For as long as she can remember, Kay Tye has wondered why she feels the way she does. Rather than just dabble in theories of the mind, however, Tye has long wanted to know what was happening in the brain. In college in the early 2000s, she could not find a class that spelled out how electrical impulses coursing through the brain’s trillions of connections could give rise to feelings. “There wasn’t the neuroscience course I wanted to take,” says Tye, who now heads a lab at the Salk Institute for Biological Studies in La Jolla, Calif. “It didn’t exist.”
When she dedicated a chapter of her Ph.D. thesis to emotion, she was criticized for it, she recalls. The study of feelings had no place in behavioral neuroscience, she was told. Tye disagreed at the time, and she still does. “Where do we think emotions are being implemented—somewhere other than the brain?”
Since then, Tye’s research team has taken a step toward deciphering the biological underpinnings of such ineffable experiences as loneliness and competitiveness. In a recent Nature study, she and her colleagues uncovered something fundamental: a molecular “switch” in the brain that flags an experience as positive or negative. Tye is no longer an outlier in pursuing these questions. Other researchers are thinking along the same lines. “If you have a brain response to anything that is important, how does it differentiate whether it is good or bad?” says Daniela Schiller, a neuroscientist at the Icahn School of Medicine at Mount Sinai in New York City, who wasn’t involved in the Nature paper. “It’s a central problem in the field.”
The switch was found in mice in Tye’s study. If it works similarly in humans, it might help a person activate a different track in the brain when hearing an ice cream truck rather than a bear’s growl. This toggling mechanism is essential to survival because animals need to act differently in the contrasting scenarios. “This is at the hub of where we translate sensory information into motivational significance,” Tye says. “In evolution, it’s going to dictate whether you survive. In our modern-day society, it will dictate your mental health and your quality of life.”
If the switch is tuned so that negative experiences dominate, anxiety or depression could result. An overactive appetite for reward, by contrast, may raise the specter of addiction. The work “may speak to pathology in a way we haven’t thought about it before,” says neuroscientist Stephen Maren of Texas A&M University, who wasn’t involved in the research. “We’ve thought about it more as a disorder of one or the other system.” But perhaps some mental illness arises from an imbalance in the positive and negative values that the brain assigns experiences, he says.
As a graduate student, Tye approached her study of emotion, logically enough, through the amygdala, a hub of emotional processing nestled deep within the brain. In 2007 she gave a talk at a conference emphasizing the structure’s importance in learning in response to rewards in addition to its known role in fear. She hypothesized that separate sets of neurons within the amygdala underlie memory for good and bad experiences.
In a paper published in 2015, Tye, then at the Massachusetts Institute of Technology, and her colleagues found those neurons in a part of the amygdala called the basolateral amygdala. One set was needed for mice to learn that a tone predicted a sip of sugar water, and the other was needed for them to link a noise with a mild electric shock. To locate the cells, the researchers used a technique Tye had developed several years before. It was twist on optogenetics, the engineering of neurons with genes for light-sensitive proteins. Typically that allows them to be activated with light. Tye devised a way to use optogenetics to trace the connections of a specific set of neural fibers.
With the reward and fear tracks nailed down, Tye wondered what determined the path a signal would take: What exactly was the positive or negative “switch”? Her team came up with a hint. When the researchers cataloged the genes that were switched on, or expressed, in each set of neurons, one difference stood out: neurons in the negative pathway showed more expression of the gene for a receptor for neurotensin, a signaling molecule that modulates the brain’s main excitatory neurotransmitter, glutamate, which causes a neuron to fire off a signal to other neurons.
Following that clue, Tye and her colleagues—in particular, Salk Institute postdoctoral fellow Hao Li—mapped out all the neurons that release neurotensin to the basolateral amygdala. They found three bunches connected to three different places in the brain. To figure out which fibers were relevant, the researchers did something unusual: they used the famed gene-editing technique CRISPR to disable the gene for neurotensin in each set of neurons. It was the first use of gene editing to selectively delete this type of neurotransmitter from a specific population of neurons, Maren says.
The result: In only one of these populations did the trick disrupt the mice’s ability to learn to associate a tone with sugar or a shock. This set came from the thalamus, a nearby sensory relay station. Deleting neurotensin in those neurons in the thalamus made mice slower to learn about the sucrose reward and faster to encode the shock, as evidenced by behaviors such as running to a spout that delivers sugar water and freezing when predicting a shock. Artificially activating those neurons led to the opposite outcome: a boost in the food response and a blunting of the fear one.
The findings suggest that the brain’s default state is negative and that neurotensin input is needed to switch it to something more positive. “We need something to put our brain into a state to say, ‘Oh, this is a rewarding environment. I should enable my system to learn about rewards,’” Tye says. “If I don’t have it on, I’m going to assume [the situation] is bad.”
Neurotensin’s involvement also solves a mystery of timing. Animals can learn to link stimuli—a gunshot with an injured soldier or a grandparent’s visit with a gift—that are separated by tens of seconds, minutes or even longer. But typical neuronal responses, such as those involving glutamate, happen within milliseconds. Neurotensin can amplify the glutamate signal and make it last longer, Tye says.
The work could ultimately lead to therapies for some mental health problems, experts say. A drug that decreases neurotensin activity might ease addiction and the attendant reward-seeking behaviors by biasing the brain more toward a fearful state. Enhancing neurotensin’s actions, by contrast, could cause anxious or depressed people to view the world in a more positive light. “The target is a very attractive one for a wide array of mental health disorders,” Tye says.
It’s unclear, however, whether this specific finding is going to help people clinically, says cognitive psychologist Michael Anderson of the University of Cambridge, who was not involved in the study. Its impact may be significant nonetheless, he adds. “The more we know about the neural circuitry underlying emotion and conditioning, the more likely we will be able to build on that to develop interventions the long run,” Anderson says.
In the short run, the work extends the hard science of emotion in significant ways in part through the new tools Tye invents for unraveling the brain’s machinery. “The work is a technical tour de force,” Maren says. “It’s really pushing the field in new directions in terms how we manipulate neural circuits.”