Photoreceptor "noise" affects quality of vision

By: Ben Kallman

Posted: 5/1/08

Humans are overwhelmingly visual animals. While most other mammals are sniffing around their respective worlds, we rely on the sharpness of our eyes for information about our environment. (Try sniffing around for a staircase, and you'll likely break a few bones.)

Much of how the visual system works has been elucidated (pun intended) in the last few decades, but a lot is still not well understood.

We know, for example, that the gift of sight boils down to about 100 million specialized cells in the retina, the thin layer of tissue at the back of the eye.

These cells, called rods and cones, are responsible for translating variations in light - different wavelengths, different intensities and so on - into an electrical signal the rest of the brain can read and ultimately use to construct a picture of the world.

How rods and cones make their electrical signals is a wonder of evolution. Each rod or cone contains a light-absorbing pigment; rods have rhodopsin and cones have cone opsin. When an opsin absorbs light, its shape changes, allowing it to bind to a certain protein.

This sets off an intricate, multistep pathway of protein activation and deactivation whose eventual outcome is the closing of millions of ion channels and the alteration of an electric signal to the brain.

When these channels are open (in other words, in the dark), positively charged ions, such as sodium, flow freely into the cell, creating what scientists call a "dark current."

When they close, however, the influx is blocked, and with time, the cell's charge becomes more and more negative. This hyperpolarization, as it's called, is the electrical signal that tells the brain that light is present.

This process is pretty well described, but one of the field's irksome mysteries is why rods and cones are differentially sensitive to light. Rods are mainly active when light is low, around dusk or in poorly lit rooms, while cones respond to higher intensities of light such as those present throughout the day.

A group of Hopkins scientists, led by King-Wai Yau of the School of Medicine, sought to find out why.

To do so, they capitalized on the fact that the brain can sometimes get confused. The inherent and necessary ability of opsins to change their shape has some unfortunate side effects, one of which is called "quantal noise."

This happens when a pigment changes shape spontaneously without having absorbed any light. This "gives rise to a false light signal that the animal cannot tell apart from real light," Yau said.

In other words, the brain reads "light" even though no light is actually present. Quantal noise thus puts a limit on the extent of our visual sensitivity since, in very low light the brain can't be trusted to distinguish between real light and quantal noise.

In rods - or more accurately, the protein rhodopsin - this noise is very low: about 0.01 false signals per second for each cell. Low quantal noise in rods is what allows us to pick up on incredibly small amounts of light.

For example, under the right conditions, humans can detect a single photon, the smallest possible amount of light energy in the universe. Cones, however, are a different, trickier story.

They are much less sensitive to low-intensity light. Hundreds of thousands of photons need to be absorbed in order to activate a single cone opsin. Based on the fact that rods have both low quantal noise and high sensitivity, the relative insensitivity in cones was thought to be a result of high quantal noise.

This, however, was just a theory. The quantal noise of a cone opsin had never been directly measured; individual false signals from cones are undetectable (with current technology, at least).

To get around this technical barrier, the Hopkins team availed themselves of some creative mouse breeding, creating a strain of mice whose rods, in addition to a full or half-size complement of rod pigments, also had genetically inserted red cone pigments.

Rods, of course, are much more sensitive to light; thus the quantal noise of the inserted red cone pigments became more easily detectable. Indeed, "the frequency of spontaneous events was low enough to be individually counted," Yau said.

That wasn't enough, however. To further boost the false signals, the red cone opsin-insertion mice were bred with another group of mutant mice that lacked a protein known to dampen the hyperpolarization signal.

Ultimately then, the researchers had mice with red cone pigments in their rods and rods, in turn, that produced amplified signals.

Several measurements and calculations later, the team had some surprising results. Spontaneous changes in the shape of the red cone opsin accounted for only about nine false events per second.

This is significantly more than the 0.01 in rods, but previous work had observed a total of 6,400 false events per second from each red cone. In other words, and contrary to the prevailing theory, the lion's share of false signals coming from red cones was not a result of quantal noise.

This revelation has produced something of a mystery: What's causing those other 6,391 false events every second? "Besides the quantal noise coming from the pigment, there is other noise originating from the steps in the phototransduction process downstream from the pigment," Yau said.

"This other noise is sometimes called the 'continuous noise' because it is not quantized like the quantal noise."

It's not easy to distinguish the two types of noise, so most scientists have in the past just lumped them into an equivalent measure of noise (the 6,400 false events). "Sometimes it's OK not to treat the two types of noise as separate," Yau said, "but other times it's important to separate them, as we have done."