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.
“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.
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.
This setup is commonly used to study addiction: when a drug such as cocaine or amphetamine is consistently administered in the reward room, a mouse learns to associate that room with the reward and later chooses to spend most of its time there.
“What we found, very strikingly, was that this worked,” says Deisseroth. One of the optoXRs, built from a receptor protein that normally responds to adrenaline and noradrenaline, produced results much like those seen with drug-based rewards. When loosed after training, mice with this optoXR strongly preferred to spend time in the reward room, where they had received light pulses activating their nucleus accumbens. The results of the study were published this week in Nature.
Many of the same proteins that Deisseroth’s team activated with light can be targeted by drugs. But light has a number of advantages over drugs, says Michael Häusser, a professor of neuroscience at University College London, who was not involved in the research. While drugs take time to work and linger after administration, light allows for exquisite control over timing. And while drugs don’t pick and choose which cells to affect, optoXRs can be genetically engineered to be expressed in only a specific type of cell.
The hybrid proteins represent a new molecular toolbox with applications beyond drug addiction and the brain’s reward system. ��There are all kinds of really cool games you can play with these new molecular tools to look at aspects of signaling pathways and how they interact,” says Häusser. For example, they open the door to studying more mysterious receptor proteins, which can’t be activated pharmaceutically and whose function is not well understood. “For some of them,” says Häusser, “our toolbox for manipulating them is limited. So this gives us a fantastic new handle on these receptor classes, and allows us to manipulate them in a really powerful way.”
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