The identification of the neurotransmitter, neurotensin, which helps assign positive or negative emotions to a memory, has given researchers a better understanding of why some people are more likely to retain negative emotions than positive ones. This finding may help scientists better understand anxiety, depression, or post-traumatic stress disorder (PTSD).

“We’ve basically gotten a handle on the fundamental biological process of how you can remember if something is good or bad,” said Kay Tye, PhD, professor in Salk’s Systems Neurobiology Laboratory and a Howard Hughes Medical Institute investigator. “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.”

This work was published in Nature, in the paper, “Neurotensin orchestrates valence assignment in the amygdala.

For a human or animal to learn whether to avoid, or seek out, a particular experience again in the future, their brain must associate a positive or negative feeling, or “valence” with that stimulus. The brain’s ability to link these feelings with a memory is called “valence assignment.”

From left: Kay Tye, PhD, and Hao Li, PhD. [Salk Institute]
In 2016, Tye discovered that a group of neurons in the brain’s basolateral amygdala (BLA) helps assign valence when mice are learning. One set of BLA neurons was activated with positive valence, as the animals learned to associate a tone with a sweet taste. A separate set of BLA neurons was activated with negative valence, as the animals learned to associate a different tone with a bitter taste.

“We found these two pathways—analogous to railroad tracks—that were leading to positive and negative valence, but we still didn’t know what signal was acting as the switch operator to direct which track should be used at any given time,” said Tye.

However, they didn’t yet understand, “how valence-specific information is routed to the BLA neurons with the appropriate downstream projections, nor how to reconcile the sub-second timescales of synaptic plasticity with the longer timescales separating the predictive cues from their outcomes.”

In the new study, the researchers homed in on the importance of the signaling molecule neurotensin to these BLA neurons.

Specifically, the team demonstrated that “neurotensin (NT)-expressing neurons in the paraventricular nucleus of the thalamus (PVT) projecting to the BLA (PVT-BLA:NT) mediate valence assignment by exerting neurotensin concentration-dependent modulation in BLA during associative learning.”

Optogenetic activation of those neurotensin expressing projections promoted reward learning whereas a neurotensin knockout augmented punishment learning.

They used CRISPR gene editing 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 said, 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.

In further experiments, Tye and her team showed that high levels of neurotensin promoted reward learning and dampened negative valence, further supporting 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, PhD, 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.