Retina

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Retina
Human eye cross-sectional view grayscale.png
Right human eye cross-sectional view; eyes vary significantly among animals.
Details
Pronunciation UK: /ˈrɛtɪnə/ ,
US: /ˈrɛtənə/ ,
pl. retinae /-ni/
Part of Eye
System Visual system
Artery Central retinal artery
Identifiers
Latin Rēte
MeSH D012160
TA A15.2.04.002
FMA 58301
Anatomical terminology

The retina is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which translates that image into electrical neural impulses to the brain to create visual perception, the retina serving a function analogous to that of the film or image sensor in a camera.

Contents

The neural retina consists of several layers of neurons interconnected by synapses, and is supported by an outer layer of pigmented epithelial cells. The primary light-sensing cells in the retina are the photoreceptor cells, which are of two types: rods and cones. Rods function mainly in dim light and provide black-and-white vision. Cones function in well-lit conditions and are responsible for the perception of colour, as well as high-acuity vision used for tasks such as reading. A third type of light-sensing cell, the photosensitive ganglion cell, is important for entrainment of circadian rhythms and reflexive responses such as the pupillary light reflex.

Light striking the retina initiates a cascade of chemical and electrical events that ultimately trigger nerve impulses that are sent to various visual centres of the brain through the fibres of the optic nerve. Neural signals from the rods and cones undergo processing by other neurons, whose output takes the form of action potentials in retinal ganglion cells whose axons form the optic nerve. [1] Several important features of visual perception can be traced to the retinal encoding and processing of light.

In vertebrate embryonic development, the retina and the optic nerve originate as outgrowths of the developing brain, specifically the embryonic diencephalon; thus, the retina is considered part of the central nervous system (CNS) and is actually brain tissue. [2] [3] It is the only part of the CNS that can be visualized non-invasively.

Structure

Inverted versus non-inverted retina

The vertebrate retina is inverted in the sense that the light sensing cells are in back of the retina, so that light has to pass through layers of neurons and capillaries before it reaches the rods and cones. [4] The ganglion cells, whose axons form the optic nerve, are at the front of the retina; therefore the optic nerve must cross through the retina en route to the brain. In this region there are no photoreceptors, giving rise to the blind spot. [5] In contrast, in the cephalopod retina the photoreceptors are in front, with processing neurons and capillaries behind them. Because of this, cephalopods do not have a blind spot.

Although the overlying neural tissue is partly transparent, and the accompanying glial cells have been shown to act as fibre-optic channels to transport photons directly to the photoreceptors, [6] [7] light scattering does occur. [8] Some vertebrates, including humans, have an area of the central retina adapted for high-acuity vision. This area, termed the fovea centralis, is avascular (does not have blood vessels), and has minimal neural tissue in front of the photoreceptors, thereby minimizing light scattering. [8]

The cephalopods have a non-inverted retina which is comparable in resolving power to the eyes of many vertebrates. Squid eyes do not have an analog of the vertebrate retinal pigment epithelium (RPE). Although their photoreceptors contain a protein, retinochrome, that recycles retinal and replicates one of the functions of the vertebrate RPE, one could argue that cephalopod photoreceptors are not maintained as well as in vertebrates and that, as a result, the useful lifetime of photoreceptors in invertebrates is much shorter than in vertebrates. [9] Having easily replaced stalk-eyes (some lobsters) or retinae (some spiders, such as Deinopis [10] ) rarely occurs.

The cephalopod retina does not originate as an outgrowth of the brain, as the vertebrate one does. It is arguable that this difference shows that vertebrate and cephalopod eyes are not homologous but have evolved separately. From an evolutionary perspective, a more complex structure such as the inverted retina can generally come about as a consequence of two alternate processes: (a) an advantageous "good" compromise between competing functional limitations, or (b) as a historical maladaptive relic of the convoluted path of organ evolution and transformation. Vision is an important adaptation in higher vertebrates.

A third view of the "inverted" vertebrate eye is that it combines two benefits: the maintenance of the photoreceptors mentioned above, and the reduction in light intensity necessary to avoid blinding the photoreceptors, which are based on the extremely sensitive eyes of the ancestors of modern hagfishes (a fish that lives in very deep, dark water). [11]

Retinal layers

Section of retina Gray881.png
Section of retina
Rods, cones and nerve layers in the retina. The front (anterior) of the eye is on the left. Light (from the left) passes through several transparent nerve layers to reach the rods and cones (far right). A chemical change in the rods and cones send a signal back to the nerves. The signal goes first to the bipolar and horizontal cells (yellow layer), then to the amacrine cells and ganglion cells (purple layer), then to the optic nerve fibres. The signals are processed in these layers. First, the signals start as raw outputs of points in the rod and cone cells. Then the nerve layers identify simple shapes, such as bright points surrounded by dark points, edges, and movement. (Based on a drawing by Ramon y Cajal, 1911.) Retina-diagram.svg
Rods, cones and nerve layers in the retina. The front (anterior) of the eye is on the left. Light (from the left) passes through several transparent nerve layers to reach the rods and cones (far right). A chemical change in the rods and cones send a signal back to the nerves. The signal goes first to the bipolar and horizontal cells (yellow layer), then to the amacrine cells and ganglion cells (purple layer), then to the optic nerve fibres. The signals are processed in these layers. First, the signals start as raw outputs of points in the rod and cone cells. Then the nerve layers identify simple shapes, such as bright points surrounded by dark points, edges, and movement. (Based on a drawing by Ramón y Cajal, 1911.)
Illustration of the distribution of cone cells in the fovea of an individual with normal colour vision (left), and a colourblind (protanopic) retina. Note that the center of the fovea holds very few blue-sensitive cones. ConeMosaics.jpg
Illustration of the distribution of cone cells in the fovea of an individual with normal colour vision (left), and a colourblind (protanopic) retina. Note that the center of the fovea holds very few blue-sensitive cones.
Distribution of rods and cones along a line passing through the fovea and the blind spot of a human eye Human photoreceptor distribution.svg
Distribution of rods and cones along a line passing through the fovea and the blind spot of a human eye

The vertebrate retina has ten distinct layers. [13] From closest to farthest from the vitreous body:

  1. Inner limiting membrane – basement membrane elaborated by Müller cells.
  2. Nerve fibre layer – axons of the ganglion cell bodies (note that a thin layer of Müller cell footplates exists between this layer and the inner limiting membrane).
  3. Ganglion cell layer – contains nuclei of ganglion cells, the axons of which become the optic nerve fibres, and some displaced amacrine cells. [2]
  4. Inner plexiform layer – contains the synapse between the bipolar cell axons and the dendrites of the ganglion and amacrine cells. [2]
  5. Inner nuclear layer – contains the nuclei and surrounding cell bodies (perikarya) of the amacrine cells, bipolar cells, and horizontal cells. [2]
  6. Outer plexiform layer – projections of rods and cones ending in the rod spherule and cone pedicle, respectively. These make synapses with dendrites of bipolar cells and horizontal cells. [2] In the macular region, this is known as the Fiber layer of Henle .
  7. Outer nuclear layer – cell bodies of rods and cones.
  8. External limiting membrane – layer that separates the inner segment portions of the photoreceptors from their cell nuclei.
  9. Inner segment / outer segment layer – inner segments and outer segments of rods and cones. The outer segments contain a highly specialized light-sensing apparatus. [14] [15]
  10. Retinal pigment epithelium – single layer of cuboidal epithelial cells (with extrusions not shown in diagram). This layer is closest to the choroid, and provides nourishment and supportive functions to the neural retina, The black pigment melanin in the pigment layer prevents light reflection throughout the globe of the eyeball; this is extremely important for clear vision [16] . [17] [18]

These layers can be grouped into 4 main processing stages: photoreception; transmission to bipolar cells; transmission to ganglion cells, which also contain photoreceptors, the photosensitive ganglion cells; and transmission along the optic nerve. At each synaptic stage there are also laterally connecting horizontal and amacrine cells.

The optic nerve is a central tract of many axons of ganglion cells connecting primarily to the lateral geniculate body, a visual relay station in the diencephalon (the rear of the forebrain). It also projects to the superior colliculus, the suprachiasmatic nucleus, and the nucleus of the optic tract. It passes through the other layers, creating the optic disc in primates. [19]

Additional structures, not directly associated with vision, are found as outgrowths of the retina in some vertebrate groups. In birds, the pecten is a vascular structure of complex shape that projects from the retina into the vitreous humour; it supplies oxygen and nutrients to the eye, and may also aid in vision. Reptiles have a similar, but much simpler, structure. [20]

In adult humans, the entire retina is approximately 72% of a sphere about 22 mm in diameter. The entire retina contains about 7 million cones and 75 to 150 million rods. The optic disc, a part of the retina sometimes called "the blind spot" because it lacks photoreceptors, is located at the optic papilla, where the optic-nerve fibres leave the eye. It appears as an oval white area of 3 mm². Temporal (in the direction of the temples) to this disc is the macula, at whose centre is the fovea, a pit that is responsible for our sharp central vision but is actually less sensitive to light because of its lack of rods. Human and non-human primates possess one fovea, as opposed to certain bird species, such as hawks, who are bifoviate, and dogs and cats, who possess no fovea but a central band known as the visual streak.[ citation needed ] Around the fovea extends the central retina for about 6 mm and then the peripheral retina. The farthest edge of the retina is defined by the ora serrata. The distance from one ora to the other (or macula), the most sensitive area along the horizontal meridian is about 32 mm.[ clarification needed ]

In section, the retina is no more than 0.5 mm thick. It has three layers of nerve cells and two of synapses, including the unique ribbon synapse. The optic nerve carries the ganglion cell axons to the brain, and the blood vessels that supply the retina. The ganglion cells lie innermost in the eye while the photoreceptive cells lie beyond. Because of this counter-intuitive arrangement, light must first pass through and around the ganglion cells and through the thickness of the retina, (including its capillary vessels, not shown) before reaching the rods and cones. Light is absorbed by the retinal pigment epithelium or the choroid (both of which are opaque).

The white blood cells in the capillaries in front of the photoreceptors can be perceived as tiny bright moving dots when looking into blue light. This is known as the blue field entoptic phenomenon (or Scheerer's phenomenon).

Between the ganglion cell layer and the rods and cones there are two layers of neuropils where synaptic contacts are made. The neuropil layers are the outer plexiform layer and the inner plexiform layer. In the outer neuropil layer, the rods and cones connect to the vertically running bipolar cells, and the horizontally oriented horizontal cells connect to ganglion cells.

The central retina predominantly contains cones, while the peripheral retina predominantly contains rods. In total, there are about seven million cones and a hundred million rods. At the centre of the macula is the foveal pit where the cones are narrow and long, and, arranged in a hexagonal mosaic, the most dense, in contradistinction to the much fatter cones located more peripherally in the retina [21] . At the foveal pit the other retinal layers are displaced, before building up along the foveal slope until the rim of the fovea, or parafovea, is reached, which is the thickest portion of the retina. The macula has a yellow pigmentation, from screening pigments, and is known as the macula lutea. The area directly surrounding the fovea has the highest density of rods converging on single bipolar cells. Since its cones have a much lesser convergence of signals, the fovea allows for the sharpest vision the eye can attain. [2]

Though the rod and cones are a mosaic of sorts, transmission from receptors, to bipolars, to ganglion cells is not direct. Since there are about 150 million receptors and only 1 million optic nerve fibres, there must be convergence and thus mixing of signals. Moreover, the horizontal action of the horizontal and amacrine cells can allow one area of the retina to control another (e.g. one stimulus inhibiting another). This inhibition is key to lessening the sum of messages sent to the higher regions of the brain. In some lower vertebrates (e.g. the pigeon), there is a "centrifugal" control of messages – that is, one layer can control another, or higher regions of the brain can drive the retinal nerve cells, but in primates this does not occur. [2]

Layers imagable with optical coherence tomography

Using optical coherence tomography (OCT) there are 18 layers that can be identified in the retina. The layers and anatomical correlation are as follows: [22] [23] [24]

Time-Domain OCT of the macular area of a retina at 800 nm, axial resolution 3 um Retina-OCT800.png
Time-Domain OCT of the macular area of a retina at 800 nm, axial resolution 3 µm
Spectral-Domain OCT macula cross-section scan. SD-OCT Macula Cross-Section.png
Spectral-Domain OCT macula cross-section scan.
macula histology (OCT) Macula Histology OCT.jpg
macula histology (OCT)

From innermost to outermost, the layers identifiable by OCT are as follows:

#OCT Layer / Conventional LabelAnatomical Correlate Reflectivity

on OCT

Specific

anatomical

boundaries?

Additional

references

1 Posterior cortical vitreous Posterior cortical vitreousHyper-reflectiveYes [23]
2 Preretinal space In eyes where the vitreous has fully or partially detached from the retina, this is the space created between the posterior cortical vitreous face and the internal limiting membrane of the retina.Hypo-reflective [23]
3 Internal limiting membrane (ILM)Formed by Müller cell endfeet

(unclear if it can be observed on OCT)

Hyper-reflectiveNo [23]
Nerve fiber layer (NFL) Ganglion cell axons travelling towards the optic nerve
4 Ganglion cell layer (GCL) Ganglion cell bodies (and some displaced amacrine cells)Hypo-reflective [23]
5 Inner plexiform layer (IPL)Synapses between bipolar, amacrine and ganglion cells Hyper-reflective [23]
6 Inner nuclear layer (INL)a) Horizontal, bipolar and amacrine cell bodies

b) Müller cell nuclei

Hypo-reflective [23]
7 Outer plexiform layer (OPL) Synapses between photoreceptor, bipolar and horizontal cells Hyper-reflective [23]
8(Inner half) Henle’s nerve fiber layer (HL) Photoreceptor axons

(obliquely orientated fibres; not present in mid-peripheral or peripheral retina)

Hypo-reflectiveNo [23]
(Outer half) Outer nuclear layer (ONL)The photoreceptor cell bodies
9 External limiting membrane (ELM)Made of zonulae adherens between Müller cells and photoreceptor inner segments Hyper-reflective [23]
10 Myoid zone (MZ) The innermost portion of the photoreceptor inner segment (IS) containing: Hypo-reflectiveNo [25] [26]
11 Ellipsoid zone (EZ) The outermost portion of the photoreceptor inner segment (IS) packed with mitochondria Very Hyper-reflectiveNo [22] [27] [25] [23] [28] [29]
IS/OS junction or Photoreceptor integrity line (PIL) The photoreceptor connecting cilia which bridge the inner and outer segments of the photoreceptor cells.
12 Photoreceptor outer segments (OS) The photoreceptor outer segments (OS) which contain disks filled with opsin, the molecule that absorbs photons.Hypo-reflective [30] [23]
13 Interdigitation zone (IZ) Apices of the RPE cells which encase part of the cone OSs.

Poorly distinguishable from RPE.Previously: "cone outer segment tips line"(COST)

Hyper-reflectiveNo
14 RPE/Bruch’s complex RPE phagosome zoneVery Hyper-reflectiveNo [22] [23]
RPE melanosome zoneHypo-reflective
RPE mitochondria zone + Junction between the RPE & Bruch's membrane Very Hyper-reflective
15 Choriocapillaris Thin layer of moderate reflectivity in inner choroidNo [23]
16 Sattler’s layer Thick layer of round or ovalshaped hyperreflective profiles, with hyporeflective cores in mid-choroid [23]
17 Haller’s layer Thick layer of oval-shaped hyperreflective profiles, with hyporeflective cores in outer choroid [23]
18 Choroidal-scleral juncture Zone at the outer choroid with a marked change in texture, in which large circular or ovoid profiles abut a

homogenous region of variable reflectivity

[23]

Development

Retinal development begins with the establishment of the eye fields mediated by the SHH and SIX3 proteins, with subsequent development of the optic vesicles regulated by the PAX6 and LHX2 proteins. [31] The role of Pax6 in eye development was elegantly demonstrated by Walter Gehring and colleagues, who showed that ectopic expression of Pax6 can lead to eye formation on Drosophila antennae, wings, and legs. [32] The optic vesicle gives rise to three structures: the neural retina, the retinal pigmented epithelium, and the optic stalk. The neural retina contains the retinal progenitor cells (RPCs) that give rise to the seven cell types of the retina. Differentiation begins with the retinal ganglion cells and concludes with production of the Muller glia. [33] Although each cell type differentiates from the RPCs in a sequential order, there is considerable overlap in the timing of when individual cell types differentiate. [31] The cues that determine a RPC daughter cell fate are coded by multiple transcription factor families including the bHLH and homeodomain factors. [34] [35]

In addition to guiding cell fate determination, cues exist in the retina to determine the dorsal-ventral (D-V) and nasal-temporal (N-T) axes. The D-V axis is established by a ventral to dorsal gradient of VAX2, whereas the N-T axis is coordinated by expression of the forkhead transcription factors FOXD1 and FOXG1. Additional gradients are formed within the retina. [35] This spatial distribution may aid in proper targeting of RGC axons that function to establish the retinotopic map. [31]

Blood supply

Fundus photograph showing the blood vessels in a normal human retina. Veins are darker and slightly wider than corresponding arteries. The optic disc is at right, and the macula lutea is near the centre. Fundus photograph of normal right eye.jpg
Fundus photograph showing the blood vessels in a normal human retina. Veins are darker and slightly wider than corresponding arteries. The optic disc is at right, and the macula lutea is near the centre.

The retina is stratified into distinct layers, each containing specific cell types or cellular compartments [36] that have metabolisms with different nutritional requirements. [37] To satisfy these requirements, the ophthalmic artery bifurcates and supplies the retina via two distinct vascular networks: the choroidal network, which supplies the choroid and the outer retina, and the retinal network, which supplies the retina's inner layer. [38]

Circulatory mechanisms

At first glance, one may think that the vertebrate retina is "wired wrongly" or "badly designed"; but in fact, the retina could not function if it were not inverted. The photoreceptor layer must be embedded in the retinal pigment epithelium (RPE), which performs at least seven vital functions, [39] one of the most obvious being to supply oxygen and other necessary nutrients needed for the photoreceptors to function. These nutrients include glucose, fatty acids, and retinal. The mammalian photoreceptor amplification process uses large quantities energy for vision in photopic conditions (requiring less under scotopic conditions) and, thus, requires the large supply nutrients supplied by the blood vessels in the choroid, which lies beyond the RPE. The choroid supplies about 75% of these nutrients to the retina and the retinal vasculature only 25%. [4]

When light strikes 11-cis-retinal (in the disks in the rods and cones), 11-cis-retinal changes to all-trans-retinal which then triggers changes in the opsins. Now, the outer segments do not regenerate the retinal back into the cis- form once it has been changed by light. Instead the retinal is pumped out to the surrounding RPE where it is regenerated and transported back into the outer segments of the photoreceptors. This recycling function of the RPE protects the photoreceptors against photo-oxidative damage [40] [41] and allows the photoreceptor cells to have decades-long useful lives.

In birds

The bird retina is devoid of blood vessels, perhaps to give unobscured passage of light for forming images, thus giving better resolution. It is, therefore, a considered view that the bird retina depends for nutrition and oxygen supply on a specialized organ, called the "pecten" or pecten oculi, located on the blind spot or optic disk. This organ is extremely rich in blood vessels and is thought to supply nutrition and oxygen to the bird retina by diffusion through the vitreous body. The pecten is highly rich in alkaline phosphatase activity and polarized cells in its bridge portion – both befitting its secretory role. [42] Pecten cells are packed with dark melanin granules, which have been theorized to keep this organ warm with the absorption of stray light falling on the pecten. This is considered to enhance metabolic rate of the pecten, thereby exporting more nutritive molecules to meet the stringent energy requirements of the retina during long periods of exposure to light. [43]

Biometric identification and diagnosis of disease

The bifurcations and other physical characteristics of the inner retinal vascular network are known to vary among individuals, [44] and these individual variances have been used for biometric identification and for early detection of the onset of disease. The mapping of vascular bifurcations is one of the basic steps in biometric identification. [45] Results of such analyses of retinal blood vessel structure can be evaluated against the ground truth data [46] of vascular bifurcations of retinal fundus images that are obtained from the DRIVE dataset. [47] In addition, the classes of vessels of the DRIVE dataset have also been identified, [48] and an automated method for accurate extraction of these bifurcations is also available. [49] Changes in retinal blood circulation are seen with aging [50] and exposure to air pollution, [51] and may indicate cardiovascular diseases such as hypertension and atherosclerosis. [52] [53] [54] Determining the equivalent width of arterioles and venules near the optic disc is also a widely used technique to identify cardiovascular risks. [55]

Function

The retina translates an optical image into neural impulses starting with the patterned excitation of the colour-sensitive pigments of its rods and cones, the retina's photoreceptor cells. The excitation is processed by the neural system and various parts of the brain working in parallel to form a representation of the external environment in the brain.

The cones respond to bright light and mediate high-resolution colour vision during daylight illumination (also called photopic vision). The rod responses are saturated at daylight levels and don't contribute to pattern vision. However, rods do respond to dim light and mediate lower-resolution, monochromatic vision under very low levels of illumination (called scotopic vision). The illumination in most office settings falls between these two levels and is called mesopic vision. At mesopic light levels, both the rods and cones are actively contributing pattern information. What contribution the rod information makes to pattern vision under these circumstances is unclear.

The response of cones to various wavelengths of light is called their spectral sensitivity. In normal human vision, the spectral sensitivity of a cone falls into one of three subtypes, often called blue, green, and red, but more accurately known as short, medium, and long wavelength-sensitive cone subtypes. It is a lack of one or more of the cone subtypes that causes individuals to have deficiencies in colour vision or various kinds of colour blindness. These individuals are not blind to objects of a particular colour, but are unable to distinguish between colours that can be distinguished by people with normal vision. Humans have this trichromatic vision, while most other mammals lack cones with red sensitive pigment and therefore have poorer dichromatic colour vision. However, some animals have four spectral subtypes, e.g. the trout adds an ultraviolet subgroup to short, medium, and long subtypes that are similar to humans. Some fish are sensitive to the polarization of light as well.

In the photoreceptors, exposure to light hyperpolarizes the membrane in a series of graded shifts. The outer cell segment contains a photopigment. Inside the cell the normal levels of cyclic guanosine monophosphate (cGMP) keep the Na+ channel open, and thus in the resting state the cell is depolarised. The photon causes the retinal bound to the receptor protein to isomerise to trans-retinal. This causes the receptor to activate multiple G-proteins. This in turn causes the Ga-subunit of the protein to activate a phosphodiesterase (PDE6), which degrades cGMP, resulting in the closing of Na+ cyclic nucleotide-gated ion channels (CNGs). Thus the cell is hyperpolarised. The amount of neurotransmitter released is reduced in bright light and increases as light levels fall. The actual photopigment is bleached away in bright light and only replaced as a chemical process, so in a transition from bright light to darkness the eye can take up to thirty minutes to reach full sensitivity.

When thus excited by light, the photoceptor sends a proportional response synaptically to bipolar cells which in turn signal the retinal ganglion cells. The photoreceptors are also cross-linked by horizontal cells and amacrine cells, which modify the synaptic signal before it reaches the ganglion cells, the neural signals being intermixed and combined. Of the retina's nerve cells, only the retinal ganglion cells and few amacrine cells create action potentials.

In the retinal ganglion cells there are two types of response, depending on the receptive field of the cell. The receptive fields of retinal ganglion cells comprise a central, approximately circular area, where light has one effect on the firing of the cell, and an annular surround, where light has the opposite effect. In ON cells, an increment in light intensity in the centre of the receptive field causes the firing rate to increase. In OFF cells, it makes it decrease. In a linear model, this response profile is well described by a difference of Gaussians and is the basis for edge detection algorithms. Beyond this simple difference, ganglion cells are also differentiated by chromatic sensitivity and the type of spatial summation. Cells showing linear spatial summation are termed X cells (also called parvocellular, P, or midget ganglion cells), and those showing non-linear summation are Y cells (also called magnocellular, M, or parasol retinal ganglion cells), although the correspondence between X and Y cells (in the cat retina) and P and M cells (in the primate retina) is not as simple as it once seemed.

In the transfer of visual signals to the brain, the visual pathway, the retina is vertically divided in two, a temporal (nearer to the temple) half and a nasal (nearer to the nose) half. The axons from the nasal half cross the brain at the optic chiasma to join with axons from the temporal half of the other eye before passing into the lateral geniculate body.

Although there are more than 130 million retinal receptors, there are only approximately 1.2 million fibres (axons) in the optic nerve. So, a large amount of pre-processing is performed within the retina. The fovea produces the most accurate information. Despite occupying about 0.01% of the visual field (less than 2° of visual angle), about 10% of axons in the optic nerve are devoted to the fovea. The resolution limit of the fovea has been determined to be around 10,000 points. The information capacity is estimated at 500,000 bits per second (for more information on bits, see information theory) without colour or around 600,000 bits per second including colour. [56]

Spatial encoding

On-centres and off-centres of the retina Receptive field.png
On-centres and off-centres of the retina

When the retina sends neural impulses representing an image to the brain, it spatially encodes (compresses) those impulses to fit the limited capacity of the optic nerve. Compression is necessary because there are 100 times more photoreceptor cells than ganglion cells. This is done by "decorrelation", which is carried out by the "centre–surround structures", which are implemented by the bipolar and ganglion cells.

There are two types of centre–surround structures in the retina – on-centres and off-centres. On-centres have a positively weighted centre and a negatively weighted surround. Off-centres are just the opposite. Positive weighting is more commonly known as excitatory, and negative weighting as inhibitory.

These centre–surround structures are not physical apparent, in the sense that one cannot see them by staining samples of tissue and examining the retina's anatomy. The centre–surround structures are logical (i.e., mathematically abstract) in the sense that they depend on the connection strengths between bipolar and ganglion cells. It is believed that the connection strength between cells is caused by the number and types of ion channels embedded in the synapses between the bipolar and ganglion cells.

The centre–surround structures are mathematically equivalent to the edge detection algorithms used by computer programmers to extract or enhance the edges in a digital photograph. Thus, the retina performs operations on the image-representing impulses to enhance the edges of objects within its visual field. For example, in a picture of a dog, a cat and a car, it is the edges of these objects that contain the most information. In order for higher functions in the brain (or in a computer for that matter) to extract and classify objects such as a dog and a cat, the retina is the first step to separating out the various objects within the scene.

As an example, the following matrix is at the heart of a computer algorithm that implements edge detection. This matrix is the computer equivalent to the centre–surround structure. In this example, each box (element) within this matrix would be connected to one photoreceptor. The photoreceptor in the centre is the current receptor being processed. The centre photoreceptor is multiplied by the +1 weight factor. The surrounding photoreceptors are the "nearest neighbors" to the centre and are multiplied by the −1/8 value. The sum of all nine of these elements is finally calculated. This summation is repeated for every photoreceptor in the image by shifting left to the end of a row and then down to the next line.

-1/8-1/8-1/8
-1/8+1-1/8
-1/8-1/8-1/8

The total sum of this matrix is zero, if all the inputs from the nine photoreceptors are of the same value. The zero result indicates the image was uniform (non-changing) within this small patch. Negative or positive sums mean the image was varying (changing) within this small patch of nine photoreceptors.

The above matrix is only an approximation to what really happens inside the retina. The differences are:

Here is an example of an input image and how edge detection would modify it.

Edge-detection-2.jpg

Once the image is spatially encoded by the centre–surround structures, the signal is sent out along the optic nerve (via the axons of the ganglion cells) through the optic chiasm to the LGN (lateral geniculate nucleus). The exact function of the LGN is unknown at this time. The output of the LGN is then sent to the back of the brain. Specifically, the output of the LGN "radiates" out to the V1 primary visual cortex.

Simplified signal flow: Photoreceptors → Bipolar → Ganglion → Chiasm → LGN → V1 cortex

ERP - optic cabling.jpg

Clinical significance

There are many inherited and acquired diseases or disorders that may affect the retina. Some of them include:

Diagnosis

A number of different instruments are available for the diagnosis of diseases and disorders affecting the retina. Ophthalmoscopy and fundus photography have long been used to examine the retina. Recently, adaptive optics has been used to image individual rods and cones in the living human retina, and a company based in Scotland has engineered technology that allows physicians to observe the complete retina without any discomfort to patients. [60]

The electroretinogram is used to non-invasively measure the retina's electrical activity, which is affected by certain diseases. A relatively new technology, now becoming widely available, is optical coherence tomography (OCT). This non-invasive technique allows one to obtain a 3D volumetric or high resolution cross-sectional tomogram of the fine structures of the retina, with histologic quality. Retinal vessel analysis is a non-invasive method to examine the small arteries and veins in the retina which allows to draw conclusions about the morphology and the function of small vessels elsewhere in the human body. It has been established as a predictor of cardiovascular disease [61] and seems to have, according to a study published in 2019, potential in the early detection of Alzheimer's disease. [62]

Treatment

Treatment depends upon the nature of the disease or disorder.

Common treatment modalities

The following are commonly modalities of management for retinal disease:

Uncommon treatment modalities

Rare or uncommon methods of treatment for retinal disease

Retinal gene therapy

Gene therapy holds promise as a potential avenue to cure a wide range of retinal diseases. This involves using a non-infectious virus to shuttle a gene into a part of the retina. Recombinant adeno-associated virus (rAAV) vectors possess a number of features that render them ideally suited for retinal gene therapy, including a lack of pathogenicity, minimal immunogenicity, and the ability to transduce postmitotic cells in a stable and efficient manner. [63] rAAV vectors are increasingly utilized for their ability to mediate efficient transduction of retinal pigment epithelium (RPE), photoreceptor cells and retinal ganglion cells. Each cell type can be specifically targeted by choosing the appropriate combination of AAV serotype, promoter, and intraocular injection site.

Several clinical trials have already reported positive results using rAAV to treat Leber's congenital amaurosis, showing that the therapy was both safe and effective. [64] [65] There were no serious adverse events, and patients in all three studies showed improvement in their visual function as measured by a number of methods. The methods used varied among the three trials, but included both functional methods such as visual acuity [65] [66] [67] and functional mobility [66] [67] [68] as well as objective measures that are less susceptible to bias, such as the pupil's ability to respond to light [64] [69] and improvements on functional MRI. [70] Improvements were sustained over the long-term, with patients continuing to do well after more than 1.5 years. [64] [65]

The unique architecture of the retina and its relatively immune-privileged environment help this process. [71] Tight junctions that form the blood retinal barrier separate the subretinal space from the blood supply, thus protecting it from microbes and most immune-mediated damage, and enhancing its potential to respond to vector-mediated therapies. The highly compartmentalized anatomy of the eye facilitates accurate delivery of therapeutic vector suspensions to specific tissues under direct visualization using microsurgical techniques. [72] In the sheltered environment of the retina, AAV vectors are able to maintain high levels of transgene expression in the retinal pigmented epithelium (RPE), photoreceptors, or ganglion cells for long periods of time after a single treatment. In addition, the eye and the visual system can be routinely and easily monitored for visual function and retinal structural changes after injections with noninvasive advanced technology, such as visual acuities, contrast sensitivity, fundus auto-fluorescence (FAF), dark-adapted visual thresholds, vascular diameters, pupillometry, electroretinography (ERG), multifocal ERG and optical coherence tomography (OCT). [73]

This strategy is effective against a number of retinal diseases that have been studied, including neovascular diseases that are features of age-related macular degeneration, diabetic retinopathy and retinopathy of prematurity. Since the regulation of vascularization in the mature retina involves a balance between endogenous positive growth factors, such as vascular endothelial growth factor (VEGF) and inhibitors of angiogenesis, such as pigment epithelium-derived factor (PEDF), rAAV-mediated expression of PEDF, angiostatin, and the soluble VEGF receptor sFlt-1, which are all antiangiogenic proteins, have been shown to reduce aberrant vessel formation in animal models. [74] Since specific gene therapies cannot readily be used to treat a significant fraction of patients with retinal dystrophy, there is a major interest in developing a more generally applicable survival factor therapy. Neurotrophic factors have the ability to modulate neuronal growth during development to maintain existing cells and to allow recovery of injured neuronal populations in the eye. AAV encoding neurotrophic factors such as fibroblast growth factor (FGF) family members and GDNF either protected photoreceptors from apoptosis or slowed down cell death. [74]

Organ transplantation Transplantation of retinas has been attempted, but without much success. At MIT, The University of Southern California, RWTH Aachen University, and the University of New South Wales, an "artificial retina" is under development: an implant which will bypass the photoreceptors of the retina and stimulate the attached nerve cells directly, with signals from a digital camera.

History

In 1894, Santiago Ramón y Cajal published the first major characterization of retinal neurons in Retina der Wirbelthiere (The Retina of Vertebrates). [75]

George Wald, Haldan Keffer Hartline, and Ragnar Granit won the 1967 Nobel Prize in Physiology or Medicine for their scientific research on the retina. [76]

A recent University of Pennsylvania study calculated that the approximate bandwidth of human retinas is 8.75 megabits per second, whereas a guinea pig's retinal transfer rate is 875 kilobits per second. [77]

MacLaren & Pearson and colleagues at University College London and Moorfields Eye Hospital in London, in 2006, showed that photoreceptor cells could be transplanted successfully in the mouse retina if donor cells were at a critical developmental stage. [78] Recently Ader and colleagues in Dublin showed, using the electron microscope, that transplanted photoreceptors formed synaptic connections. [79]

In 2012, Sebastian Seung and his laboratory at MIT launched EyeWire, an online Citizen science game where players trace neurons in the retina. [80] The goals of the EyeWire project are to identify specific cell types within the known broad classes of retinal cells, and to map the connections between neurons in the retina, which will help to determine how vision works. [81] [82]

Additional images

See also

Related Research Articles

Optic nerve paired nerve that transmits visual information from the retina to the brain

The optic nerve, also known as cranial nerve II, or simply as CN II, is a paired cranial nerve that transmits visual information from the retina to the brain. In humans, the optic nerve is derived from optic stalks during the seventh week of development and is composed of retinal ganglion cell axons and glial cells; it extends from the optic disc to the optic chiasma and continues as the optic tract to the lateral geniculate nucleus, pretectal nuclei, and superior colliculus.

Eye Organ that detects light and converts it into electro-chemical impulses in neurons

Eyes are organs of the visual system. They provide animals with vision, the ability to receive and process visual detail, as well as enabling several photo response functions that are independent of vision. Eyes detect light and convert it into electro-chemical impulses in neurons. In higher organisms, the eye is a complex optical system which collects light from the surrounding environment, regulates its intensity through a diaphragm, focuses it through an adjustable assembly of lenses to form an image, converts this image into a set of electrical signals, and transmits these signals to the brain through complex neural pathways that connect the eye via the optic nerve to the visual cortex and other areas of the brain. Eyes with resolving power have come in ten fundamentally different forms, and 96% of animal species possess a complex optical system. Image-resolving eyes are present in molluscs, chordates and arthropods.

Macula of retina Oval-shaped pigmented area near the center of the retina

The macula or macula lutea is an oval-shaped pigmented area near the center of the retina of the human eye and some other animalian eyes. The macula in humans has a diameter of around 5.5 mm (0.22 in) and is subdivided into the umbo, foveola, foveal avascular zone, fovea, parafovea, and perifovea areas.

Visual system part of the central nervous system responsible for sight

The visual system is the part of the central nervous system which gives organisms the ability to process visual detail as sight, as well as enabling the formation of several non-image photo response functions. It detects and interprets information from visible light to build a representation of the surrounding environment. The visual system carries out a number of complex tasks, including the reception of light and the formation of monocular representations; the buildup of a nuclear binocular perception from a pair of two dimensional projections; the identification and categorization of visual objects; assessing distances to and between objects; and guiding body movements in relation to the objects seen. The psychological process of visual information is known as visual perception, a lack of which is called blindness. Non-image forming visual functions, independent of visual perception, include the pupillary light reflex (PLR) and circadian photoentrainment.

Photoreceptor cell specialized type of cell found in the retina that is capable of visual phototransduction

A photoreceptor cell is a specialized type of neuroepithelial cell found in the retina that is capable of visual phototransduction. The great biological importance of photoreceptors is that they convert light into signals that can stimulate biological processes. To be more specific, photoreceptor proteins in the cell absorb photons, triggering a change in the cell's membrane potential.

Rod cell

Rod cells are photoreceptor cells in the retina of the eye that can function in less intense light than the other type of visual photoreceptor, cone cells. Rods are usually found concentrated at the outer edges of the retina and are used in peripheral vision. On average, there are approximately 92 million rod cells in the human retina. Rod cells are more sensitive than cone cells and are almost entirely responsible for night vision. However, rods have little role in color vision, which is the main reason why colors are much less apparent in dim light.

Cone cell

Cone cells, or cones, are photoreceptor cells in the retinas of vertebrate eyes. They respond differently to light of different wavelengths, and are thus responsible for color vision and function best in relatively bright light, as opposed to rod cells, which work better in dim light. Cone cells are densely packed in the fovea centralis, a 0.3 mm diameter rod-free area with very thin, densely packed cones which quickly reduce in number towards the periphery of the retina. There are about six to seven million cones in a human eye and are most concentrated towards the macula. The commonly cited figure of six million cone cells in the human eye was found by Osterberg in 1935. Oyster's textbook (1998) cites work by Curcio et al. (1990) indicating an average close to 4.5 million cone cells and 90 million rod cells in the human retina.

In visual physiology, adaptation is the ability of the retina of the eye to adjust to various levels of light. Natural night vision, or scotopic vision, is the ability to see under low-light conditions. In humans, rod cells are exclusively responsible for night vision as cone cells are only able to function at higher illumination levels. Night vision is of lower quality than day vision because it is limited in resolution and colors cannot be discerned; only shades of gray are seen. In order for humans to transition from day to night vision they must undergo a dark adaptation period of up to two hours in which each eye adjusts from a high to a low luminescence "setting", increasing sensitivity hugely, by many orders of magnitude. This adaptation period is different between rod and cone cells and results from the regeneration of photopigments to increase retinal sensitivity. Light adaptation, in contrast, works very quickly, within seconds.

Fovea centralis

The fovea centralis is a small, central pit composed of closely packed cones in the eye. It is located in the center of the macula lutea of the retina.

Retinal ganglion cell type of neuron located near the inner surface (ganglion cell layer) of the retina of the eye

A retinal ganglion cell (RGC) is a type of neuron located near the inner surface of the retina of the eye. It receives visual information from photoreceptors via two intermediate neuron types: bipolar cells and retina amacrine cells. Retina amacrine cells, particularly narrow field cells, are important for creating functional subunits within the ganglion cell layer and making it so that ganglion cells can observe a small dot moving a small distance. Retinal ganglion cells collectively transmit image-forming and non-image forming visual information from the retina in the form of action potential to several regions in the thalamus, hypothalamus, and mesencephalon, or midbrain.

Retina bipolar cell

As a part of the retina, bipolar cells exist between photoreceptors and ganglion cells. They act, directly or indirectly, to transmit signals from the photoreceptors to the ganglion cells.

Melanopsin mammalian protein found in Homo sapiens

Melanopsin is a type of photopigment belonging to a larger family of light-sensitive retinal proteins called opsins and encoded by the gene Opn4. In the mammalian retina, there are two additional categories of opsins, both involved in the formation of visual images: rhodopsin and photopsin in the rod and cone photoreceptor cells, respectively.

Intrinsically photosensitive retinal ganglion cells

Intrinsically photosensitive retinal ganglion cells (ipRGCs), also called photosensitive retinal ganglion cells (pRGC), or melanopsin-containing retinal ganglion cells (mRGCs), are a type of neuron in the retina of the mammalian eye. The presence of ipRGCs were first noted in 1923 when rodless, coneless mice still responded to a light stimulus through pupil constriction, suggesting that rods and cones are not the only light sensitive neurons in the retina. It wasn't until the 1980s that advancements in research on these cells began. Recent research has shown that these retinal ganglion cells, unlike other retinal ganglion cells, are intrinsically photosensitive due to the presence of melanopsin, a light sensitive protein. Therefore they constitute a third class of photoreceptors, in addition to rod and cone cells.

Retinal implant

Retinal prostheses for restoration of sight to patients blinded by retinal degeneration are being developed by a number of private companies and research institutions worldwide. The system is meant to partially restore useful vision to people who have lost their photoreceptors due to retinal diseases such as retinitis pigmentosa (RP) or age-related macular degeneration (AMD). Three types of retinal implants are currently in clinical trials: epiretinal, subretinal, and suprachoroidal. Retinal implants introduce visual information into the retina by electrically stimulating the surviving retinal neurons. So far, elicited percepts had rather low resolution, and may be suitable for light perception and recognition of simple objects.

Eye development Formation of the eye during embryonic development

Eye formation in the human embryo begins at approximately three weeks into embryonic development and continues through the tenth week. Cells from both the mesodermal and the ectodermal tissues contribute to the formation of the eye. Specifically, the eye is derived from the neuroepithelium, surface ectoderm, and the extracellular mesenchyme which consists of both the neural crest and mesoderm.

Müller glia glial cell type in the retina

Müller glia, or Müller cells, are a type of retinal glial cells, first recognized and described by Heinrich Müller. They are found in the vertebrate retina, which serve as support cells for the neurons, as all glial cells do. They are the most common type of glial cell found in the retina. While their cell bodies are located in the inner nuclear layer of the retina, they span across the entire retina.

Mammalian eye eye of a mammal

Mammals normally have a pair of eyes. Although mammalian vision is not so excellent as bird vision, it is at least dichromatic for most of mammalian species, with certain families possessing a trichromatic color perception.

Retinal gene therapy holds a promise in treating different forms of non-inherited and inherited blindness.

Retinal precursor cells

Retinal precursor cells are biological cells that differentiate into the various cell types of the retina during development. In the vertebrate, these retinal cells differentiate into seven cell types, including retinal ganglion cells, amacrine cells, bipolar cells, horizontal cells, rod photoreceptors, cone photoreceptors, and Müller glia cells. During embryogenesis, retinal cells originate from the anterior portion of the neural plate termed the eye field. Eye field cells with a retinal fate express several transcription factor markers including Rx1, Pax6, and Lhx2. The eye field gives rise to the optic vesicle and then to the optic cup. The retina is generated from the precursor cells within the inner layer of the optic cup, as opposed to the retinal pigment epithelium that originate from the outer layer of the optic cup. In general, the developing retina is organized so that the least-committed precursor cells are located in the periphery of the retina, while the committed cells are located in the center of the retina. The differentiation of retinal precursor cells into the mature cell types found in the retina is coordinated in time and space by factors within the cell as well as factors in the environment of the cell. One example of an intrinsic regulator of this process is the transcription factor Ath5. Ath5 expression in retinal progenitor cells biases their differentiation into a retinal ganglion cell fate. An example of an environmental factor is the morphogen sonic hedge hog (Shh). Shh has been shown to repress the differentiation of precursor cells into retinal ganglion cells.

AII amacrine cells are a subtype of amacrine cells present in the retina of mammals. AII amacrine cell serve the critical role of transferring light signals from rod photoreceptors to the retinal ganglion cells

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