Visual pathway

Retina

The innermost layer of the eye is the retina. The ten layered membrane is bathed in vitreous humor and contains the cells necessary for transduction of photon energy. The ten cellular layers are listed below from the layer next to the vitreous humor to the layer closest to the choroid:

• Retinal pigmented epithelium
• Photoreceptor layer
• Outer limiting membrane
• Outer nuclear layer
• Outer plexiform layer
• Inner nuclear layer
• Inner plexiform layer
• Ganglion cell layer
• Nerve fiber layer
• Inner limiting membrane

The retina covers the visceral surface of the globe circumferentially up to the cilioretinal junction (i.e. the ora serrata; the serrated border where the retina meets the ciliary body). After passing through the optic components of the eye (i.e. cornea, lens, and humors), light rays penetrate all the layers of the retina to reach the photoreceptor layer. Activation of the photoreceptors then initiates the transduction cascade.

Also recall that the retina can be divided into four quadrants such that the parts closest to the nose are referred to as the upper and lower nasal retina, and the parts closer to the temporal side of the head are the upper and lower temporal retina. The nasal retina of the left eye and the temporal retina of the right eye receives visual input from the left visual field. Similarly, the upper parts of the retina receive visual stimuli from the inferior visual field, while the lower part of the retina is stimulated by input from the upper visual field. Reversal of this logic is applicable.

Retinal pigmented epithelium

The retinal pigmented epithelium is the most superficial (i.e. outermost) layer of the retina. It is made up of simple cuboidal to low columnar epithelium that is affixed to Bruch’s membrane (innermost layer of the choroid). The layer is characterized by numerous mitochondria-rich invaginations into the basement membrane, multiple gap junctions, and other junctional complexes. The apices of the cells are richly populated with melanin granules, as well as secondary lysosomes, peroxisomes, and phagocytic vacuoles. There are also numerous smooth endoplasmic reticula that specifically facilitate vitamin A isomerization.

The retinal pigmented epithelium is instrumental in establishing and maintaining the blood-retinal barrier. It controls the ion exchange between the vascular choroid and the photoreceptors layer of the retina. The cells of this epithelium also have phagocytic properties; therefore, they are able to clear the cellular debris generated by the photoreceptors. The pigmented layer supplies the photoreceptors with additional adenosine triphosphate (ATP), immunomodulatory, and polypeptide growth factor molecules to carry out the transduction process.

During photopic conditions (when the light intensity is high), the villous processes of the pigmented epithelium elongate into the photoreceptor layer of the retina. The processes also retract under scotopic (low-intensity light) conditions. Therefore, it is able to absorb scattered light as it passes through the layers of the retina and protect the photoreceptors from excess light exposure. Lastly, the pigmented layer produces antioxidants that help neutralize the free radicals generated in the transduction process.

Photoreceptor layer

Humans have two types of photoreceptors that are named according to the morphology of the cell bodies. The rods are cylindrical cells that operate best in low-intensity light; while cones are (surprise!) conical cells that function best in high-intensity light and facilitate color perception. The rods are more often than not, longer and more slender than the cones. However, the converse is true when comparing the photoreceptors toward the peripheral aspect of the retina. The distribution of the photoreceptors throughout the retina is such that the rods are widely scattered throughout the entire retina except at the fovea (minute central depression within the macula; about 4 mm lateral to the optic disc). The fovea is solely occupied by cones (which are relatively scarce throughout the rest of the retina). It should be noted; however, that neither rods nor cones can be found in the optic disc.

The photoreceptors are the cells responsible for converting energy from photons to electrical energy that can be conducted by the nerve fibers. While the actual cell bodies of the photoreceptors are within the outer nuclear layer (discussed below), the peripheral connection between the photoreceptors and the retinal pigmented epithelium (i.e. the outer segment, primary cilium, and inner segment of each photoreceptor) form the photoreceptor layers. The axons of the rods and cones are stimulated by energy from the photons as they reflect off the retinal pigmented layer.

Outer nuclear layer

Each photoreceptor has four major components. There is an outer segment, inner segment, nucleus, and a synaptic body (spherule). The outer segment is highly folded and contains the photosensitive chemicals necessary for initiating the visual impulse. The membrane of the outer segment is also highly folded into discs to increase the surface area of the cell. It also contains photochemicals (rhodopsin in rods and color pigments in cones) which are proteins that are conjugated to the transmembrane proteins of the outer segment discs.

The inner segment is the cytoplasmic region of the cell. It houses the cell cytoplasm and other cellular organelles integral for cell function. The mitochondria are likely the most abundant and most important organelles in these cells, as a large amount of energy is needed to facilitate the photoreaction. The outer and inner segments communicate via a slender stalk known as the cilium (filled with microtubules that facilitate the signal transduction).

The nucleus is separated from the rest of the cell body by the outer limiting membrane. Therefore, a large portion of the photoreceptor (outer and inner segments) is found in the photoreceptor layer, while the nucleus is located in the outer nuclear layer.

The synaptic body is the innermost part of the photoreceptor. It communicates with the second order neurons (i.e. horizontal and bipolar cells) of the inner cell nuclear layer in the outer plexiform layer. The differences between the rods and cones are found in the table below.

Rods

Rods are ubiquitously distributed throughout the periphery of the retina. Unlike cones, the cylindrical stacks of membrane discs are encased within a membrane. The outer segment of the rods contains high resting levels of cyclic guanosine monophosphate (cGMP) as well as inactive rhodopsin molecules. The inactive rhodopsin moieties are bound to the membranous discs of the outer segment, while the cGMP molecules are continuously released in the absence of light. Elevated cGMP levels promote an influx of sodium (Na+) ions into the outer segment; giving rise to an elevated resting membrane potential.  

Rhodopsin undergoes molecular rearrangement with exposure to light; and together with other photosensitive molecules in the outer membrane, they cause a fall in the quantity of cGMP. As a result of the fall in cGMP, the sodium channels close. Consequently, there is a shift in the ionic preference of the cells and they become hyperpolarized (unlike other afferent neurons that become depolarized following a stimulus).

Instead of initiating an action potential to spread the effect of the stimulus, the hyperpolarization gradually moves across the cell membrane. Once at the synaptic bulb of the rods, the hyperpolarization gradually reduces the amount of glutamate (a neurotransmitter) being produced at the synapse (rod spherules). This can have a depolarizing or hyperpolarizing effect depending on the cells at the other end of the synapse. Although it is able to complete a relatively large number of photoisomerization, rhodopsin molecules eventually require replacement. Since they are bound to the discs of the cell membrane, the distal fragment of the rod undergoes rod shedding every ten days, and proximally the discs are renewed.

Cones

In contrast to the rods, the cones are not enclosed within a membrane and are in constant communication with the extracellular space. Furthermore, the stacks of discs progressively get smaller and further away from the inner segment. Therefore, the cones have a characteristic conical shape. There are three types of cones, each responsible for detecting light within a particular spectrum:

• The long wavelength cones (L – cones) are sensitive mostly to light within the red spectrum.
• The medium wavelength cones (M – cones) are highly responsive to light in the green spectrum.
• The short wavelength cones (S – cones) primarily detects light in the blue spectrum.

Therefore, the cones are responsible for color vision; the perception of which will be mitigated by any particular combination of stimuli generated from the three cones. The photopigment of the cones is similar to those found in the rods, with the exception that there are three different types (one for each type of cone). Those differences aside, they are also found in the outer segment of the cones, and also undergo light-induced conformational changes. The change in molecular structure triggers a similar hyperpolarization reaction that gradually spreads over the cell membrane toward the synaptic bulb of the cone (cone pedicles). The decline in glutamate release and resultant depolarizing or hyperpolarizing phenomenon also occurs. 

Inner nuclear layer

There are several accessory cells within the retina that form regulatory connections with the photoreceptors. Their cell bodies are found in the inner nuclear layer of the retina (between the inner and outer plexiform layers). It contains the cell bodies of amacrine, horizontal, and bipolar cells.

Bipolar cells

The type of synaptic input that enters a bipolar cell determines whether or not it will be classified as a cone or rod bipolar cell. These cells form the bridges between the ganglion cells and photoreceptors of the retina. They are particularly important in detecting the edges of images sent to the visual system.

They are further categorized into “on” or “depolarizing”, or “off” or “hyperpolarizing” bipolar cells. The “on” pathways are activated by light, while the “off ” pathways are activated during darkness. The logic behind “on” and “off” bipolar cells can become rather discombobulating owing to the fact that glutamate has always been regarded as an excitatory neurotransmitter. To avoid further confusion, just think of it this way: stopping the flow of glutamate (i.e. exposing the photoreceptors to light) causes “on” bipolar cells to depolarize, and “off” bipolar cells to hyperpolarize.

Amacrine cells

The small-bodied amacrine cells do not demonstrate prominent axons, but undergo significant arborization, with their axons extending widely. Several neurotransmitters such as gamma (γ)-aminobutyric acid (GABA), glycine or acetylcholine (ACh), and other neuropeptides can be found in amacrine cells. They regulate the activity of bipolar cells and increase the sensitivity of class Y ganglion cells to moving stimuli.

Horizontal cells

The horizontal cells are characterized by cells with axons of varying lengths (to access photoreceptors both near and far) that travel parallel to the retinal plane and numerous dendrites. The cell bodies are restricted to the inner nuclear layer. In response to the glutamine released from the photoreceptors, horizontal cells secrete GABA to nearby rods and cones. This action regulates the response of the ganglion cells, as well as sharpening the periphery of the images transmitted to the visual system.

Ganglion cell and nerve fiber layer

The second order neurons that form the bridge between the photoreceptors and the lateral geniculate body of the thalamus are the ganglion cells. Their cell bodies are located within the ganglion cell layer, and their nerve fibers travel in the nerve fiber layer (adjacent to the vitreous humor) toward the optic disc. Here, they form the optic nerve.

Ganglion cells are subdivided based on morphological and physiological features. The alpha cells have larger cell bodies, thicker axons, and diffusely-arborizing dendrites. They are more commonly encountered in the peripheral aspect of the retina and receive stimulation from the rods. From a physiological perspective, they are referred to as Y cells as they have little color sensitivity. They are also referred to as M cells owing to the fact that they synapse with the magnocellular layers of the lateral geniculate body. 

The beta cells are another category of ganglion cells that have medium sized soma and fewer dendrites. They are more common in the central aspect of the retina and receive visual stimuli from the cones. Therefore, they respond to color stimuli; and as such, are categorized as X cells. They are also called P cells because they synapse on the parvocellular layers of the lateral geniculate body.

Other ganglion cells are physiologically classified as W cells and anatomically referred to as delta, epsilon, and gamma cells. A unique group of W cells that have little to no communication with the photoreceptors is known as the melanopsin-containing ganglion cells. In addition to their lack of participation in visual imaging and cell size, these cells are typified by their connection to the pretectal (main and accessory CN III) and suprachiasmatic nuclei, location in the ganglion layer, and sensitivity to blue light. Most significantly, these cells are extremely sensitive to light and will propagate an action potential in response to direct exposure to light.

Plexiform layers

There are two separate, dense fibrous networks found between the three neuronal layers of the retina. The outer plexiform layer is found between the outer nuclear layer and the inner nuclear layer, while the inner plexiform layer exists between the inner nuclear layer and the ganglion cell layer. The outer plexiform layer contains the neurons of the bipolar and horizontal cells of the inner nuclear layer, as well as the axons of the photoreceptors. There is usually a triad of communicating processes formed among a solitary rod spherule or cone pedicle, two laterally positioned horizontal cell processes, and a central postsynaptic bipolar cell.

On the other hand, the inner plexiform layer contains the bridging axons that connect the cells of the inner nuclear layer (from bipolar or amacrine cells) with those of the ganglion layer. The amacrine cells have connections with other amacrine cells, as well as with both bipolar and ganglion cells. Bipolar cells also communicate with corresponding ganglion cells.

Limiting membranes

In addition to the plexiform layers, there are two other partitioning membranes found throughout the retina. There is an array of junctional complexes that form a distinct, albeit dim, layer at the level of the rods and cones. This is known as the outer limiting membrane (layer) which separates the photoreceptors from the Müller cell processes. An inner limiting membrane (layer) containing the terminal processes of the Müller cells covers the peripheral part of the vitreous body.

Macula

On the temporal side optic disc (roughly 4 mm laterally) and opposite to the pupil is a yellow area known as the macula lutea. At the middle of the macula is the fovea centralis; otherwise called the fovea. Going from the periphery of the center of the macula, there is a reduction in the thickness of the inner layers to the point that only the photoreceptor layers remain at the foveal pit. Consequently, larger quantities of photons make it to the photoreceptors as there are fewer intervening cells. This region is exclusively populated by cones and accounts for the majority of the visual afferent stimuli that is transmitted to the brain.

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Optic nerve (CN II)

Approximately one million myelinated axons arising from the ganglion cells of the retina come together at the optic disc to form the optic nerves (CN II). Unlike other nerves of the body that are myelinated by Schwann cells, the fibers of the optic nerve are myelinated by oligodendrocytes. Arising from the posterior pole of each eye, each optic nerve is about 35 mm and 55 mm in length and can be subdivided as follows:

• The optic nerve head.
• The intraorbital part. 
• The intracanalicular part.
• The Intracranial part.

As the axons of the ganglion cells converge at the optic nerve head, there are no associated photoreceptors in this region. As a result, any light hitting the neurons in this area will not be perceived. Therefore, a physiological blind spot exists where no light stimuli can be appreciated. The tubular optic nerve exits the orbit through the optic canal and meets with the contralateral CN II above the diaphragma sella. Along this course, they become encased in layers of dura and arachnoid mater, which are in direct communication with the same meningeal layers of the brain. Here it forms the optic chiasm.

Optic chiasm and tract (reticulogeniculate tract)

The optic chiasm is not only a point of union but also a point of decussation of the bilateral CN II. Here, the nasal fibers of each eye cross the midline to join the temporal fibers of the contralateral eye. As highlighted earlier, the nasal fibers of the right eye and the temporal fibers of the left eye are stimulated by photons that are emitted on the right half of the visual field. Similarly, the nasal fibers of the left and temporal fibers of the right eye receive visual stimuli from the left half of the visual field. Following the decussation, the visual input from the right half of the visual field will travel in the left optic tract, while the stimuli from the left half of the visual field will pass through the right optic tract. 

The optic tracts are the compact, caudolateral continuations of the retinal ganglion layer. Each tract carries fibers that are stimulated from the contralateral visual field. As the optic tracts move toward the ipsilateral lateral geniculate body of the thalamus, they cross over the crus cerebri (where it joins with the cerebrum).

Pretectal connections of the visual pathway

About 1% of the retinal ganglion cells are highly responsive to light. The axons of these melanopsin-containing ganglion cells also travel in the optic nerve. However, instead of traveling to the lateral geniculate nucleus, they diverge to the pretectal area. This part of the midbrain is anterior to the central aqueduct of Sylvius. The fibers then synapse on the ipsilateral and contralateral oculomotor (CN III) and Edinger-Westphal (accessory CN III) nuclei. These nuclei, along with other cortical influences, are responsible for several visual reflexes including accommodation, direct and consensual light reflex, and saccadic response of the eyes. 

Lateral geniculate body

Laterally and inferiorly on either side of the inferior surface of the diencephalon are two rounded protuberances known as the lateral geniculate bodies. They house the multi-layered lateral geniculate nuclei that are critical in processing vision. The six layers of the lateral geniculate nucleus contain cells that are similar to those of the ganglion layer of the retina. The fibers arriving from the ipsilateral optic tract form the ventral base of the nucleus, while the outflow tracts that form the optic radiation also form the lateral and dorsal borders. The layers are numerically labeled one to six, with the larger magnocellular (M) cells being restricted to layers one and two, and the smaller parvocellular (P) cells found throughout layers three to six. 

The magnocellular layer receives input from the Y cells of the ganglion layer. As a result, they receive input from a larger visual field, respond to moving stimuli, and obtain stimuli primarily from rods. In contrast, the parvocellular layer is stimulated by X cells. Therefore, they respond to color stimuli of high acuity, receive input from a smaller area, and respond to stationary stimuli. The remaining W cells terminate on the intervening thin layers of the lateral geniculate body.

Further retinotopic division of the lateral geniculate body relates to the decussation that occurred at the chiasm. The axons arising from the nasal retina that crossed the midline eventually terminate on layers 1, 4, and 6 of the contralateral geniculate nucleus. While the axons of the ganglion fibers originating from the temporal retina that did not cross the midline will terminate on layers 2, 3, and 5 of the ipsilateral geniculate nucleus. 

Optic radiation and visual cortex

The optic radiation (geniculocalcarine tract) represents the visual tracts that extend from the lateral geniculate body to the primary visual cortex (Brodmann 17) on the same side. The retinotopic distribution of the nerve fibers also continues along this path. Like the corresponding optic tract, the ipsilateral optic radiation only carries visual input from the contralateral visual field. The optic radiation is separated into two main tracts that correspond to the upper and lower quadrants of the respective visual field. 

The second order axons corresponding to the contralateral upper quadrant originate from the ventrolateral aspect of the lateral geniculate nucleus. They are referred to as Meyer’s loop and take an indirect course through the white matter of the temporal lobe to access the inferior bank of the calcarine sulcus of the lingual gyrus.

On the other hand, the second order neurons responsible for the contralateral lower quadrant emerge from the dorsomedial part of the lateral geniculate nucleus. They have a more direct course to the superior bank of the calcarine sulcus of the cuneus, as they pass through the retrolenticular part of the internal capsule. The tracts corresponding to the macula and fovea are referred to as the geniculostriate fibers and they arise from the center of the lateral geniculate nucleus to access the caudal visual cortex.

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