Microscopic Anatomy 11/11/09 Mary Ann Stepp, Ph.D. Ross Hall, Rm. 226C, x4-0557 mastepp@gwu.

edu The Eye Functions of the eye: As one of the organs of the special senses, the eye functions both to acquire and to begin the initial processing of visual information. The cornea and lens focus light on the retina and the retina integrates and sends the information to the visual cortex of the brain. The demand for the processing of visual information by the brain is one of the major forces behind its evolution into the complex structure it is in humans.

The human eye consists of 3 primary layers. 1. Inner: the retina-- both a photosensitive and a nonphotosensitive part. 2. Middle: uvea or vascular tunic and consists of the choroid, ciliary body and process, zonule fibers, and iris. 3. Outer: fibrous tunic or tunica fibrosa and includes the lamina cribosa, the sclera, trabecular meshwork, canal of Schlemm, corneoscleral junction (limbus), and the cornea.

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And the eye has 3 major compartments. The main cavity of the eye behind the lens is called the vitreous space and is filled with the vitreous humor, a transparent gelatinous substance. The area behind the cornea but in front of the iris is called the anterior chamber. The area behind the iris and in front of the lens is called the posterior chamber. Both anterior and posterior chambers are filled with aqueous humor.

Development
The optic sulcus forms as a depression in the developing forebrain. It continues to enlarge and it becomes termed the optic vesicle. A region in the overlying ectoderm begins to thicken and is then termed the lens placode. As the lens placode continues to thicken and the optic vesicle enlarge, they come in contact. Once they touch, the cells of the lens placode begin to invaginate forming the lens vesicle and the optic cup--the outer-most layer will become the retinal pigment epithelium (RPE) and the innermost layer the neural retina. The lens is finally pinched off completely. The cornea will form from the overlying ectoderm. Thus, both lens and cornea are derived from the ectoderm,

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The Inner Layer: Has 2 major components… 1.  photosensitive retina 2. non-photosensitive retina

The Inner Layer The inner layer of the eye consists of a neural photosensitive aspect called the retina located in the posterior globe and a two cell layer anterior aspect, starting at the ora serrata and continuing over the ciliary body and processes and over the posterior aspect of the iris. Here, after a brief mention of the retinal pigment epithelium, we will discuss the photosensitive (neural) retina.

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The retinal pigment epithelium (RPE): The basal membrane of the RPE abuts Bruch's membrane and the choriocapillary layer of the middle layer of the eye called the choroid. The apical membrane has extensive invaginations: microvilli and cylindrical sheaths. These projections are not anatomically sealed by any specialized junctional complexes.

The functions of the RPE include: 1)  transport of Vit A to the photoreceptors 2)  phagocytosis of discarded rod/cone outer segments 3)  absorb excess light after photoreceptors have been stimulated, 4)  support attachment of the photoreceptors.

Note: each RPE cell likely phagcytoses 7,500 shed disc’s per day

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Clinical Relevance 1: Retinitis Pigmentosum(RP)

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Genetic mutations in various genes cause damage to the RPE reducing the ability of the RPE to remove shed rod and cone outer segments and resulting loss of rods and then cones. There are over 100 different mutations to date have been found that lead to RP. They fall in all three categories: autosomal dominant, autosomal recessive, or X-linked inheritance and the incidence is believed to be 1:4000.

Clinical Relevance 2: Retinal Detachment

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The neural retina detaches from the RPE cells and the choroid and the rods and cone begin to starve. Patients suddenly see lots of floaters and can see flashes of light or what seems like a veil interfering with their vision. If not repositioned quickly, the rods and cones die and fibroblast-like cells grow over the RPE. Lasers are used to reattach the retina.

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Photosensitive retina is complex consisting of over 15 types of neurons including the rods and cones, the bipolar cells and the ganglion cells. The retina has an inverted structure: light initially goes past the neurons without exciting them. Only after excitation of the photoreceptors in the inner most layers are signals transmitted back to the bipolar and ganglion cells.

The layers of the retina are distinct in histological sections. The (1) internal or inner limiting membrane serves as a kind to protective basement membrane for the ganglion cells. It overlies the (2) ganglion cells which are above a synaptic layer where the ganglion cells make contact with the underlying bipolar cells. This layer is called the (3) internal or inner plexiform layer. Next comes the (4) internal or inner nuclear layer where the nuclei of the bipolar cells are located. Another synaptic layer is next where the bipolar cells contact the photoreceptor cells and this layer is called the (5) external or outer plexiform layer.

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The photoreceptor (rod and cone) nuclei are located next in the (6) external or outer nuclear layer. The photoreceptors must pass through (7) the external or outer limiting membrane next. This is where the cells interact with junctional processes formed by specialized glial cells called Mueller cells. The next layer visible is the layer containing (8) the rod and cone inner segments, then (9) the rod and cone outer segments, and finally the outer segments interdigitate with the (10) RPE. The RPE lie over Bruch's membrane and the choriocapillary layer of the choroid.

Rods and cones are polarized neurons. There are ~120 million rods in the human eye and only 6 million cones. Rods function in low levels of light, and have no capability of differentiating among colors. Cones function in daylight. There are 3 types of cone cells.

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Cones come in three types each of which is “tuned” to a different wavelenth of light: red, green, and blue. The cells contain one of three visual pigments, called photopsins. As a result, humans see in trichromy. Some people have mutations that shift the wavelength optima in their photopsins but they still have 3 types of cone cells; others have just two types of cone cells since they have mutations that prevent the formation of one of the 3 photopsins.

Ishihara Plates

http://www.toledo-bend.com/colorblind/Ishihara.html

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The density of rods and cones is not uniform across the globe; some parts of the retina are more sensitive to light than others because of differences in the distribution of neurons.

In bright light, the contraction of the iris allows the the cornea and lens to focus the light on a region of the retina called the fovea centralis (1.5 mm diameter) which is located within a depression in the retina called the macula (5.5.mm diameter). The foveola (200 µm diameter) is located within the fovea; it is a where blood vessels are sequestered to the periphery of the choroid layer. The bodies of the ganglion and bipolar cells are restricted to the periphery of the fovea. The density of ganglion cells in the at the fovea is much greater than any where else in the retina. The macula is also called the macula lutea and it appears yellow in fundus photographs. Also, the cone cells are tightly packed within the macula and there are no rods. This means that visual acuity and color discrimination are optimal when light is focused on the macula.

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In the TEM and SEM images shown, A and B show the fovea and C and D regions at the periphery of the retina. Images are shown in two orientations. Notice that in the fovea, there is only one type of photoreceptor, cones, and the cones are very much squished together and elongated compared to cones in the periphery.

Clincal Correlation: Age-Related Macular Degeneration (AMD) is the most frequent cause of blindness in people over 65. 1.75 million people in the USA have it. Yellow pigment (drusen) accumulates in and around the macula and interferes with vision. The disease has no treatment and progresses from a socalled dry form (non-vascular) to a wet form (vascular). Recently, progress have been made trying to sort out the diseases genetics. Most likely, macular degeneration is autoimmune in nature and is made worse be smoking, hypertension, and obesity.

Dry AMD

Wet AMD

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Bipolar cell bodies are in the internal nuclear layer; these neurons integrate signals from rods and cones and send the signals on the the ganglion cells. Bipolar cells form junctions with the rods and cones in the external plexiform layer and with the ganglion cells in the internal plexiform layer.

The ganglion cells project their axons to a specific region of the retina where they come together. This site is called the optic papilla or optic disk. The bundle of axons is called the optic nerve and this site is also called the optic nerve head. Because there are no rods or cones here, this is a "blind spot" in the eye.

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Other cells in the retina include horizontal cells which facilitate interaction between photoreceptors, amacrine cells which connect ganglion cells and various types of supporting cells including Mueller cells. All these support cells have their nuclei in the inner or internal nuclear layer.

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Mueller cells form the scaffold for the entire retina. They span the width of the neural retina. Both the internal and external limiting membranes are formed from the Mueller cells. Mueller cells therefore face the vitreous internally and the subretinal space externally. The superficial blood vessels within the neural retina are also enfolded by Mueller cells. The Meuller cells are the primary cells that make the vitreous. The vitreous is a clear, gel-like substance containing collagen and proteoglycans present posterior to the lens whose function appears to be related to maintaining the shape of the eye and in maintaining retinal attachment.

The Middle Layer (Uveal Tract) Also has 4 major parts… 1. Choroid 2. Ciliary Body 3. Ciliary Processes 4. Iris

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1. Choroid: Primarily functions as vascular support for the neural retina and other ocular structures. The melanocytes help to absorb any light not absorbed by rods and cones of the neural retina. Consists of loose connective tissue, leukocytes, fibroblasts, melanocytes, and the endothelial cells comprising the vessel walls. The choroid has an outer and inner layer. The outer layer has no specific name. The inner layer is called the choriocapillary layer and it is richer in smaller vessels than is the outer layer. A membrane separating the choriocapillary layer from the retina is called Bruch's membrane; the choriocapillary layer and Bruch’s membrane are present from the ora serrata to the optic disk.

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2. Ciliary Body: At the level of the lens, the choroid becomes the ciliary body. The ciliary body is triangular and contacts on one side the vitreous humor, on another the sclera, and on the third side it contacts the posterior chamber (area between iris and lens). The ciliary muscles are within the ciliary body. The surface of the ciliary body is lined with a 2 cell layer, nonphotosensitive, anterior extension of the retina. The outermost cells are an extension of the RPE cells and are melanin rich. The innermost cells are derived from the neural retina and are a simple columnar epithelium. The epithelial cells of the ciliary body and processes produce the aqueous humor.

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3. Ciliary Processes: Ridge-like protrusions arising from the ciliary body which are also covered on their surface by the non-photosensitive aspect of the anterior retina. From the ciliary process emerge the ciliary zonules which insert into the lens capsule to keep the lens in place and to allow the lens to change shape during accommodation. The cells which make up the internal aspect of the ciliary process transport nutrients from the plasma through vessel walls into the posterior chamber and are thus responsible for the formation of the aqueous humor.

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Ciliary Processes, cont’d The aqueous flows from the posterior chamber, past the iris, through the pupil, and into the anterior chamber to the limbus where it passes through the trabecular meshwork and into the canal of Schlemm.

Red arrows indicate direction of aqueous humor flow

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Ciliary Processes, cont’d Clinical Correlation: Glaucoma is caused by blockage aqueous outflow via Schlemm’s Canal: Open vs Closed angle glaucoma.

4. Iris: The function of the iris is to block stray light from entering the eye during daylight vision; during night vision, the opening of the pupil by dilation of the iris allows for maximum light entry into the eye. The iris is an extension of the choroid which lies anterior to the ciliary body and processes. It partially covers the lens leaving a hole called the pupil. The anterior surface of the iris is lined by mesothelial cells sitting on a basement membrane continuous with that of the posterior surface of the cornea. Beneath this basement membrane is a stroma formed by fibroblasts and melanocytes. The middle layer of the iris consists of circular and radiating muscle bundles which interact closely with the posterior aspect of the iris. The posterior surface of the iris is lined by the 2 cell layer non-photosensitive aspect of the neural retina. This part of the iris is heavily pigmented and has a purple hue.

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Summary: The Middle Layer (Uveal Tract) 1. 2. 3. 4. Choroid: Ciliary Body: Ciliary Processes Iris

The outer layer Has 4 major parts… 1. Sclera 2. Lamina cribosa 3. Corneoscleral junction (limbus) 4. Cornea

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The outer layer
1. The sclera: thick collagen rich tunic to support the globe of the eye. Allows the eye to achieve the high intraocular fluid pressures necessary to maintain its shape. By maintaining its shape, the eye can provide stable refractive surfaces necessary to permit focusing of light on the retina. Animal models studying the causes of myopia show that you can induce myopia by occluding one of the eyes during certain critical stages of eye deveopment. When the sclera grows too much, myopia develops. The anterior aspect of the sclera at the level of the ora serrata is covered by a specialized epithelial cell layer called the conjunctiva which is continuous with the cells lining the inner aspect of the eyelids.

2. Lamina cribosa: specialized area of the sclera which helps to protect and support the optic nerve as it leaves the eye. Located beneath the optic papilla or optic nerve head. This is the structure the ophthalmologist views when looking for early signs of glaucoma; it is sensitive to increased intraocular pressure and begins to show signs of breakdown in the diseased eye.

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OD= optic disk, BV=blood vessels, LC= lamina cribosa, ON= optic nerve

3. Corneoscleral junction (limbus): region where the sclera and cornea meet. The limbal epithelial layer contains specialized stem cells which serve as the source of the cells of the central corneal epithelium. This region also functions in maintaining intraocular pressure since within the stroma beneath the limbus lies the trabecular meshwork and the canal of Schlemm. The aqueous humor drains into these structures to exit the eye. Blockage of this drainage system causes elevated intraocular pressure, a condition called glaucoma. Glaucoma left untreated will cause damage to the optic nerve, severe ocular pain, and lead to detachments of the retina and blindness.

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4. Cornea: The transparent, anterior 1/6th of the sclera. The function of the cornea is to provide a clear refractive surface to allow light into the eye; its tough surfaces protect the inner neuronal tissues from injury. The curved shape allows light to be focused on the retina. The cornea has several layers: An outer stratified squamous epithelial cell layer which sits on a specialized acellular basement membrane, called Bowman's layer. The middle layer or corneal stroma is lined above by Bowman’s layer and below by another specialized basement membrane called Descemet's membrane. The inner layer of the cornea is composed of the corneal endothelial cells which interact with Descemet's membrane above and with aqueous humor below.

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The epithelial cells of the cornea have two principle functions: to provide a smooth surface on which the tear film may spread and to act as a barrier to block microbial entry into the inner layers of the eye. These cells are similar in many ways to the cells which make up the epidermis but are also quite unique in that they have a surface designed to promote tear film spreading, they do not have a vascular source, and they do not differentiate from stem cells located in their basal cell layer. In response to injury, these cells migrate quickly to cover exposed basement membranes and stroma. The corneal epithelium can become hazy after surgery (LASIK, PRK) and can detach after healing in some patients with recurrent erosions.

Human Corneas

After PRK

Recurrent Epithelial Erosion

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In contrast, in skin, the basal cells layer, called stratum germanitivum contains the stem cells and is not smooth and refractive but undulating.

5. The stromal fibroblasts produce the collagen molecules and proteoglycans which form the ordered arrays of collagen bundles necessary to maintain both corneal clarity and strength. These cells also are important in the healing process since they produce the matrix degrading enzymes required to degrade defective collagen fibers. In response to injury these cells can convert from a fibroblast phenotype to cells which act like myofibroblasts; they become motile and help in wound contraction after injury.

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6. The endothelial cells are essential to the health of the cornea. They are the cells which pump nutrients from the aqueous humor and release them into the stroma where they passively diffuse to feed the stromal fibroblasts and the epithelium. The endothelial cells also act as pumps to regulate the flow of water into and out of the cornea. They respond rapidly to changes in the water content of the cornea. Unfortunately, in adult humans, the endothelial cells do not replicate and over the lifetime of an individual, they continually decrease in number. Injury to these cells was common during the early days of cataract extraction procedures and caused many corneas to become cloudy and opaque requiring the need for corneal transplantation.

Cornea Review:

The cornea is the most frequently transplanted organ. "Immune privileged" is a term frequently used when referring to the cornea since corneal transplants are usually performed without tissue typing. The cornea functions primarily in vision to refract light. Changes in corneal shape can alter this refractive power. For many people, their cornea is not the optimal shape to allow light to focus on the retina properly. This is usually easily corrected by wearing glasses, contact lens, or by surgical intervention. eg.LASIK.

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The lens has a thick capsule which covers the entire outer surface. The capsule is collagenrich, refractive, elastic, and is the site where the ciliary zonules attach to hold the lens in place and change its shape. At the anterior aspect of the lens, beneath the capsule, there is a single layer of cuboidal epithelial cells, called the subcapsular epithelium. As the lens ages, new cells are derived from the cells at the equator of this region. Cells leave the equator of the epithelial layer and elongate, become post-mitotic, and fill up with proteins called crystallins and become known as lens fibers. Their nuclei shrink and RNA synthesis stops. The center of the lens is called the nucleus or medulla; the outer layer is called the cortex. Both nucleus and cortex are filled with lens fibers. The nearer to the nucleus, the older the fibers are because the fibers are laid down in layers. The lens fibers in the nucleus of the lens contain crystallin proteins synthesized within the embryo.

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The lens functions in accommodation, that is the ability to focus light on the retina from both near and far objects. The lens does this by changing its shape. The shape changes are controlled by the muscles of the ciliary body and processes. At birth the lens is highly elastic and can change shape readily. As it ages, it becomes increasingly more rigid resulting in decreased accommodation, a condition termed presbiopia. In addition to losing elasticity as it ages, the lens also begins to become less transparent. This cloudiness is caused by precipitation and coagulation of proteins within the lens fibers and is called a cataract. It can also result from injury to the lens. Precipitation of proteins within the lens is speeded up by elevated exposure to UV light, by elevated mineral levels (Mg2+, Ca2+) and by elevated glucose (eg. more common in diabetics). Removal of cataracts and insertion of artificial intraocular lenses is highly successful. The mammalian lens is optically a better lens than anything man can make.

Associated structures 1). Conjunctiva: bulbar (covers anterior aspect of the eye up to the corneal limbus) and palpebral (lines the inner surface of the eyelid) conj function as barriers and contain goblet cells which secret mucins which help promote the spreading of the tear film over the corneal surface.

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2). Eyelids: The inner eyelid is lined by the conjunctiva; the outer surface by a thin epidermis. Within the tarsal plate in connective tissue adjacent to the conjunctiva are the Meibomian Glands. Eyelashes arise at the conjunctival: tarsal border with glands of Zeiss near their base and the gland of Moll nearby. The orbicularus oculi muscles are also present near the midline of the eyelid; these muscle participate in opening and closing the lid. The primary function of the blink is to distribute the tear film over the eye surface; a secondary function is to prevent injury to the eye. All of the glands, and including the lacrimal glands which are located in the anterior superior temporal orbit of the eye and the goblet cells of the conjunctiva, participate in maintaining a moist ocular surface.

2). Eyelids, continued… Conditions which inhibit tear production and/or the blink reflex are serious and cause a condition called dry eye. Dry eye allows corneal epithelial denudation to occur which then allows bacteria to adhere and infections to occur. Scaring from these infections eventually interferes with vision.

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Review:

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For answers to questions consult the following sources: Mary Ann Stepp mastepp@gwu.edu Ross 226C Or:
Histology:A Text and Atlas, Ross, et al., 4th edition,2003. Basic Histology, Junqueira, et al., 10thth edition, 2003. Grey's Anatomy, 30th American Addition Molecular Biology of the Cell, 3rd Addition, Alberts, et al., 1994 Principles and Practice of Ophthalmology, Volume 1: Basic Sciences, Alberts and Jacobiac et al., 1994. The Cornea, Smolin and Thoft, 1994.

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