The ability to detect light is common to most organisms, including bacteria, reflecting the importance of the visual sense. Designs for visual organs have arisen multiple times and many remain extant. In humans, photoreception is the purview of the eyes. Each eye comprises a sheet of photoreceptive cells (the retina) housed within an optical apparatus (Figure 8.1). The optics project a spatially accurate representation of the visual field onto the photoreceptors, much as a camera lens projects an image onto photographic film or a photosensor array. The simplest cameras use a pinhole as an aperture, which projects an inverted image of the subject onto film.
An eye functions similarly, but aperture size (the pupil) is variable to control the amount of light falling on the photoreceptors. The inclusion of a variable-focus lens ensures that the projected image stays sharp when the aperture changes. The retina, which is located at the back of the eye, contains two types of photoreceptor cells. One is optimized to function in daylight and provide data that can be used to construct a color image (cones). The other is optimized to collect data under minimal lighting conditions, but the data is sufficient only to construct a monochromatic image (rods).
Figure 8.1 Eye structure.
Modified from Krebs, C., Weinberg, J., and Akesson, E. Lippincott’s Illustrated Review of Neuroscience. Lippincott Williams ; Wilkins, 2012
II. Eye Structure
The eye is a roughly spherical organ enclosed within a thick layer of connective tissue (the sclera) that is usually white (see Figure 8.1). The sclera is protective and creates attachment points for three pairs of skeletal (extraocular) muscles that are used to adjust the direction of gaze, stabilize gaze during head movement, and track moving objects. Because the photoreceptors are located at the back of the eye, photons entering the eye must travel through multiple layers and compartments before they can be detected.
Light enters the eye via the cornea, which is continuous with the sclera. The cornea comprises several thin, transparent layers delimited by specialized epithelia. The middle layers are composed of collagen fibers along with supportive keratinocytes and an extensive sensory nerve supply. Blood vessels would interfere with light transmission so the cornea is avascular.
B. Anterior chamber
The anterior chamber is filled with aqueous humor, a watery plasma derivative. It is secreted into the posterior chamber by a specialized ciliary epithelium that covers the ciliary body. It then flows through the pupil, into the anterior chamber, and drains via the canals of Schlemm to the venous system. Humor is produced continuously to deliver nutrients to the cornea and to create a positive pressure of ~8–22 mm Hg that stabilizes corneal curvature and its optical properties (Figure 8.2).
Figure 8.2 Aqueous humor secretion and flow.
The iris is a pigmented, fibrous sheet with an aperture (the pupil) at its center that regulates how much light enters the eye. Pupil diameter is determined by two smooth muscle groups that are under autonomic control. Rings of sphincter muscles that are controlled by postganglionic parasympathetic fibers from the ciliary ganglion decrease pupil diameter when they contract (miosis) as shown in Figure 8.3. A second group of radial muscles controlled by postganglionic sympathetic fibers originating in the superior cervical ganglion widen the pupil (mydriasis). Changes in pupil diameter are reflex responses to the amount of light falling on specialized photosensitive ganglion cells located in the retina (the pupillary light reflex).
Signals from these cells travel via the optic nerve to nuclei in the midbrain and then to the Edinger-Westphal nuclei (see Figure 7.8). Here, they trigger a reflex increase in parasympathetic activity via the oculomotor nerve (cranial nerve [CN] III), and the pupil constricts. Pupillary constriction reduces the amount of light entering the eye and helps prevent photoreceptor saturation. Saturation is undesirable in that it functionally blinds an individual. When light levels are low, a reflex pupillary dilation increases the amount of light reaching the retina. The pupillary reflexes elicit identical muscle responses in both eyes, even though light levels may be changing in one eye only.
Figure 8.3 Regulation of pupil diameter.
Clinical Application 8.1: Glaucoma
Glaucoma is an optic neuropathy that is the second most common cause of blindness worldwide and a leading cause of blindness among African Americans. Glaucoma commonly occurs when the pathway that allows aqueous humor to pass through the pupil and then drain via the canals of Schlemm is obstructed. Humor production continues unabated, and, thus, intraocular pressure (IOP) rises. Once IOP exceeds 30 mm Hg, there is a danger that axons traveling in the optic nerve may be damaged irreversibly. Patients typically remain asymptomatic, their condition being discovered accidentally during a routine ophthalmic examination.
Vision loss occurs peripherally during the initial stages. Because central vision is preserved, patients tend not to notice their deficit until retinal damage is extensive. Ophthalmic examination often shows the optic disc to have taken on a hollowed out or “cupped” appearance due to blood vessel displacement, a finding diagnostic of glaucoma. Treatment includes reducing IOP by using ?-adrenergic antagonists (e.g., timolol) to decrease aqueous humor production, for example,1 and surgical intervention to correct the cause of obstruction.
From Tasman, W. and Jaeger, E. The Wills Eye Hospital Atlas of Clinical Ophthalmology. Second Edition. Lippincott Williams ; Wilkins, 2007
Pupil diameter always reflects a balance between tonic sympathetic and parasympathetic nerve activity. Thus, when atropine (an acetylcholine-receptor antagonist) is applied topically to the cornea during an ophthalmic examination, the pupil dilates because the balance between sympathetic and parasympathetic influence has been shifted in favor of the sympathetic nervous system.
The lens is a transparent, ellipsoid disk suspended in the light path by radial bands of connective tissue fibers (zonule fibers), attached to the ciliary body. The ciliary body is contractile and functions to modify lens shape and adjust its focus (see below). The lens is composed of long, thin cells that are arranged in tightly packed, concentric layers, much like the layers of an onion. The cells are dense with crystallins, proteins that give the lens its transparency and determine its optical properties. The lens is enclosed within a capsule composed of connective tissue and an epithelial layer.
E. Vitreous humor
Vitreous humor is a gelatinous substance composed largely of water and proteins. It is maintained under slight positive pressure to hold the retina against the sclera.
When light reaches the retina, it still has to penetrate multiple layers of neurons and their supporting structures before it can be detected by photoreceptors. The neuronal layers are transparent, so light loss during passage is minimal. The retina contains two specialized regions. The optic disc is a small area where the photoreceptor array is interrupted to allow blood vessels and axons from the retinal neurons to exit the eye, creating a blind spot (Figure 8.4). Nearby, in the center of the field of vision, is a circular area called the macula lutea. At its center is a small (;1-mm diameter) pit called the fovea. The neuronal layers separate here to allow light to fall directly on photoreceptors, creating an area of maximal visual acuity (see below).
Figure 8.4 Retinal landmarks.
From Tasman, W. and Jaeger, E. The Wills Eye Hospital Atlas of Clinical Ophthalmology. Second Edition. Lippincott Williams ; Wilkins, 2007
Retinal photoreceptors are arranged in highly regular arrays so that spatial information can be extracted from the photoreceptor excitation patterns. The retina contains two types of photoreceptors that share a similar cellular structure.
Rods are specialized to detect single photons of light. They cannot differentiate color but they can generate an image under low-light conditions and thereby facilitate scotopic vision (derived from the Greek word for darkness, skotos). Cones function optimally in daylight and mediate photopic, or color, vision.
Photoreceptors are long, thin, excitable cells (Figure 8.5). At the center is a cell body that encloses the nucleus. The cell body extends in one direction to form a short axon that branches into several presynaptic structures. The opposite end of the cell is long and cylindrical and divided into two segments. The inner segment contains all the other organelles required for normal cell function, including numerous mitochondria. The inner segment gives rise to a cilium (connecting cilium) that is grossly modified to house the phototransduction machinery. This compartment, which is known as the outer segment, is connected to the inner segment by a short ciliary stalk.
Figure 8.5 Photoreceptor structure.
C. Disk membranes
The bloated sensory cilium that comprises the rod outer segment is packed with ;1,000 discrete, flattened, membranous disks that are stacked like dinner plates alongside the ciliary axoneme. Cones contain similar but less numerous stacks that are infoldings of the surface membrane. The rod stacks are designed to capture a single photon as it traverses the eye’s photosensitive layer. To make this a reality, the disk membrane is so densely packed with photosensory pigment molecules that there is little room left over for lipid!
The retina lines the inside surface of the eye, covering roughly 75% (~11 cm2) of its total surface area. Photoreceptors are densely packed within the sheet, with rods outnumbering cones ~20-fold (~130 million rods versus 7 million cones). Although both rods and cones are found throughout the retina, their distribution is unequal.
Rods dominate the peripheral retina, which optimizes these areas for night vision.
Cones are concentrated in the central retina, which imparts this area with a high degree of visual acuity. At its center is the fovea, which contains cones alone (see Figures 8.1 and 8.4). The fovea’s lack of rods means that it cannot participate in night vision.
The ability to capture the energy of a single photon requires a chromophore, a molecule that absorbs certain light wavelengths while reflecting or transmitting others. This property gives the molecule color. The chromophore used in the eye is retinal, which can exist in several different conformations. The 11-cis conformation is very unstable and, when hit by a photon, immediately flips into a more stable all-trans configuration. Transition is rapid (femtoseconds), which makes it an ideal photoreceptive pigment. The task of detecting and reporting the conformational change falls on opsin, which is a G protein–coupled receptor.
Opsin covalently binds 11-cis retinal in the same way that a hormone receptor binds its ligand. The receptor and chromophore combine to create a visual pigment called rhodopsin, which has a reddish purple color. When retinal absorbs a photon and transitions, it triggers a change in opsin conformation to generate metarhodopsin II. This event initiates a signal cascade that ultimately converts photonic energy into an electrical signal.
V. Photosensory Transduction
Phototransduction is highly unusual in that stimulus detection causes receptor hyperpolarization rather than depolarization, as is the case in other sensory systems.
A. Dark current
The rod outer-segment membrane contains a nonspecific cation channel that is gated by cyclic guanosine monophosphate (cGMP) as shown in Figure 8.6. A constitutively active guanylyl cyclase (GC) maintains high intracellular cGMP levels in the dark, and the channel is always open. Na+ and small amounts of Ca2+ flow into the photoreceptor, creating an inward dark current. K+ leak channels in the inner segment allow K+ to escape the cell and help offset the current, but membrane potential (Vm) still rests at a relatively shallow ?40 mV.
Figure 8.6 Dark current origins.
ATP = adenosine triphosphate; cGMP = cyclic guanosine monophosphate; GTP = guanosine triphosphate.
When a photon hits retinal, rhodopsin contorts and activates transducin, which is a G protein ([GT] Figure 8.7). When activated, the GT ? subunit dissociates and activates a membrane-associated phosphodiesterase (PDE). PDE hydrolyzes cGMP to GMP, and intracellular cGMP levels fall. The cation channel deactivates and closes as a result, and the dark current terminates. The K+ channel in the inner segment remains open, however, which causes Vm to drift negative. This Vm change constitutes a signal that light has been detected. Although the transduction cascade is relatively slow (tens to hundreds of milliseconds), it does provide for tremendous signal amplification that allows the eye to register single photons.
Figure 8.7 Phototransduction under low light conditions.
ATP = adenosine triphosphate; cGMP = cyclic guanosine monophosphate.
C. Signal termination
The amplification cascade is so powerful that a rod relies on multiple negative feedback mechanisms to limit and terminate signaling in a timely manner (Figure 8.8).
Figure 8.8 Photosensory transduction pathway and mechanisms for limiting and terminating signaling.
cGMP = cyclic guanosine monophosphate.
1. Opsin inactivation
The active form of opsin is a substrate for rhodopsin kinase activity. Opsin has multiple phosphorylation sites, and each successive phosphate transfer further reduces its ability to interact with GT. Phosphorylation also makes the receptor a favorable target for arrestin binding. Arrestin is a small protein whose sole function is to block interaction between opsin and transducin and thereby prevent further signaling.
2. Transducin deactivation
Rods also contain a “regulator of G-protein signaling” protein that enhances the GT ? subunit’s GTPase activity and thereby speeds its deactivation.
3. Guanylyl cyclase activation
The dark current is mediated, in part, by Ca2+ influx. Light stops this influx, and intracellular Ca2+ concentrations fall. This is sensed by one or more Ca2+-dependent GC-activating proteins, which respond by stimulating GC activity, which, in turn, counteracts the effects of PDE. This pathway is important for helping photoreceptors adapt to light levels that saturate the signaling pathway and also helps restore the dark current once signaling ends.
Prolonged exposure to bright light desensitizes the rods. Desensitization is partly an extension of the opsin inactivation process described above. Rhodopsin kinase phosphorylates opsin at multiple sites, which increases arrestin-binding affinity and blocks further opsin–transducin interactions. With time, transducin is translocated from the outer segment to the inner segment, effectively breaking the first crucial link in the phototransduction chain and preventing further signaling.
E. Retinal recycling
Retinal is released from opsin shortly after activation, and the pigment turns yellow (bleaching). It is then converted to retinol, also known as vitamin A. Vitamin A is converted to 11-cis retinal, which binds to opsin and restores the visual pigment.
Vitamin A is essential for synthesis of visual pigments. Inadequate dietary intake results in night blindness, characterized by an inability to see in low light due to impaired rod cell function. The condition can be reversed within hours by administering vitamin A