Channelrhodopsins are photosensitive ion channels that open in response to light. They evolved as sensory receptors in photosynthetic green algae to allow the algae to swim toward light. The structure of channelrhodopsin closely resembles that of bacteriorhodopsin (see Figure 10–31). It contains a covalently bound retinal group that absorbs light and undergoes an isomerization reaction, which triggers a conformational change in the protein, opening an ion channel in the plasma membrane. In contrast to bacteriorhodopsin, which is a light-driven proton pump, channelrhodopsin is a light-driven cation channel.
Using genetic engineering techniques, channelrhodopsin can be expressed in virtually any cell type in vertebrates and invertebrates. Researchers first introduced the gene into cultured neurons and showed that flashing light could now activate the channelrhodopsin and induce the neurons to fire action potentials. Because the frequency of the light flashes determined the frequency of the action potentials, one can control the frequency of neuronal firing with millisecond precision.
Next, neurobiologists used the approach to activate specific neurons in the brain of experimental animals. Using a tiny fiber optic cable implanted near the axon at time = 0 (triggering of action potential)
Figure 11–31 The propagation of an action potential along an axon. (A) The voltages that would be recorded from a set of intracellular electrodes placed at intervals along the axon. (B) The changes in the Na+ channels and the current flows (curved red arrows) that give rise to a traveling action potential. The region of the axon with a depolarized membrane is shaded in blue. Note that once an action potential has started to progress, it has to continue in the same direction, traveling only away from the site of depolarization, because Na+-channel inactivation prevents the depolarization from spreading backward.
relevant brain region, they could flash light to specifically activate the channelrhodopsin-containing neurons to fire action potentials. One group of researchers expressed channelrhodopsin in a subset of mouse neurons thought to be involved in aggression: when these cells were activated by light, the mouse immediately attacked anything in its environment—including other mice or even an inflated rubber glove (Figure 11–32); when the light was switched off, the neurons fell silent and the mouse’s behavior returned to normal.
Since these pioneering studies, researchers have engineered additional light-responsive ion channels and transporters, including some that can rapidly
Figure 11–32 Optogenetic control of aggression neurons in a living mouse.
A gene encoding channelrhodopsin was introduced into a subpopulation of neurons in the hypothalamus of a mouse. When the neurons were exposed to flashing blue light using a tiny, implanted fiber optic cable, the channelrhodopsin channels opened, depolarizing and activating the cells. When the light was switched on, the mouse immediately became aggressive and attacked the inflated rubber glove; when the light was switched off, its behavior immediately returned to normal (Movie 11.11). (From D. Lin et al., Nature 470:221–226, 2011. With permission from Macmillan Publishers Ltd.) inactivate specific neurons. It is therefore now possible to transiently activate or inhibit specific neurons in the brains of awake animals with remarkable spatial and temporal precision. In this way, the rapidly expanding new field of optogenetics is revolutionizing neurobiology, allowing neuroscientists to analyze the neurons and circuits underlying even the most complex behaviors in experimental animals, including nonhuman primates.
Myelination Increases the Speed and Efficiency of Action Potential Propagation in Nerve Cells
The axons of many vertebrate neurons are insulated by a myelin sheath, which greatly increases the rate at which an axon can conduct an action potential. The importance of myelination is dramatically demonstrated by the demyelinating disease multiple sclerosis, in which the immune system destroys myelin sheaths in some regions of the central nervous system; in the affected regions, nerve impulse propagation greatly slows or even fails, often with devastating neurological consequences.