Mice Get Hooked on Light

Hybrid proteins that respond to light could reveal the biochemistry of addiction.

A newly created set of light-sensitive proteins grants scientists unprecedented control over the brain's biochemistry, potentially shedding light on addiction and other complex neural processes. To demonstrate the potential of this novel molecular toolbox, researchers from Stanford University engineered mice to carry light-sensitive proteins in the brain's reward center, which responds to drugs of abuse. Using pulses of light delivered directly to the brain, researchers were able to induce a druglike state, ultimately conditioning the mice to behave like drug-addicted animals.

Light the way: As this mouse wanders through a series of chambers, a researcher keeps close watch. Whenever the mouse enters one chamber in particular, the researcher delivers a pulse of light through the optical fiber wired into its brain. The light triggers specially engineered proteins to launch a cascade of biochemical reactions that act as a reward--much like a dose of cocaine or methamphetamine. After this training exercise, the mouse exhibits a strong preference for the chamber where it received the light pulses. Credit: Raag Airan et al., Stanford University

"Drug addiction is one of the leading causes of disability worldwide, and it all funnels through the reward system," says senior researcher Karl Deisseroth, a bioengineer and psychiatrist at Stanford, who frequently works with drug-addicted patients. Addiction is immensely difficult to treat, in part because drugs create such potent and stable changes in the brain's reward system. "If we can understand better what those internal states are and how they become so stable--which we started to scratch the surface of in this paper--maybe we can develop more effective and potent therapies for substance abuse," he says.

Researchers created hybrid proteins by fusing the gene for a light-sensing pigment normally found in the eye to the genes for various members of a family of receptor proteins. The hybrid proteins sit in the cell membranes of neurons, with the light-sensitive portion protruding from the cell; when it absorbs photons of a certain wavelength, it changes shape, triggering the intracellular portion of the protein to launch a cascade of biochemical reactions inside the cell.

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Deisseroth's team had previously engineered light-sensitive proteins that triggered neurons to fire. But this new system is more specific: rather than stimulating the entire neuron, it targets individual signaling pathways within the cell. The researchers can control different pathways by selecting the intracellular domain from a diverse palette of existing signaling proteins and pairing it with the light-sensitive proteins. "This allows us now to access a whole new dimension of cell states and brain states that we couldn't before," says Deisseroth.

Researchers used a virus to deliver genes encoding the hybrid proteins, dubbed optoXRs, to the animals' nucleus accumbens, a brain region that responds to pleasurable stimuli, such as food, sex, and drugs. Each mouse was allowed to roam freely through a series of adjoining chambers, one of which was preselected as a reward room. Whenever the mouse entered the reward room, a researcher fired a pulse of light through a fiber-optic cable into its nucleus accumbens, setting off whatever biochemical cascade corresponded to the particular optoXR it carried.