Make a memory positive or negative

Summary: Researchers have discovered a specific neurotransmitter that helps attribute positive or negative emotions to memories.

Source: Salk Institute

Salk Institute researchers and colleagues have discovered the molecule in the brain responsible for associating good or bad feelings with a memory.

Their discovery, published in Nature July 20, 2022, paves the way for a better understanding of why some people are more likely to retain negative emotions than positive emotions, as can occur with anxiety, depression, or post-stress stress disorder. trauma (PTSD).

“We’ve basically mastered the fundamental biological process of how you can remember if something is good or bad,” says lead author Kay Tye, a professor in Salk’s Systems Neurobiology Laboratory and a researcher at the Medical Institute. Howard Hughes. “It’s something that’s central to our experience of life, and the idea that it can be all down to one molecule is incredibly exciting.”

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 to a memory is called “valence assignment.”

In 2016, Tye discovered that a group of neurons in the basolateral amygdala (BLA) of the brain help assign valence when mice learn. A set of BLA neurons were activated with a positive valence, as the animals learned to associate a tone with a sweet taste. A separate set of BLA neurons were activated with negative valence, as the animals learned to associate a different pitch with a bitter taste.

“We found these two lanes, analogous to train tracks, leading to positive and negative valence, but we still didn’t know which signal acted as a switch operator to indicate which lane should be used at any given time. “, explains Tye, holder of the Wylie Vale Chair.

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

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

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

This shows neurons
Expression of various genes and proteins (white, red and green) in neurons among mouse brain cells (blue). Credit: Salk Institute

In other experiments, Tye and his 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,” says co-first author Hao Li, a postdoctoral fellow at Tye Lab. “Ultimately, we would like to try to identify new therapeutic targets for this pathway.”

Researchers are still wondering if neurotensin levels can be modulated in people’s brains to treat anxiety or PTSD. They also plan future studies to probe which other brain pathways and molecules are responsible for triggering neurotensin release.

The other authors of the article were Matilde Borio, Mackenzie Lemieux, Austin Coley, Avraham Libster, Aneesh Bal, Caroline Jia, Jasmin Revanna, Kanha Batra, Kyle Fischer, Laurel Keyes, Nancy Padilla-Coreano and Romy Wichmann from Salk; Praneeth Namburi, Jacob Olson, Anna Beyeler, Gwendolyn Calhoon, Natsuko Hitora-Imamura, Ada Felix-Ortiz, Veronica de la Fontaine, Vanessa Barth, Hunter King, Ehsan Izadmehr, Cody Siciliano, and Ila Fiete from MIT; Xin Jin, Sourav Choudhury, Xi Shi and Feng Zhang of the Broad Institute of MIT and Harvard; Huan Wang and Yulong Li from Peking University; and Kenneth McCullough and Kerry Ressler of Harvard Medical School.

Funding: The work was supported by the JPB Foundation, PIIF, PNDRF, JFDP, Alfred P. Sloan Foundation, New York Stem Cell Foundation, Klingenstein Foundation, McKnight Foundation, Clayton Foundation, National Institutes of Health (R01-MH102441, RF1-AG047661, DP2 -DK102256, DP1-AT009925, F32 MH115446-01 and K99 DA055111), the Brain and Behavior Research Foundation, MEXT (15K21744, 17H06043), the Uehara Memorial Foundation, the Singleton, Leventhal and Whitaker scholarships, a scholarship from the Swiss National Fund of scientific research and a Fulbright scholarship.

About this memory research news

Author: Press office
Source: Salk Institute
Contact: Press Office – Salk Institute
Image: Image is credited to the Salk Institute

See also

It shows a brain

Original research: Access closed.
“Neurotensin orchestrates valence assignment in the amygdala” by Kay Tye et al. Nature


Summary

Neurotensin orchestrates valence assignment in the amygdala

The ability to associate time-segregated information and assign positive or negative valence to environmental cues is paramount for survival. Studies have shown that different basolateral amygdala (BLA) projections are potentiated following reward or punishment learning.

However, we do not yet understand how valence-specific information is routed to BLA neurons with the appropriate downstream projections, nor do we understand how to reconcile the subsecond time scales of synaptic plasticity with the longer timescales separating predictive signals from their results. .

Here, we demonstrate 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 a concentration-dependent modulation of NT in the BLA during associative learning.

We found that optogenetic activation of the PVT-BLA:NT projection promotes reward learning, whereas specific inactivation of the PVT-BLA projection of the NT gene (NTs) increases the learning of punishment. Using genetically encoded calcium and NT sensors, we further revealed that calcium dynamics in the PVT-BLA:NT projection and NT concentrations in the BLA are enhanced after reward learning and reduced after learning about punishment.

Finally, we showed that CRISPR-mediated inactivation of Nts gene in the PVT-BLA pathway blunts BLA neuronal dynamics and dampens preference for active behavioral strategies to reward and punish predictive cues. In sum, we identified NT as a valence-signaling neuropeptide in BLA, and showed that NT is a critical neuromodulator that orchestrates positive and negative valence assignment in amygdala neurons by extending plasticity. valence-specific at behaviorally relevant time scales.

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