What makes up the fovea

In both images it is clear that the second and third order neurons of the inner nuclear and ganglion cell layers respectively are not present in the foveal pit. Figure 4.

The second and third order neurons of the retinal inner nuclear and ganglion cell layers respectively are not present in the foveal pit. In the foveal pit the only neurons are cone photoreceptors, all with slim inner segments, packed cell bodies, up to 6 layers deep reaching to the floor of the foveal pit Figure 5, green cells.

A central bouquet of cones has their synaptic pedicles ending at the foveal pit floor Figure 5, green spots, arrows , whereas the cones surrounding them stretch their axons known as Henle fibers and presynaptic pedicles away from the center of the foveal pit to the foveal slope area Figure 5, green spots form a continuous line, arrows. The lack of blood vessels in the central pit can be seen by the absence of the blue circular profiles there Figure 5, bv. Figure 5. The picture would be very similar in a human retina.

It is interesting to note in Figure 5 that the pedicles of the very central bouquet of cones are widely spaced ending on the foveal pit floor. Figure 6. A wholemount monkey fovea immunostained with cone arrestin. The axons of the cones radiate out to a ring of cone pedicles. Central bouquet cone axons stay in the foveal pit. Understanding how the primate fovea develops from fetal to adult stage of the retina has been a very difficult task in vision research.

This has, of course been due to the difficulty of obtaining retinas from human pre-birth and baby eyes. Even fetal monkey material has been scarce to obtain.

Anita Hendrickson Figure 7 at the University of Washington, Seattle, spent most of her career pursuing this subject of retinal research, and has contributed almost all we know. Figure 7. A young Anita Hendrickson at her microscope. From her obituary in The earliest fetal retinas examined 2 were from a week eye. The fovea is not recognizable at this stage, because the central region of the retina, where the fovea will develop, consists primarily of several layers of ganglion cell bodies and inner nuclear layer cells INL , presumably amacrine and bipolar cells Figure 8, a.

A single layer of developing cones stretches from outer plexiform layer OPL to pigment epithelium and choroid Figure 8, a, right inset. A hint of a developing cone pedicle is seen Figure 8, right red arrow but there is no sign of outer segments of cones Figure 8, right, apposing red arrowheads. By fetal week 28, an indentation of the retina at the thickest ganglion cell layer appears and can be considered the earliest sign of the foveal pit Figure 8, b, P.

The inner nuclear layer has become thinner and appears pushed out of the pit P but a kind of split is occurring in the middle of the INL known as the transient layer of Chievitz TC, Figure 8, c 3. Through the latter two fetal stages, where the foveal pit is becoming obvious, the cones are still immature, arranged in a single layer and have no visible outer segments Figure 8, b and c.

However, there is the first suggestion of the cone axons being tilted away from their cell bodies to form the early Henle fiber layer. Figure 8. Foetal human retina at a foetal week Fwk 22, b Fwk 28, and c Fwk The foveal position is not noticed at week 22 but in later weeks becomes dimpled as ganglion cells become displaced out radially from the developing foveal pit.

In the beginning the retina is thick, multilayered and cones are undeveloped with no outer segments or visual pigment a: right enlarged photo, red arrow heads point to a cone nucleus, a stubby inner segment, and a developing cone pedicle. From Hendrickson et al. It is interesting to closely examine the cone photoreceptors in the fetal toweek retinas as illustrated by Hendrickson and coauthors 2. Figure 9 shows how immature the cones of the foveal pit are compared with those of the cones at some distance from the fovea Figure 9.

At the foveal pit area, the cones are just stubby cells with a synaptic pedicle, little to no lengthened inner segment and zero outer segments Figure 9, fovea.

Most cell bodies descend away from the external limiting membrane and have elongating axons that are angled away from the foveal pit, forming the early Henle fiber layer. Inner segments are long, but the outer segments are still not formed.

Figure 9. Sections of the retina of a human foetus at 25 weeks gestation. The cones of the fovea are still undeveloped with no outer segments, and a synaptic area with no axon.

The slanting of the cone axons out radially is beginning to be evidence of a developing Henle fiber layer. At birth of the human baby the retina in the eye is looking recognizably foveate Figure 10, a. The foveal pit now contains a very thin, only one layer thick, ganglion cell layer, a thin inner plexiform layer IPL but a prominent inner nuclear layer INL Figure 10, a. The cones are now evident as straight vertical cones with synaptic pedicles, cell bodies and inner segments.

There are probably developing cone outer segments too not easy to see at this magnification. But the pit is still several cell layers thick with only the cones on the foveal slope beginning to angle away from the pit. Further out on the foveal slope the cone Henle fiber layer is obvious now Figure 10, a. By 15 months after birth, the baby retina has a definite fovea and even the central cones are angling out to the foveal slope. Inner and outer segments are well developed in the pit and no other layers of the retina are here anymore Figure 10, b and c.

By 13 years the fovea is completely developed Figure 10, d 2. Figure The foveal retina sections of a human from a postnatal 8 days P8d , through b 15 months, to fully formed d 13 years. Second order neurons and ganglion cells are pushed along the foveal slope to form a pile of ganglion cell bodies at the foveal rim.

What forces could cause this remarkable transformation of an evenly thick multi-cell, layered retina to become concavely dimpled, buckled up and stretched outwards to form a single layered pit at the fovea and a high sided sloping tissue with the highest concentration of cell layers at the foveal rim. The developmental effort is to ensure that a central area of the retina is concentrated with the slimmest packed cones with no obstruction of incoming light by secondary and tertiary cell layers.

B Drawing to show the central foveal cone bouquet of thin and closely packed cones in the foveal pit. Blue arrows show the vertical squeezing and packing of the cones in the foveal pit and orange arrows show the displacement horizontally of the foveal cone axons, during development of the adult fovea.

The less familiar and less understood part of foveal cones is the further course towards their synaptic terminals. It includes a two-step transition. From a two-dimensional mosaic for image reception it is rearranged into to a three-dimensional somata tiling, which then again spreads out to establish the concentric monolayered pedicle meshwork The mature human fovea consists of 3 spectral types of cone: red or long wavelength sensitive cones, L-cones; green or medium wavelength cones, or M-cones; and blue or short wavelength cones, S-cones.

It is extremely difficult to get a horizontal section through the central fovea particularly including the central bouquet of cones because of the concave nature of the fovea. The tiniest central cones in the center of the photograph Figure It is noticeable that the cones are not uniformly distributed in a hexagonal mosaic.

Small patches of cones are hexagonal and then the patch is interrupted and shifts the surrounding patches slightly Figure Ahnelt and coauthors 11 noticed that these shifts in the mosaic usually were associated with the position of a slightly larger diameter cone. They proposed that these larger cones were the short wavelength cones, the S-cones, and described their morphological differences from the surrounding, more common L- and M-cones A horizontally sectioned and stained human retina at the foveal pit and rod free area.

From Ahnelt et al, S-cones are relatively rare in the retina compared with the much more dominant L- and M- cones. The S-cones are, however, ubiquitous in all vertebrate retinas, with the exception of cetaceans As far as other mammals are concerned S-cones are commonly paired with L-cones to give them a dichromatic color sense.

These L-cones vary in spectral peak, and the more mid-spectral types are called M-cones. In old world monkeys and apes, and in man an L-opsin gene duplication and further mutation produced an extra mid-spectral L-cone opsin subtype, M-cone opsin.

The combination of L-cones, M-cones and S-cones provides trichromacy. In primates and humans of course, the S-cones are rather scarce in the foveal pit. Some authors suggest that there is a so-called blue cone blind spot In Figure A whole-mount photograph of the foveal slope of a human retina.

P upper right corner is the foveal pit. Larger cone profiles break up the mosaic of cones into disjointed groups of closely packed smaller profile cones [arrows in a, b and colored in as S-blue cones in b ]. From Ahnelt et al.

Since these earlier identifications of foveal S-cones on morphological criteria 11 , antibodies against the S-cone pigments in the cone outer segments have been developed and are able to positively identify the S-cones in the overall population by immunocytochemical methods. In figure 13, the human foveal pit FP and foveal slope are immunostained with an S-cone antibody and illustrate the S-cones as black spots and angled black cone outer segments. In the foveal pit only a few S-cones appear interspersed in the mosaic of highest density Figure However, their proportion increases in surrounding areas and are at their highest density on the foveal slope Figure 13 brown spots, top and right-hand side.

The foveal pit FP and part of the foveal slope are immunostained with an S-cone opsin in a human retina. Figure 14 illustrates immunostaining in vertical section and the scarcity of S-cones in the foveal pit compared to the increase in number of this population of cones on the foveal slope, of a human retina. A map of the S- cone distribution in another human fovea is shown in Figure The lighter to darker blue shading indicates less dense to denser S- cone presence.

Note in both images Figs. Vertical section of a human foveal pit immunostained with antibodies against cone arrestin for all cones red , and JH, which labels S-cones green. Few S-cones are found in the foveal pit. Every S-cone is labelled with S-cone opsin antibody in a human fovea. It has been rather easy to identify S-cones in the human fovea and the rest of the retina by these immunocytochemical techniques where S- cones can be visualized and distinguished from the surrounding L- or M-cones.

Figure 16 shows a spectacular confocal image of the cones in near peripheral human retina by immunolabeling with cone arrestin, and by the HJ antibody to S-cones, that shows up the S-cone opsin both in the outer and inner segments.

Near peripheral retinal human cones stained with HJ antibody that identifies the S-cones green amongst the arrestin red labeled cones. Sadly, the L-cones and M-cones are not distinguishable on immunostaining techniques because their visual pigments are so close in structure.

There is presently no antibody developed to separately mark them into L- or M- cone types. So, to identify L- and M-cones in the human fovea we must go to other more sophisticated techniques. Psychophysical measurements have suggested that L- cones usually outnumber M-cones by in the human fovea Microspectrophotometry of all cones in small patches of cones in the fovea of monkeys, has revealed that L- and M-cones occur in about equal proportion Newer techniques, introduced by Roorda and Williams 19 , use adaptive optics to make direct measurements of spectral sensitivity of foveal cones in the living human eye Figure They found that humans varied greatly in the proportions of L-cones to M-cones: some individuals have almost equal proportions while others have a higher proportion of L-cones, even to the extreme of 16 L-cones to every M-cone Figure17, BS.

Roorda and coauthors 20 concluded that L- and M-cones are in a random distribution in the foveal center Nevertheless, the human subjects HS and BS in Figure 17 would seem intuitively to have a different perception of color. But both subjects were reported to have normal color vision This comparison is done by retinal and brain neural circuitry see later section on horizontal cell roles in spectral antagonism.

Interestingly, others, using similar techniques of adaptive optics and human reports of hue for single cone stimulation with colored light in the fovea, found a considerable proportion of cones produced only white sensations Method of adaptive optics shows mosaics of L red , M green and S blue cones in four human subjects with normal color vision.

Adapted from Roorda and Williams, The process of centrifugal displacement by the Henle layer affects cone pedicles in different ways, depending on their eccentricity Figure Foveal pit in blue and the foveal slope to the foveal edge in grey.

Cone pedicles lack telodendria in the foveal pit. Pedicles with increasing eccentricity along the slope have tadpole-like shape. More peripherally cone pedicles are round in shape and have telodendrial interconnections. The transition coincides with the appearance of capillaries red and microglia green spots.

In the central bouquet of cones in the foveal pit, the pedicles appear to stay in place Figure In serial semithin Figure 19, a and electron microscopic Figure 19, b sections, a few roundish pedicles can be found at the foveal floor Figure 19, a-c, circles.

They are isolated from each other, thus lacking any connections to other cones via telodendria. LM and EM appearances of cone pedicles. From the outer central cones, Henle fibers of short length terminate in peculiar tadpole-like pedicles Figure 18, Figure 19, d-e.

Beyond this zone — still almost entirely established by cone terminals only — the pedicles make up a patchy mosaic Figure 19, f-g. These terminals elaborate telodendrial networks that end on neighboring cone pedicles at gap junction connections 1, This pedicle mosaic tends to establish radial arrays yet is locally influenced by interspersed glia Figure 19, g.

The cones of the foveal pit project vertically downwards Figure 20, a. Cone morphology in the foveal pit a , foveal slope b and peripheral retina c. Drawing d shows the cone morphologies in the different areas. Ahnelt and coworkers 7 have noted that cones likely to be short wavelength sensitive tend to occur in irregular positions in both, foveal and peripheral areas.

Figure 21A. Human cone inner segment mosaic on the foveal slope. Note the first rod r , and the bead-like arrangement colored lines of the M- and L-cones circumventing an S-cone labeled by an S-opsin antibody asterisk. Here they approach a non-random distribution Figure 21B shows a schematic summary 7 of cone arrangement in the mosaic of the foveal slope area where the S-cones develop first and reach the non-random mosaic arrangement 25, Their axons Henle fibers emerge from the cone nuclear layer and radiate centrifugally towards their pedicles.

Figure 21B. Apparently, S-cones blue do not participate in this process, as their cell bodies stay close to the ELM external limiting membrane, large arrow.

Adapted from Ahnelt et al, 7. As we have illustrated in Figure 2B, the whole fovea is roughly 1. The shape and size of horizontal cells in the human fovea Golgi staining. From Kolb et al. These horizontal cells are elongated and arranged concentrically in a circle around the foveal center and on the far edge of the foveal pit.

The area could still be in the avascular zone. Note the dendrites are reaching quite far to contact central cones. The cells are axon bearing, but morphologically it is difficult to judge of which type.

The smallest are the H1 cells that appear to contact about cones, judging by their dendritic clusters. H2 cells are wirier and more irregular than H1 and H3 cells but have quite closely packed and profuse dendrites Figure These H2 cells would be reaching into the foveal slope area, where we know there is the highest density of S-cones, to contact the latter cone type.

H3 cells may also be reaching into the foveal slope but we know from previous data they do not receive synapses from S-cones 29, As can be seen they are a little larger in dendritic field size Figure The H1 cell contacts 6 cones and the H3 about cones Figure H1 and H2 types here have axons small arrows in Figure 22 , which will expand into axon terminals in contact with rods in the case of H1, and with S-cones in the case of H2 cells By confocal microscopy the central human fovea can be seen to contain parvalbumin immunoreactive horizontal cells Figure 23, a-b; green cells under the cone pedicles.

They are elongated and not closely packed. Their dendrites would be reaching to contact central foveal bouquet cones Figure 23, b. In contrast, the H1s of the foveal slope are closely packed with vertically squashed cell bodies and small bushy dendrites reaching to the closely packed cone pedicles at the ends of the Henle-fiber-layer cone axons Figure 23, c.

Vertical section of the human fovea cut along the edge of the foveal pit. H1 horizontal cells are immunostained with anti-parvalbumin green and cone photoreceptors with recoverin red. H1 cells are very crowded together in the foveal slope. The H2 cells of the human retina are known to be particularly associated with the S-cone blue photoreceptors see Webvision chapter on S-cone pathways.

Figure 24 white arrows shows a few calbindin positive HCs red cells, arrows on the foveal slope in human retina. In addition to the H2 cells with cell bodies close to the OPL, there are diffuse cone bipolar cells contacting several cones, and amacrine cells stained with calbindin.

These red, diffuse bipolar cells have cell bodies lower in the inner nuclear layer and long slanted single apical dendrites as compared to the red H2 cells. Note in this section of human fovea the first rods are present on the foveal slope and the first rod bipolar cells are staining for the antibody to PKC Figure 24, green cells.

Human foveal slope area immunolabeled with antibodies against calbindin red that marks H2 horizontal cells, some bipolar and some amacrine cell types.

H2 cells are marked with arrows. The first rod bipolar cells on the foveal slope are labeled with PKC-alpha antibodies green. Horizontal cells of the vertebrate retina are known to have important roles in sharpening and scaling of responses from photoreceptors through the subsequent retinal pathways to influence the ganglion cell output This large feedback effect provokes an expanded region of antagonistic signal compared with the central cone signal.

In the case of M- or L-cones the antagonistic surround is a mixed M- and L-cone signal. The feedback in the case of an S-cone would come from H2 cells, whose contacts include surrounding M- and L-cones. Indeed S-cones have been recorded from in monkey retina and found to have blue—yellow spectral opponency as well as center-surround organization 34, Presumably spatial opponency would be transmitted from the M- and L-cones to their respective bipolar cell connections, and in the case of the S-cone, a true spectral opponency has been proven to be transmitted as well No recordings have been made in foveal cones to really see if an M- or L-cone has a spectrally opponent surround like that of albeit peripheral S-cones He noted many different types of bipolar cells in the various species and that there were particularly tiny dendritic spreads for some bipolar cells in the bird retina He suggested that these bipolar cells contacted single cones.

In , Stephen Polyak Figure 25 published books on the neural cell types revealed by Golgi and other silver methods in monkey and human retinas and brain. In central monkey and human retinas Polyak observed and illustrated several types of bipolar cells, but he was very concentrated on the remarkably small dendritic tops of some types that he construed as contacting single cones.

He named these bipolar cells, midget bipolar cells mbc. Steven Polyak circa Polyak also drew and commented briefly that the midget bipolar cells appeared to be of two varieties, one that had a long axon to the inner plexiform layer, and the other a much shorter axon ending higher in the inner plexiform layer. At the same time, there were midget ganglion cells that had small dendritic trees that came in the two varieties possibly reaching to the axon terminals of the two types of midget bipolar cells Figure 26, mgcs.

Original drawings of Polyak Bipolar cells and ganglion cells of the central retina. We now know that the invaginating midget bipolar cells imb and flat midget bipolar cells fmb are physiologically different. Polyak described midget ganglion cells mgc as of two types, which we now know are OFF mgc and ON mgc. These connect to fmbs and imbs respectively. Large field bipolar cells dfb and parasol ganglion cells were also described by Polyak.

Multiple diseases can directly or indirectly affect the fovea, thus reducing or erasing perfect vision. A well-known disease that involves the fovea is age-related macular degeneration AMD. AMD is a degenerative disorder of the retina that affects the macula lutea. Individuals with AMD retain their peripheral vision but lose their central vision, which manifests as scotomas and metamorphopsias. Despite the loss of photoreceptors within the fovea, the retina has an innate ability to use the remaining photoreceptors in the most effective manner possible.

The retina creates a pseudo fovea, which is a fixation point that stabilizes vision. AMD is the most common cause of blindness for people older than the age of 75 affects over 13 million Americans.

There is no proven effective treatment or prevention of dry AMD. Wet AMD is characterized by choroidal neovascularization that can lead to rapid loss of vision due to bleeding. Standard treatment of wet AMD involves serial anti-vascular endothelial growth factor anti-VEGF injections to stop choroidal neovascularization and promote macular healing.

Risk factors for AMD have been identified and include age, ethnicity, smoking, alcohol use, diet, family history, and certain chronic medical conditions such as cardiovascular disease or myeloproliferative disorders. Most of the time macular degeneration, which results in the death of photoreceptors cells in the fovea, occurs in older individuals.

However, it is possible for younger individuals to suffer from macular degeneration is possible. Stargardt disease is the most common form of juvenile macular degeneration.

Stargardt disease is almost always inherited in an autosomal recessive manner. The most common cause of Stargardt disease is a mutation in the ABCA4 gene that is responsible for creating proteins that clear away vitamin A byproducts inside photoreceptors; as these byproducts accumulate, central vision decreases. The progressive vision loss from this disease also results from the death of photoreceptor cells in the macula. Stargardt disease usually destroys central vision but preserves peripheral vision.

The vision loss is not correctable with prescription eyeglasses, contact lenses, or refractive surgery. Retinal detachment — When the retina lifts or tears away from the back of the eye. Retinoblastoma — Cancer of the eye that begins in the retina. Retinal vein occlusion — When a vein or artery in the retina becomes blocked. Retinopathy of prematurity — Condition in which abnormal blood vessels grow on the retina; affects babies born prematurely. Choroidal neovascular membranes — Irregular, damaged blood vessels that begin to develop under the retina in an area called the choroid.

Retinitis pigmentosa — Genetic condition that affects how the retina responds to light; commonly seen in individuals with Usher syndrome. Macular telangiectasia — A condition that causes blood vessels around the fovea to dilate and leak.

The best way to protect your sight and keep your eyes healthy is to undergo routine comprehensive eye exams — it may be possible for an eye doctor to detect early signs of a fovea-related condition before you notice any symptoms. IMAIOS and selected third parties, use cookies or similar technologies, in particular for audience measurement.

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