What’s Making a Memory Positive or Negative

In the new study, the researchers homed in on the importance of the signaling molecule neurotensin to these BLA neurons. They already knew that neurotensin is a neuropeptide produced by the cells associated with valence processing, but so are a few other neurotransmitters. So, they used CRISPR gene editing approaches to selectively remove the gene for neurotensin from the cells—the first time that CRISPR has been used to isolate specific neurotransmitter function.

Without neurotensin signaling in the BLA, mice could no longer assign positive valence and didn’t learn to associate the first tone with a positive stimulus. Interestingly, the absence of neurotensin did not block negative valence. The animals instead became even better at negative valence, having a stronger association between the second tone and a negative stimulus.

The findings suggest that the brain’s default state is to have a bias toward fear—the neurons associated with negative valence are activated until neurotensin is released, switching on the neurons associated with positive valence. From an evolutionary perspective, Tye says, this makes sense because it helps people avoid potentially dangerous situations—and it probably resonates with people who tend to find the worst in a situation.

“We can actually manipulate this switch to turn on positive or negative learning,” says co-first author Hao Li, a postdoctoral fellow in the Tye Lab. “Ultimately, we’d like to try to identify novel therapeutic targets for this pathway.”

The researchers still have questions about whether levels of neurotensin can be modulated in people’s brains to treat anxiety or PTSD. They are also planning future studies to probe what other brain pathways and molecules are responsible for triggering the release of neurotensin.

“We’ve basically gotten a handle on the fundamental biological process of how you can remember if something is good or bad,” says senior author Kay Tye. “This is something that’s core to our experience of life, and the notion that it can boil down to a single molecule is incredibly exciting.”