The Retina: A Window into the Brain

In the course of evolution, animals have obtained the capacity to perceive and encode their environment via the development of sensory systems such as touch, olfaction, audition, and vision [...].

. Snapshots of the habitat of different species along with their representative RGC density distribution across their retinal surfaces. (Left) Habitat of simians (jungle) and the RGC density distribution in the human retina. (Center) example of a typical habitat of the hawk (sky) and its retina RGC density distribution. (Right) example of a typical habitat of the mouse (ground) and its retina RGC density distribution. D, dorsal; N, nasal; T, temporal; V, ventral. Redrawn from [1].
The human retina is a complex mosaic ( Figure 2B,C) comprised of five classes of neurons specialised in processing the visual information received by the eye. These neuron types are the photoreceptors, bipolar cells, ganglion cells, horizontal cells and amacrine cells [4]. These neurons have a characteristic distribution in the ten distinct layers of the retina, and have interconnections via two different pathways, namely, the vertical and horizontal pathways. Their extensive interconnections enable the processing of the visual image projected on the retina and its transmission to the brain through the optic nerve. The vertical pathway begins with the transduction of light signals by the photoreceptors and ends with transmission to the brain via the axons of retinal ganglion cells (RGCs). The horizontal pathway is comprised of horizontal cells and amacrine cells that connect laterally to provide feedback and feedforward signals between photoreceptors and bipolar cells (for horizontal cells) and between bipolar cells and RGCs (for the amacrine cells) [10]. The horizontal pathway mediates photoreceptor convergence, motion processing and contextual modulation [11]. Therefore, these two pathways embody the basic characteristics of retinal architecture and, hence, visual processing through their connections within the retinal layers.
The ten layers of the retina ( Figure 2B,C), proceeding from the innermost to the outermost, are traditionally named as follows: the inner limiting membrane, nerve fibre layer (NFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), external limiting membrane, photoreceptors layer (PL), and the retinal pigment epithelium (RPE). The RPE is composed of epithelial cells with a rich content of melanosomes and melanin granules. RPE cells support the metabolic activity of the retina and supply the photoreceptors with nutrients and oxygen [12][13][14]. The photoreceptor layer is composed of the photosensitive outer segments and inner segments of the photoreceptors, the rods and cones, which are specialized for capturing and transducing light energy into electrochemical signals. The next layer, the outer limiting membrane, is formed by the extensions of large glial cells, known as the retinal Müller cells. The fourth layer is the outer nuclear layer, which contains the photoreceptors somata and nuclei. The photoreceptors then make synaptic contact with the bipolar and horizontal cells in the fifth layer, forming the outer plexiform layer. The sixth layer, the inner nuclear layer, is composed of cell bodies of horizontal, amacrine and The ten layers of the retina ( Figure 2B,C), proceeding from the innermost to the outermost, are traditionally named as follows: the inner limiting membrane, nerve fibre layer (NFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), external limiting membrane, photoreceptors layer (PL), and the retinal pigment epithelium (RPE). The RPE is composed of epithelial cells with a rich content of melanosomes and melanin granules. RPE cells support the metabolic activity of the retina and supply the photoreceptors with nutrients and oxygen [12][13][14]. The photoreceptor layer is composed of the photosensitive outer segments and inner segments of the photoreceptors, the rods and cones, which are specialized for capturing and transducing light energy into electrochemical signals. The next layer, the outer limiting membrane, is formed by the extensions of large glial cells, known as the retinal Müller cells. The fourth layer is the outer nuclear layer, which contains the photoreceptors somata and nuclei. The photoreceptors then make synaptic contact with the bipolar and horizontal cells in the fifth layer, forming the outer plexiform layer. The sixth layer, the inner nuclear layer, is composed of cell bodies of horizontal, amacrine and bipolar cells. The latter cell type makes synapses with amacrine and ganglion cells in the inner plexiform layer. Ganglion cells bodies then form the ganglion cell layer, where their long axons run horizontally along the nerve fiber layer towards the optic disk. The tenth and final layer, the inner limiting membrane, is formed by extensions of Müller cells. bipolar cells. The latter cell type makes synapses with amacrine and ganglion cells in the inner plexiform layer. Ganglion cells bodies then form the ganglion cell layer, where their long axons run horizontally along the nerve fiber layer towards the optic disk. The tenth and final layer, the inner limiting membrane, is formed by extensions of Müller cells. The vertical pathway ( Figure 3) is defined by the capture and transduction of photons by the photoreceptors and the transmission of the resulting electrical signal to RGCs via their connections with bipolar cells. The main neurochemical involved in this pathway is glutamate, an excitatory neurotransmitter. There are two types of photoreceptors, the rods and cones, which both possess outer segments that are composed of stacked disks of infolded membranes containing the visual photopigments (opsin or rhodopsin coupled to a chromophore) [17]. Rods and cones differ not only in shape but also with respect to the composition of their outer segment disks, light and spectral sensitivity, and convergence towards RGCs. Rods are thinner (averaging 2 µm) and longer (averaging 50 µm) than cones. The functional particularity of rod outer segments derives from their abundant photopigment disks [18]. This property imparts greater light absorption capacity and, thus, higher light sensitivity compared to cones [13]. Moreover, through the retina, rods have a greater degree of convergence towards RGCs through their connections with bipolar cells, which serves to provide greater signal amplification, but with lower visual acuity. As such, rods are responsible for scotopic vision, but are saturated during the day or in other situations of high luminosity [19].
Cones, on the other hand, are generally thicker (3 to 5 µm) and shorter (40 µm) than rods and have a lower degree of convergence; this ratio even reaches 1 RGC for 1 cone in The vertical pathway ( Figure 3) is defined by the capture and transduction of photons by the photoreceptors and the transmission of the resulting electrical signal to RGCs via their connections with bipolar cells. The main neurochemical involved in this pathway is glutamate, an excitatory neurotransmitter. There are two types of photoreceptors, the rods and cones, which both possess outer segments that are composed of stacked disks of infolded membranes containing the visual photopigments (opsin or rhodopsin coupled to a chromophore) [17]. Rods and cones differ not only in shape but also with respect to the composition of their outer segment disks, light and spectral sensitivity, and convergence towards RGCs. Rods are thinner (averaging 2 µm) and longer (averaging 50 µm) than cones. The functional particularity of rod outer segments derives from their abundant photopigment disks [18]. This property imparts greater light absorption capacity and, thus, higher light sensitivity compared to cones [13]. Moreover, through the retina, rods have a greater degree of convergence towards RGCs through their connections with bipolar cells, which serves to provide greater signal amplification, but with lower visual acuity. As such, rods are responsible for scotopic vision, but are saturated during the day or in other situations of high luminosity [19].
Cones, on the other hand, are generally thicker (3 to 5 µm) and shorter (40 µm) than rods and have a lower degree of convergence; this ratio even reaches 1 RGC for 1 cone in the fovea. The less numerous photopigment disks of the cones float freely in their outer segments [20,21]. Being less sensitive to low levels of light and only activated in situations of high luminosity, cones mediate photopic vision, operating when rods are saturated. However, both cones and rods are active in intermediate lighting conditions, such as daybreak and twilight [22]. Cones are also responsible for high-acuity vision, based on their 1-to-1 ratio of convergence in the central retina. Furthermore, three types of cones (S, L and M cones) are present in the human and nonhuman primate retina and contain the three types of opsins with different spectral sensitivity [3,23,24].
Populations of cones and rods have different distributions throughout the retina ( Figure 2D). Typically, cones are outnumbered by rods by a ratio of 20-or 30-to-1 [3]. The human retina contains approximately 90 to 120 millions rods and 5 to 7 millions cones [16,25]. Throughout the peripheral retina, the density of rods greatly exceeds that of cones. However, this ratio is shifted in the fovea, where the density of cones increases almost 200-fold [25]. In that region, the individual cones are thinner ( Figure 3B), allowing for the highest photoreceptor density recorded in the retina [13,25]. As a result, the central retina mediates photopic vision with a high degree of resolution (or visual acuity) and color perception, while the periphery is responsible for scotopic vision and motion sensitivity, albeit with lower visual acuity. Both types of photoreceptors send signals to the parallel pathways of bipolar cells (reviewed in [3]) via the release of glutamate.
Bipolar cells ( Figure 3C) are the interneurons linking photoreceptors to RGCs and amacrine cells. Morphologically, bipolar cells are recognized by their two protrusions, one extending in the outer retina and making synaptic contact with photoreceptors and horizontal cells, and the other protrusion extending in the inner retina as the axon that relays signals from the photoreceptors to RGCs and amacrine cells. There are diverse morphological types of bipolar cells, of which the axons terminate different levels, or strata, of the inner plexiform layer. Bipolar cells thus contact different types and sets of RGCs and amacrine cells (reviewed in [26]). There are 12 types of cone bipolar cell types, and only one type of rod bipolar cell that relay the signals from rods at low light intensities [27][28][29][30]. Bipolar cells are divided into ON and OFF types, thus subserving the first step in encoding visual information according to the intensity of light received by photoreceptors [26,31,32].
In the second synaptic layer of the retina, the inner plexiform layer, bipolar cells make synaptic contact with the dendritic arborizations of the third-order neurons, namely, the RGCs ( Figure 3D). These cells have relatively large somata located in the ganglion cells layer that give rise to long axons extending horizontally in the nerve fiber layer and exiting the eye through the optic nerve. As such, the RGCs are the direct portal from the retina to the brain. Numbering around 0.7 to 1.5 million in the human retina [33][34][35], RGCs are separated from each other by glial processes of Müller cells. They are arranged in a single cell layer, except at the macula, where the ganglion cell layer is about 8 to 10 cells thick and contains 50% of all RGCs due to the far lesser photoreceptor convergence [2,36]. RGCs were traditionally classified as ON-and OFF-center RGCs, responding to increases or decreases in light intensity presented at the center of their receptive field [37]. However, there are many subtypes of RGCs differentiated by morphological criteria (e.g., dendritic arborisation), functional criteria (response to different stimuli) and molecular criteria [38][39][40]. There are also five types of intrinsically photosensitive RGCs (ipRGCs), which were discovered only recently [41]. These light-sensitive cells express melanopsin, which, upon stimulation by light, activates a signaling cascade that hyperpolarizes the neuron. ipRGCs mostly project to the suprachiasmatic nucleus and thus contribute to the synchronization of the circadian oscillator [40,42,43]. There are also three types of alpha RGCs [44], three types of Local Edge Detectors RGCs [45] and three types of J-RGCs expressing junctional adhesion molecule B [46]. Because of this high diversity of ganglion cell types, each sensitive to different visual features, the retina is not a simple relay structure but the first center of complex visual processing, sending preprocessed images of the external world to the brain.  The horizontal pathway (Figure 4) is comprised of two types of interneurons, horizontal and amacrine cells, which together subserve the connectivity and complementarity of subparts of the vertical circuitry at two different levels of the retina (OPL and IPL). This cellular architecture establishes the interconnected mosaic that defines the vast array of retinal image-processing functions. Indeed, horizontal and amacrine cells are essential for the creation of the center-surround properties of RGC receptive fields, along with many other visual functions observed in the retina, such as surround inhibition of photoreceptor cells [3,10,33]. The main chemical involved in this pathway is gamma aminobutyric acid (GABA), an inhibitory neurotransmitter. Horizontal cell types ( Figure 4B) are distinguishable by morphological criteria and molecular markers [47]. The main classification is into A-type, or axon-bearing horizontal cells, and B-type, or axon-less horizontal cells [47]. Both subtypes are GABAergic interneurons, providing inhibitory feedback to cones or rods.
Amacrine cells mainly extend laterally (but some vertically) in the inner plexiform layer and receive inputs from bipolar cells ( Figure 4C). Amacrine cells are astonishingly specialized interneurons that send feedforward signals to RGCs, feedback signals to bipolar cells and even inhibitory signals to other nearby amacrine cells (reviewed in [10,33]). Indeed, amacrine cells are inhibitory interneurons that mediate the spatial and temporal characteristics of RGCs' receptive fields and light responses [48,49], refine the center-surround receptive fields of bipolar cells [50], sharpen the bipolar cell responses timing [51] and can regulate the gain of feedforward signals [52]. Amacrine cells, similar to horizontal cells, express the atypical endocannabinoid receptor TRPV1 [53].
The numerous subtypes of amacrine cells are all inhibitory (GABAergic or glycinergic, along with a secondary neurotransmitter such as acetylcholine) and are mostly categorized functionally into narrow-, medium-and wide-field amacrine cells, according to the size of their dendritic arborization [10,33]. Wide-field amacrine cells are mostly GA-BAergic interneurons with arborizations that extend in diameter from 100 µm (average The horizontal pathway (Figure 4) is comprised of two types of interneurons, horizontal and amacrine cells, which together subserve the connectivity and complementarity of subparts of the vertical circuitry at two different levels of the retina (OPL and IPL). This cellular architecture establishes the interconnected mosaic that defines the vast array of retinal image-processing functions. Indeed, horizontal and amacrine cells are essential for the creation of the center-surround properties of RGC receptive fields, along with many other visual functions observed in the retina, such as surround inhibition of photoreceptor cells [3,10,33]. The main chemical involved in this pathway is gamma aminobutyric acid (GABA), an inhibitory neurotransmitter. Horizontal cell types ( Figure 4B) are distinguishable by morphological criteria and molecular markers [47]. The main classification is into A-type, or axon-bearing horizontal cells, and B-type, or axon-less horizontal cells [47]. Both subtypes are GABAergic interneurons, providing inhibitory feedback to cones or rods.
Amacrine cells mainly extend laterally (but some vertically) in the inner plexiform layer and receive inputs from bipolar cells ( Figure 4C). Amacrine cells are astonishingly specialized interneurons that send feedforward signals to RGCs, feedback signals to bipolar cells and even inhibitory signals to other nearby amacrine cells (reviewed in [10,33]). Indeed, amacrine cells are inhibitory interneurons that mediate the spatial and temporal characteristics of RGCs' receptive fields and light responses [48,49], refine the centersurround receptive fields of bipolar cells [50], sharpen the bipolar cell responses timing [51] and can regulate the gain of feedforward signals [52]. Amacrine cells, similar to horizontal cells, express the atypical endocannabinoid receptor TRPV1 [53].
The numerous subtypes of amacrine cells are all inhibitory (GABAergic or glycinergic, along with a secondary neurotransmitter such as acetylcholine) and are mostly categorized functionally into narrow-, medium-and wide-field amacrine cells, according to the size of their dendritic arborization [10,33]. Wide-field amacrine cells are mostly GABAergic interneurons with arborizations that extend in diameter from 100 µm (average 350 µm) to the millimeter scale [54], whereby they mediate long-range interactions as well as inhibitory surrounds in RGCs [3,55,56]. Starburst amacrine cells are a subtype of GABAergic/cholinergic wide-field amacrine cells that impart direction of movement selectivity in some RGCs [33,57]. Medium-field amacrine cells, of which there are at least eight types, including spiny AC, secretoneurin AC are GABAergic/glycinergic, have stratified dendritic arborizations extending between 100 and 500 µm. These cells gather and distribute signals across multiple levels of the IPL [33]. Finally, narrow-field amacrine cells, of which there are at least nine types, have dendritic arborization less than 100 µm wide and are commonly glycinergic interneurons [58,59].
Cells 2021, 10, x FOR PEER REVIEW 6 of 11 350 µm) to the millimeter scale [54], whereby they mediate long-range interactions as well as inhibitory surrounds in RGCs [3,55,56]. Starburst amacrine cells are a subtype of GA-BAergic/cholinergic wide-field amacrine cells that impart direction of movement selectivity in some RGCs [33,57]. Medium-field amacrine cells, of which there are at least eight types, including spiny AC, secretoneurin AC are GABAergic/glycinergic, have stratified dendritic arborizations extending between 100 and 500 µm. These cells gather and distribute signals across multiple levels of the IPL [33]. Finally, narrow-field amacrine cells, of which there are at least nine types, have dendritic arborization less than 100 µm wide and are commonly glycinergic interneurons [58,59]. The intricate organization of the retina makes it the perfect window into the brain. Unsurprisingly, vision is the dominant sense in many species, such that 30 to 55% of the brain is devoted to vision, depending on the species [62]. As a result, any loss of retinal function will have dire consequences, extending from various perceptual impairments to blindness (see Table 1). Indeed, many visual problems diagnosed in patients arise due to a disorder of the retinal mosaic. Most human retinal diseases mainly affect one of two sites in the human retina: the photoreceptor layer and the RPE or RGC and nerve fibers layers. The RPE and photoreceptors layers are the main locus of serious pathologies such as Age-Related Macular Degeneration (AMD) and autosomal disorders such as Retinitis Pigmentosa (RP), Juvenile Macular Degeneration (Stargardt's disease and Best's disease), achromatopsia and retinal detachment. AMD is the most prevalent cause of visual loss in older adults around the globe. It is characterized by the deposition of lipids and proteins (Drusen) in RPE cells, along with the degeneration of photoreceptors, especially in the macula region (reviewed in [63]). The onset of AMD is marked by progressive loss of acuity in the central vision (scotoma), which impedes important visual functions such as reading and face recognition. RP is an autosomal-dominant retinal dystrophy marked by the progressive loss of RPE cells and apoptosis of photoreceptor cells, causing progressive vision loss, extending from the peripheral to central vision (i.e., ring scotoma or tunnel vision). Peripheral vision loss often leads to night blindness and challenges during The intricate organization of the retina makes it the perfect window into the brain. Unsurprisingly, vision is the dominant sense in many species, such that 30 to 55% of the brain is devoted to vision, depending on the species [62]. As a result, any loss of retinal function will have dire consequences, extending from various perceptual impairments to blindness (see Table 1). Indeed, many visual problems diagnosed in patients arise due to a disorder of the retinal mosaic. Most human retinal diseases mainly affect one of two sites in the human retina: the photoreceptor layer and the RPE or RGC and nerve fibers layers. The RPE and photoreceptors layers are the main locus of serious pathologies such as Age-Related Macular Degeneration (AMD) and autosomal disorders such as Retinitis Pigmentosa (RP), Juvenile Macular Degeneration (Stargardt's disease and Best's disease), achromatopsia and retinal detachment. AMD is the most prevalent cause of visual loss in older adults around the globe. It is characterized by the deposition of lipids and proteins (Drusen) in RPE cells, along with the degeneration of photoreceptors, especially in the macula region (reviewed in [63]). The onset of AMD is marked by progressive loss of acuity in the central vision (scotoma), which impedes important visual functions such as reading and face recognition. RP is an autosomal-dominant retinal dystrophy marked by the progressive loss of RPE cells and apoptosis of photoreceptor cells, causing progressive vision loss, extending from the peripheral to central vision (i.e., ring scotoma or tunnel vision). Peripheral vision loss often leads to night blindness and challenges during locomotion, such as collisions with unseen obstacles. Stargardt's disease is an autosomal recessive disorder affecting photoreceptor cells and causing vision loss at an early age, whereas Best's disease (or vitelliform macular dystrophy) is an autosomal dominant disorder the leads to protein/lipid deposits between the RPE and photoreceptor layers [64]. Furthermore, achromatopsia, or color blindness, is an X-linked form of congenital cone dystrophy, leading to improper light transduction and reduced perception [65]. The junction between the RPE and photoreceptor cell layers is also a common site of retinal detachment. RGCs and their axons (GCL and NFL) are also commonly affected in glaucoma and other retinopathies (i.e., diabetic, hypertensive and retinopathy of prematurity) associated with micro-haemorrhages in the NFL. Glaucoma, which usually results from increased intraocular pressure, is marked by the degeneration of RGCs, leading to significant losses in visual field and contrast sensitivity [66].
Vision is undoubtedly the most important sense for humans, and visual impairments have dire consequences for quality of life and productive activities [67][68][69][70]. The retina contains a surprising complexity in its cellular architecture, and literally presents a window to the brain; no other part of the central nervous system is amenable to direct observation. Because of the importance of human vision, researchers are making a broad effort to understand better the complex details of retinal function, even to the extent of developing highly invasive cybernetic inputs replacing the retina, or advanced methods for behavioral sensory substitution [71][72][73].
Therefore, this Special Issue of Cells is timely and brings a collection of groundbreaking novel research on the cellular and molecular aspects of healthy and diseased retinas. We present here 20 original articles and six reviews from the international research community, all with the goal of advancing knowledge towards the prevention and cure of visual pathologies, mainly AMD, RP and diabetic retinopathy. Papers in this Special Issue can be regrouped into five major themes.
The  The second group of articles deals with diabetic retinopathy, its ischemic and hemorrhagic mechanisms, related markers and possible therapies in many species, including man. We sincerely hope that the papers presented in this Special Issue of Cells will contribute to the understanding of retinal diseases and their underlying mechanisms and will lead to the development of new pharmaceutical tools to treat visual disorders.
Funding: This research received no external funding.