By Patricia Valderrama
That voice in the back of your head that warns you off a risky decision? Stanford researchers have identified the rodent equivalent and turned up its volume, using an incredible new tool that allows scientists to observe and manipulate specific cells in the brain.
Restraining reward-seeking is a vital skill: It prevents hungry animals from foraging when predators are lurking; and it malfunctions when humans suffering from substance abuse continue to seek and consume drugs despite potentially deadly consequences. Neuroscientists have known for years the general regions in the brain that are responsible for this restraint, but they lacked a precise explanation. Now, they have narrowed it down to a specific neural circuit. The Stanford team published their results in Cell on August 24.
“We found this one little pathway that contained neurons whose activity can predict whether a mouse will decide to seek a reward or to restrain itself and not go after it,” said co-author Christina K. Kim, a postdoctoral scholar in the lab of Karl Deisseroth, professor of bioengineering and of psychiatry and behavioral sciences.
Scientists have long suspected that the prefrontal cortex restrains the reward-seeking part of the brain called the nucleus accumbens (which is also an center for action of drugs of abuse). But they had no way to pinpoint how this restraint happened or which specific neurons were involved. To find out, the team trained mice to press a lever to receive a reward, chocolate milk. Afterwards, the mice sometimes felt a mild foot-shock when they pressed the lever instead of receiving the reward. The mice had to decide whether the risk of punishment was worth the potential reward of pushing the lever.
Neurons communicate across brain regions by sending electrical signals through axons, which are like threads linking one cell to another. To identify the specific circuit from the prefrontal cortex to the nucleus accumbens that restrains reward-seeking, they injected genes into the brain that make neurons light up when they fire. Certain neurons were very active in communicating with other cells when a mouse refrained from pressing the lever, but were less talkative when the mouse decided to press it. These same neurons lit up when the mouse received a shock without a lever press.
To confirm that the shock-activated neurons in this circuit were responsible for restraining reward, the team came up with a new method, called vCAPTURE, which allowed them to label just the neurons that responded to foot shocks. They could then re-activate these shock neurons at a later time to determine their function in reward-seeking. vCAPTURE involves scientists injecting two viruses into a mouse’s brain: One delivers a gene called an opsin that makes neurons light-sensitive, and one delivers an enzyme that activates opsin when exposed to a particular drug. They then administer this drug while exposing the mice to a specific experience, such as a foot shock; this ensures that only these experience-defined neurons become sensitive to light. Scientists can then manipulate these neurons just by shining a light in the right area. “Using our method, you can reactivate a memory that was permanently stored in a subset of particular neurons,” Kim said. With vCAPTURE, the scientists were able to use light to make the mouse refrain from pressing the lever.
The finding has implications for psychiatric illnesses like substance abuse and depression; there is too much restraint of reward-seeking in people with depression, and too little in people with substance abuse problems. “Knowing the precise neural circuit is a basic science question, but it has significant clinical implications for understanding underlying causes,” Deisseroth said. “For psychiatric illness that’s a big deal, because we really understand very little.”