The latest Nature paper uses Pavlov’s method 130 years ago

Why are some people more active and some people more “mournful”?

Experiencing similar things, why are some people more inclined to save good memories, and some people are more likely to keep bad feelings?

In a recent paper published in the journal Nature, scientists found that just a small molecule can give our memory an “emotional stamp” that determines whether you’ll feel happy or sad when you remember it later.


“What’s even more interesting is that we seem to be able to manipulate this ‘molecular switch’ to decide to ‘write’ positive or negative memories to the brain.” Li Hao, co-first author of the paper, said, “People with anxiety, depression or post-traumatic stress disorder (PTSD) are always more likely to remember bad feelings and hope that our findings will provide new treatment options.” ”

The work was led by Kay Tye, a researcher at the Salk Institute for Biology, with postdocs Hao Li, Praneeth Namburi and Jacob Olson as co-first authors. Professor Zhang Feng of the Broad Institute and Yulong Li, a researcher at Peking University, also participated in the study.

A tribute to the classic Pavlovian method


Li Hao and his upcoming admission to the Department of Psychiatry and Behavioral Sciences at Northwestern University

Li Hao, 34, is a Beijing-born young man who, like many young people, enjoys playing football, climbing rocks, watching cartoons and petting cats.

After receiving his bachelor’s degree from Shandong University, Li Hao went to the United States for further study. The paper was his research work as a postdoc in the Kay Tye lab at the Salk Institute.

At present, Li Hao has received an offer from Northwestern University in the United States and is expected to open his own independent laboratory in 2023. He crafted a website for his future lab, writing on the Research Goals page: “Our goal is to understand how neuropeptides play a role in mediating health or disease. ”

“The motivation for almost all biological actions can be boiled down to two broad categories: seeking reward or escaping punishment. If the nervous system is dysfunctional in the processing of motivation, it can lead to anxiety, depression, addiction and other problems. Li Hao explained to China Science Daily.

As early as the 1890s, the famous Russian biologist Pavlov used a series of classic conditioned reflex experiments to show the physiological response of organisms in the face of “reward and punishment”.

His method of experimentation is well-known: let the dog see the food and measure its saliva secretion. After that, every time you give food, you provide a ringing sound at the same time. Soon after, even without food, dogs will automatically secrete saliva when the bell rings.

The story of “hoping for plums to quench thirst” in ancient China, and the symptoms of “nervousness” that some people begin to “nervous” when they hear the bell ringing in class, are related to conditioned reflexes.

In the latest Nature paper, Li Hao and others also used the classic “Pavlov conditioned reflex experiment”. In the reward behavior model, they would first listen to a piece of audio to the mice, and then give them a little sugar water; In the model of punitive behavior, mice are given another piece of audio and then an electric shock is given to their feet.

Like Pavlov’s dogs, mice learned quickly that when they heard a sound, they could predict what would be good or bad and react accordingly.

The next experiment is handed over to more advanced modern biological technology.

Zhang Feng’s team assisted in the design of “Gene Magic Scissors”

The researchers found that the brains of mice regulate the release of a small molecule polypeptide, neurotensin, based on rewards or punishments.

In reward learning, neurons are enhanced by the release to the amygdala’s base lateral nucleus, prompting neurons here to respond to reward stimuli, thereby enhancing reward learning.

In punitive learning, the release of neurotensin is inhibited, which prompts the amygdala’s base-side nucleus to respond to punitive stimuli and enhances the efficiency of punitive learning.

To learn more about how neurotensin works, they used the CRISPR-Cas9 system, a “gene-editing magic scissor,” to knock out genes encoding neurons in specific amygdala neurons.

Mice that had been knocked out of their genes had difficulty associating the sweetness of the sugar water with the corresponding audio, but their response to negative information became more intense: when sounds associated with foot shocks sounded, they “scared away” or “stunned” more quickly.

This suggests that the brain’s default state is one of fear-prone, and the presence of neurons helps turn on neurons associated with active learning.

“From an evolutionary point of view, this makes sense because it helps people avoid potentially dangerous situations.” Kay Tye said, “People who are good at finding the worst-case scenarios may resonate with this result.” ”

It is worth mentioning that Kay Tye once worked in the same laboratory as the famous Chinese scientist Zhang Feng. When she was a postdoc in The Karl Deisseroth Lab at Stanford University, Zhang Feng was also a PhD student here. In this study, Zhang’s team helped design the CRISPR system for experiments — the first time CRISPR has been used to isolate specific neurotransmitter functions.

Want to build a “happy” laboratory


Kay Tye (left) and Li Hao

In Li Hao’s view, the lab where he conducts postdoctoral research has a relaxed and pleasant atmosphere, and the supervisor Kay Tye is a “very interesting person, especially very active.”

In 2020, laboratories in U.S. universities were locked down for a period of time due to the pandemic. When it was first unsealed, everyone was not fully in the state. Seeing this, Kay exclaimed that “the laboratory is going to be ashes” and decided to be the first to do the experiment and set an example for the team.

At that time, Li Yulong’s team at Peking University sent a neuronaltin probe to verify whether the probe was effective. Kay, who had not done the experiment himself for 7 or 8 years, was successful in one fell swoop and did not do it a second time. “She’s so proud that she wants the world to know.” Li Hao said with a smile.

In addition, Kay is also very good at describing research work vividly and interestingly, and stimulating everyone’s enthusiasm for work.

Li Hao hopes that in the future, he will also be able to build a laboratory that “ensures that all laboratory members thrive, so that they can develop their scientific potential in health and happiness, and achieve their career goals.”

As a young neurobiology researcher, Li Hao has his own unique understanding of “happiness”: “The same thing, some brains will process it into pleasant memories, and some brains will process it into sad memories.” Therefore, happiness or unhappiness is relative. Knowing this, there will be a sense of normalcy toward many things. (Source: China Science Daily Li Chenyang)

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