Optogenetics: Controlling Neurons with Light

Borrowing light-sensitive proteins from algae to switch specific neurons on and off in milliseconds: how optogenetics works, what it has revealed, chemogenetics, and its first steps toward human therapy.

Crick's wish

In 1979 Francis Crick wrote that a major challenge for neuroscience was finding a way to control one type of cell in the brain while leaving others unaltered — and speculated that light might do it. Electrodes stimulate every cell near their tip; drugs act slowly and broadly. What was needed was speed and specificity.

Proteins from pond scum

Certain algae and microbes use light-sensitive proteins called opsins. In 2002–2003, Georg Nagel, Peter Hegemann and colleagues characterised channelrhodopsin-2, a channel from the green alga Chlamydomonas that opens and lets in positive ions when hit by blue light. In 2005 Ed Boyden, Karl Deisseroth and colleagues at Stanford showed that inserting channelrhodopsin into mammalian neurons let them trigger action potentials with millisecond flashes of light. Other groups made similar advances around the same time. Soon after, inhibitory opsins such as halorhodopsin and archaerhodopsin, pumping ions to silence neurons with yellow or green light, completed the toolkit.

How it works

Researchers use viruses or genetically engineered animals to place the opsin gene under the control of a promoter active only in one cell type — for example, dopamine neurons or a class of inhibitory interneurons. An optical fibre then delivers light to the region. Flash the light, and only the chosen cells respond, on a millisecond timescale.

What it has revealed

Optogenetics transformed neuroscience by enabling causal tests. Examples: activating specific hypothalamic neurons drives eating or aggression; stimulating dopamine neurons is reinforcing; reactivating hippocampal engram cells recalls a memory; and parts of the circuitry of fear, anxiety, sleep, social behaviour and reward have been dissected.

Chemogenetics and clinical steps

Chemogenetics, for example DREADDs (designer receptors exclusively activated by designer drugs), uses engineered receptors that respond only to an otherwise inert drug — slower than light but needing no implanted fibre. In 2021 researchers reported the first partial recovery of vision in a blind patient (with retinitis pigmentosa) using optogenetic therapy delivered to the retina plus special light-amplifying goggles — a first step toward clinical use.