina 4C. Within lamina 4C., a prominent striped pattern was evident. The darker bands of the stripe closely matched widths and positions of the lighter CO columns associated with the enucleated eye. On the other hand, immunocytochemical staining for the astrocytic intermediate filament protein, GFAP, within V1 of monocular monkeys revealed no inter-columnar difference in the density of astrocytic cell bodies or processes. Nissl stain also revealed no overt inter-columnar differences in cell density. V1 of visually intact monkeys exhibited a similar laminar distribution pattern of βAR-li and of CO. Within lamina 4C., βAR-li was uniformly faint and CO staining was uniformly intense. This suggests that the striped pattern of βAR-li seen in lamina 4C of monocular monkeys results from elevation of the βAR-antigen within the inactive columns. The results indicate that astrocytic βAR density is regulated by local neural activity. The mechanisms regulating βAR density are likely to be independent of those regulating glial cell proliferation or GFAP synthesis. In vitro experimental results of others suggest that elevation of astrocytic βAR may be a mechanism compensating for chronic neural inactivity, since the coincident release of noradrenaline with visual stimulation would elevate neuropil excitability via the astrocytic mechanism of (1) decreasing the uptake of neuronally released L-glutamate; (2) increasing GABA uptake; and (3) stimulating glycogenolysis. Alternatively, the changes in βAR-li may reflect an up-regulation of the receptors within inactive columns due to reduced levels of noradrenaline release.

Platyrrhine monkeys typically have only a single X-chromosome opsin gene. Alleles of this gene code for multiple versions of middle- to long-wavelength cone photopigments. X-chromosome inactivation provides heterozygous females with a retinal mosaic of cones containing either of two types of M and L pigment, thus establishing the photopigment basis for trichromatic color vision. This study examined the proportions of L and M cones created by this process. For that purpose, electroretinogram flicker photometry was used to obtain complete spectral sensitivity functions from 60 heterozygous female monkeys drawn from seven genera of platyrrhine monkeys. To obtain estimates of cone proportions, these functions were subsequently fit with linear combinations of L and M cone fundamentals that were derived from similar recordings made on conspecific animals having only one type of M/L pigment. Consistent with a random X-chromosome inactivation process, the average L:M cone weighting across the sample was close to unity. At the same time, there were significant individual variations in L:M cone proportions. The genesis of this variation and its implications for seeing are discussed.

Primary open angle glaucoma (POAG) is a leading cause of late onset, progressive, irreversible blindness and, although its etiology is poorly understood, elevated intraocular pressure (IOP) often appears to be a contributory factor. Proteomic and Western analyses of trabecular meshwork (TM) from patients with POAG and age-matched controls originally implicated cochlin as possibly contributing to glaucoma pathogenesis. Cochlin deposits were subsequently detected in glaucomatous but not in control TM and older glaucomatous TM was found to contain higher levels of cochlin and significantly lower amounts of collagen type II. More recently, similar results were reported in DBA/2J mice, which at older ages develop elevated IOP, retinal ganglion cell degeneration, and optic nerve damage. Notably, cochlin was absent in TM from C57BL/6J, CD1, and BALBc/ByJ mice, which do not exhibit elevated IOP or glaucoma. Cochlin was found in the TM of very young DBA/2J mice, prior to elevated IOP, suggesting that over time the protein may contribute to the events leading to increased IOP and optic nerve damage. Here we review these findings and describe how future studies in DBA/2J mice can help resolve whether cochlin plays a causal role in mechanisms of POAG and elevated IOP.

Feedback is a ubiquitous feature of neural circuits in the mammalian central nervous system (CNS). Analogous to pure electronic circuits, neuronal feedback provides either a positive or negative influence on the output of upstream components/neurons. Although the particulars (i.e., connectivity, physiological encoding/processing/signaling) of circuits in higher areas of the brain are often unclear, the inner retina proves an excellent model for studying both the anatomy and physiology of feedback circuits within the functional context of visual processing. Inner retinal feedback to bipolar cells is almost entirely mediated by a single class of interneurons, the amacrine cells. Although this might sound like a simple circuit arrangement with an equally simple function, anatomical, molecular, and functional evidence suggest that amacrine cells represent an extremely diverse class of CNS interneurons that contribute to a variety of retinal processes. In this review, I classify the amacrine cells according to their anatomical output synapses and target cell(s) (i.e., bipolar cells, ganglion cells, and/or amacrine cells) and discuss specifically our current understandings of amacrine cell-mediated feedback and output to bipolar cells on the synaptic, cellular, and circuit levels, while drawing connections to visual processing.

The lateral eyes of the horseshoe crab Limulus contain about 80 pmoles of retinal, 30 pmoles of retinol, and 4 pmoles of retinyl esters. More all-trans than 11-cis isomer was found in each category of retinoid. No consistent changes were observed in the amounts of retinal, retinol, or retinyl esters as a function of time of day. No 3,4-dehydro- nor hydroxyretinoids were found.

Aqueous extracts of the eye support the stereospecific formation of 11 -cis retinal from a11-trans retinal when irradiated with light. The reaction requires a protein that is apparently recognized by polyclonal antibodies raised against the retinal photoisomerase extracted from honeybee eyes. The isomerase is able to use as substrate either endogenous all-trans retinal in the extract or retinal supplied in vesicles of phospholipid. The spectral efficiency of this isomerization has λmax at 550 nm, but the spectrum appears too narrow compared with the absorbance spectrum of retinoid-binding proteins, probably because of inadequate correction for nonspecific isomerization at short wavelengths.

Orientation adaptation and perceptual learning change orientation tuning curves of V1 cells. Adaptation shifts tuning curve peaks away from the adapted orientation, reduces tuning curve slopes near the adapted orientation, and increases the responses on the far flank of tuning curves. Learning an orientation discrimination task increases tuning curve slopes near the trained orientation. These changes have been explained previously in a recurrent model (RM) of orientation selectivity. However, the RM generates only complex cells when they are well tuned, so that there is currently no model of orientation plasticity for simple cells. In addition, some feedforward models, such as the modified feedforward model (MFM), also contain recurrent cortical excitation, and it is unknown whether they can explain plasticity. Here, we compare plasticity in the MFM, which simulates simple cells, and a recent modification of the RM (MRM), which displays a continuum of simple-to-complex characteristics. Both pre- and postsynaptic-based modifications of the recurrent and feedforward connections in the models are investigated. The MRM can account for all the learning- and adaptation-induced plasticity, for both simple and complex cells, while the MFM cannot. The key features from the MRM required for explaining plasticity are broadly tuned feedforward inputs and sharpening by a Mexican hat intracortical interaction profile. The mere presence of recurrent cortical interactions in feedforward models like the MFM is insufficient; such models have more rigid tuning curves. We predict that the plastic properties must be absent for cells whose orientation tuning arises from a feedforward mechanism.

Although galvanic vestibular stimulation (GVS) is known to affect the speed and accuracy of visual judgments, the underlying electrophysiological response has not been explored. In the present study, we therefore investigated the effect of GVS on the N170 event-related potential, a marker commonly associated with early visual structural encoding. To elicit the waveform, participants distinguished famous from nonfamous faces that were presented in either upright or inverted orientation. Relative to a sham, stimulation increased the amplitude of the N170 and also elevated power spectra within the delta and theta frequency bands, components that have likewise been associated with face processing. This study constitutes the first attempt to model the effects of GVS on the electrophysiological response and, more specifically, indicates that unisensory visual processes linked to object construction are influenced by vestibular information. Given that reductions in the magnitude of both the N170 event-related potential and delta/theta activity accompany certain disease states, GVS may provide hitherto unreported therapeutic benefit.

Light-microscopic immunocytochemistry was used to study serotonin (5HT)-containing retinal cells in the lamprey (Lampetra fluviatilis). Observations of sections and flatmounted retinas enabled us to distinguish four principal types of 5HT-immunoreactive neurons, on the basis of the localization of their somata and the arrangement of their processes in the inner plexiform layer, (IPL). Type 1 cell bodies (9 μm mean diameter) were numerous and were found in the innermost row of the inner nuclear layer (INL). They sent their processes into a dense plexus in sublamina a of the IPL. Type 2 cell bodies (12 μm mean diameter) were observed near the inner limiting membrane, their processes forming a plexus in sublamina b of the IPL. Most of the type 3 cells were bistratified, their cell bodies (similar in dimension to type 1) were located in the INL and their dendrites projected to both plexuses. Type 4 cell bodies (15 μm mean diameter) were observed in the middle of the IPL and could be compared with the interstitial described elsewhere. Their processes probably ended in the 5HT plexus of sublamina b but because of their sinuous course in the IPL, we could not affirm this fact. Most of 5HT immunoreactive cells were thought to be amacrine cells, but the presence of some thin processes emerging either from the soma or the primary dendrite, principally in type 1 and 2 cells, raises the possibility that some ganglion cells could be 5HT immunoreactive. The organization of the 5HT processes into two plexuses located in sublaminae a and b of the IPL resemble the functional ON and OFF pathway seen in the other vertebrates.

We have purified a protein that changes in relative concentration during the development of the kitten visual cortex. It resembles GAP-43 (a neuronal protein that is expressed at elevated levels during periods of development and regenerative axon growth) in the following respects: (1) it is an acidic protein (pI=4.7) whose electrophoretic mobility on SDS-PAGE is similar to, but lower than rat GAP-43, suggesting that the cat protein is larger; (2) its electrophoretic mobility varies with the acrylamide concentration in a manner that is characteristic of GAP-43; (3) its concentration in kitten forebrain is elevated during early postnatal development; (4) the sequence of ten consecutive amino acids from a chemically generated fragment matches the expected sequence from GAP-43; and (5) its amino-acid content also matches GAP-43. We conclude that our purified protein is cat GAP-43. Immunoblots with an antibody prepared against rat GAP-43 suggested that the concentration of GAP-43 in the visual cortex declines with age.

Psychophysical studies have documented that many observers show lower thresholds for rapid-off than for rapid-on sawtooth luminance modulation. This finding, together with physiological findings from chromatically opponent ganglion cells of the macaque monkey, prompted a search for a similar bias in psychophysical detection of chromatic increments and decrements of light. Using a luminance pedestal in conjunction with a luminance background to favor detection by chromatic mechanisms, we measured spectral sensitivity for rapid-on and rapid-off sawtooth stimuli presented spatially coextensive with the pedestal. There were two different pedestal chromaticities: one broadband, and the second composed only of long-wavelength light to enhance short-wavelength-sensitive, cone-mediated detection. Spectral-sensitivity measurements for different wavelength stimuli revealed no systematic differences across the visible spectrum as a function of sawtooth waveform polarity or pedestal chromaticity. Similarly, temporal contrast-sensitivity functions for hetero-chromatically modulated red-green sawtooth stimuli did not reveal an asymmetry in sensitivity for rapid-red and rapid-green chromatic change. Some of the observers showed a higher sensitivity for luminance modulated rapid-off sawtooth stimuli, as also noted in previous studies. This asymmetry was not found when a white luminance pedestal and background was used. These results suggest that the cone inputs to chromatically opponent ON- and OFF-center cells are sufficiently balanced to provide equivalent psychophysical thresholds for chromatic increments and decrements of light.

Diabetic retinopathy (DR) is a frequent complication of diabetes mellitus and an increasingly common cause of visual impairment. Blood vessel damage occurs as the disease progresses, leading to ischemia, neovascularization, blood–retina barrier (BRB) failure and eventual blindness. Although detection and treatment strategies have improved considerably over the past years, there is room for a better understanding of the pathophysiology of the diabetic retina. Indeed, it has been increasingly realized that DR is in fact a disease of the retina’s neurovascular unit (NVU), the multi-cellular framework underlying functional hyperemia, coupling neuronal computations to blood flow. The accumulating evidence reveals that both neurochemical (synapses) and electrical (gap junctions) means of communications between retinal cells are affected at the onset of hyperglycemia, warranting a global assessment of cellular interactions and their role in DR. This is further supported by the recent data showing down-regulation of connexin 43 gap junctions along the vascular relay from capillary to feeding arteriole as one of the earliest indicators of experimental DR, with rippling consequences to the anatomical and physiological integrity of the retina. Here, recent advancements in our knowledge of mechanisms controlling the retinal neurovascular unit will be assessed, along with their implications for future treatment and diagnosis of DR.