How the Retina Works
Much of the construction of an image takes place in the retina itself through the use of specialized neural circuits
Building Images with Amacrine Cells
There is more to understand about the messages ganglion cells receive before they transmit a signal to the brain. For that, it is important to appreciate the organization of the inner plexiform layer, where 22 or more different types of amacrine cells make synaptic connections with about 20 different types of ganglion cells.
It was already clear from Cajal's description in the 19th century that amacrine-, ganglion- and bipolar-cell dendrites and axons were organized into distinct layers; Cajal himself divided the inner plexiform layer into five strata. But what sorts of synapses were formed among the tangle of intermeshing processes and what this organization meant were not immediately apparent. Electron microscopy helped to unravel this neurocircuitry. Now the interconnections of nine types of bipolar cells, 14 types of amacrine cells and eight types of ganglion cells are understood quite well. We can say we are half way to the goal of understanding the neural interplay between all the nerve cells in the retina.
Much is now known about what types of neurotransmitters different amacrine cells contain and about the organization of receptors at the different synapses. Amacrine cells are about equally divided between those that use glycine and those that use GABA (gamma-aminobutyric acid) neurotransmitters.
Glycinergic amacrine cells are usually "small field." Their processes can spread vertically across several strata within the inner plexiform layer, but they extend relatively short distances horizontally. Glycinergic amacrine cells receive information from bipolar cells and transmit information to ganglion cells and to other bipolar and amacrine cells. Some glycinergic amacrine cells provide interconnections between ON and OFF systems of bipolar and ganglion cells. The most famous of these is called the AII cell; the AII and a GABA-releasing amacrine cell called A17 are pivotal in the circuitry of rod-based, dim-light vision in the mammalian retina. These cells aren't found in mammalian species that are active solely in daylight and have very few rods—for example, squirrels.
In the earlier discussion of ON and OFF channels emanating from cones, I neglected to talk about the channels from rod cells. Whereas cones connect in a direct pipeline to bipolar cells to ganglion cells, the bipolar cells that receive input from rods do not synapse with ganglion cells directly. The bipolar cells connected to rods are all of one type, solely transmitting an ON signal, and use the AII and A17 amacrine cells as intermediaries to get signals to ganglion cells. The small-field AII cell collects from about 30 rod-connected bipolar cells and transmits a depolarizing message both to ON (light-detecting) cone bipolar cells and to their ON ganglion cells and to OFF cone bipolar cells and OFF ganglion cells (Figure 11). It is as if the AII cells developed in the rod-dominated parts of the retina as an afterthought to the cone-to-ganglion cell architecture and now takes advantage of the preexisting cone pathway circuitry.
At the same time, the A17 amacrine cell collects rod messages from thousands of rod-connected bipolar cells. It somehow amplifies and modulates the information from the rod bipolar cells to transmit to the AII cells, but how it does this is not completely understood. In any case, the rod pathway with its series of convergent and then divergent intermediary neurons is clearly well designed to collect and amplify scattered vestiges of light for twilight and night vision.
Wide-field amacrine cells sometimes stretch horizontally across the inner plexiform layer for hundreds of microns and interact with hundreds of bipolar cells and many ganglion cells. Such amacrines are usually confined to one of the five different strata of the inner plexiform layer and create elegant meshworks of dendrites. Usually, they emit GABA as a neurotransmitter. Sometimes they connect to neighboring amacrine cells by gap junctions, increasing their sphere of influence and the speed at which signals transmit across large areas of retina.
Most GABA-releasing amacrine cells also release at least one other neuroactive substance. The secondary substances are usually neuromodulators rather than fast-acting neurotransmitters. The substances include peptides—"substance P," somatostatin, vasointestinal peptide and cholecystokinin—as well as the more familiar biomolecules serotonin, dopamine, acetylcholine, adenosine and nitric oxide. A variety of receptors have been found on ganglion and bipolar cells—for example, receptors for peptides, nicotine and muscarine (mushroom toxin) in addition to different forms of GABA receptors—indicating that amacrine cells are releasing such agents. Most of these neuromodulators are not active at conventional synapses; their release is thought to influence neurons even at a distance by diffusion. Such neuromodulators apparently influence the retinal circuitry under changing light conditions or even cause retinal activity to reflect the different times of day in the circadian clock.
A specialized amacrine cell releases dopamine when the retina is stimulated with intermittent flashing light. Dopamine causes the gap junctions among horizontal cells to become uncoupled, reducing the size of their receptive fields. Furthermore, the neurotransmitter affects the glutamate receptor on horizontal cells so that the amplitude of the light response declines. Again in the inner plexiform layer, dopamine closes gap junctions, this time the ones that link AII amacrine cells in large networks. The resulting uncoupling of the AII cells makes the effective field of influence of the rod-system amacrine cells much less significant in lighter conditions. Similarly in bright light conditions, another wide-field amacrine cell releases nitric oxide to uncouple the AII cell from the cone-bipolar system. All this removes the interference of the large-field rod pathway from the narrow-field cone pathways.
The above broad sketch of retinal circuitry suggests that the retina is remarkably complex. As vision research advances, the retina seems to take on an increasingly active role in perception. Although we do not fully understand the neural code that the ganglion-cell axons send as trains of spikes into the brain, we are coming close to understanding how ensembles of ganglion cells respond differently to aspects of the visual scene and how fields of influence on particular ganglion cells are constructed. Much of the construction of the visual images does seem to take place in the retina itself, although the final perception of sight is indisputably done in the brain.
Given how much is now known, it might be fair to ask, are we finished with the retina, or are there more surprises on the horizon? Earlier surprises included finding that much of the information transfer depended on electrical connections among cells rather than standard chemical synapses. For example, the major neural pathway from the rods depends on direct electrical connections. Some other fast-acting signals pass from amacrine cells into ganglion cells at gap junctions. Neuromodulators change the milieu of the neuron circuits but act from a distance by diffusion rather than at closely apposed synapses. Again, this is a surprising concept compared to the previous view that all neural interactions take place via neurotransmitters at specialized isolated patches of membrane apposition—that is, synapses. The most recent surprise has been that a previously unknown ganglion cell type appears to function as a giant photoreceptor itself, without needing input from rods or cones. This ganglion's cell membrane contains light-reactive molecules known as melanopsins. Given such unexpected findings, it appears that there may still be much more to learn about how the retina works.
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