Being able to emotionally tag important experiences as either “positive” or “negative” and to remember those associations is one of the great achievements and marvels of evolution. When our ancient ancestors visited a place where dangerous animals lurked, or when they ate an unfamiliar food that supplied them with energy or whose flavor they particularly liked, they stood to profit by forming memories of these experiences that could be recalled to inform future behavior. This was a boon to survival.

In a range of psychiatric disorders, including depression, anxiety, and post-traumatic stress, people can fixate or rely to an unhealthy degree on memories of negative experiences and emotions. In the language of neuroscience, such individuals tend to accentuate or keep in mind memories with a negative “valence.” Experiences that may have contributed to formation of such negative memories may indeed have been painful or fear-provoking. The problem comes when the individual fixates or stresses the negative to the point where it impairs normal functioning in life.

Several years ago, Kay M. Tye, Ph.D., of The Salk Institute, a BBRF Scientific Council member, winner of the 2016 BBRF Freedman Prize for Exceptional Basic Research, and 2013 BBRF Young Investigator, led a team that discovered a group of neurons in the brain that help assign a valence when mice are learning. Located within a structure called the basolateral amygdala (BLA), one set of neurons was activated with positive valence—when the animals learned to associate a tone with a sweet taste. A separate set of neurons in the BLA was activated, the team found, when the animals learned to associate a different tone with a bitter taste.

Commenting on that discovery, Dr. Tye says, “We found these two pathways—analogous to railroad tracks—that were leading to positive and negative valence.” But, she adds, “we still didn’t know what signal was acting as the ‘switch operator’ to direct which track should be used” in a given situation in which a positive or negative experience was being tied to a memory.

In a vivid example of how one basic research result forms the basis for another, with even greater import, Dr. Tye and a large group of collaborators from Salk, MIT, the Broad Institute, and Harvard Medical School, have published a new paper in the journal Nature describing experiments which enabled them to discover the “switch operator.” It turns out to be a molecule—a neuropeptide that acts as a neurotransmitter—called neurotensin.

In addition to shedding new light on the problem of how valence is linked with memory, the research is important because it suggests a potential biological target for new therapies to treat psychiatric conditions in which emotional valence is problematic.

Dr. Tye and her colleagues already knew that neurotensin is released to neurons in the BLA that her team previously associated with valence processing. But other signaling molecules, such as dopamine, are also released to these neurons. To tease out neurotensin’s role, they used a gene-editing technology called CRISPR to remove the gene that encodes neurotensin from neurons that release it to the BLA. It was the first time CRISPR had ever been used to isolate specific neurotransmitter function.

In mice, when the neurotensin-encoding gene had been deleted from its “upstream” source to the BLA, the team found that the animals could no longer assign positive valence to new experiences and specifically could not learn to associate a tone, for example, with a positive experience. Yet these same mice were still able to assign negative valence to new experiences and to learn the association.

Additional experiments, some involving the use of optogenetics, in which specific neurons or groups of them can be switched on or off with beams of colored light, indicated that neurons in the BLA associated with negative valence are activated by default until neurotensin is released—at which point neurons in the BLA associated with positive valence are activated. This suggests that the brain’s default state is to have a bias toward fear, the researchers suggested.

This makes sense, according to Dr. Tye, because it helps animals and people avoid potentially dangerous situations. Still other experiments by the team showed that high levels of neurotensin promoted reward learning and dampened negative valence. This further supports the idea that neurotensin is responsible for positive valence.

“We can actually manipulate this switch to turn on positive or negative learning,” said Hao Li, Ph.D., a postdoctoral investigator in the Tye lab who was first author of the team’s paper. “Ultimately, we’d like to try to identify novel therapeutic targets for this pathway,” for example, targets such as neurotensin and/or its cellular receptors that would potentially prevent overactive assignment of negative valence to specific memories. Such treatments might one day be tested in people with anxiety and PTSD.

The team also included Kerry J. Ressler, M.D., Ph.D., BBRF Scientific Council, 2009 BBRF Freedman Prize, 2005 and 2002 BBRF Young Investigator; Romy Wichmann, Ph.D., 2016 BBRF Young Investigator; Cody A. Siciliano, Ph.D., 2017 BBRF Young Investigator; Xin Jin, Ph.D., 2018 BBRF Young Investigator; and Anna Beyeler, Ph.D., 2015 BBRF Young Investigator.