Nav: Home

Stanford scientists study Pavlovian conditioning in neural networks

March 22, 2017

In the decades following the work by physiologist Ivan Pavlov and his famous salivating dogs, scientists have discovered how molecules and cells in the brain learn to associate two stimuli, like Pavlov's bell and the resulting food. What they haven't been able to study is how whole groups of neurons work together to form that association. Now, Stanford University researchers have observed how large groups of neurons in the brain both learn and unlearn a new association.

"It's been over 100 years since Pavlov did his amazing work but we still haven't had a glimpse of how neural ensembles encode a long-term memory," said Mark Schnitzer, associate professor of biology and applied physics, who led the research. "This was an opportunity to examine that."

The researchers worked with mice and focused on the amygdala, a part of the brain known to be involved in learning that is extremely similar across species. They taught mice to associate a tone with a mild shock and found that, once the mice learned the association, the pattern of neurons that activated in response to tone alone resembled the pattern that activated in response to the shock. Using Pavlov's dogs as an analogy, this would mean that, as the dogs learned to associate the bell with the food, the neural network activation in their amygdalas would look similar whether they were presented with food or just heard the bell.

The researchers' results, published in Nature on March 22, also reveal that the neurons never returned to their original state, even after the training was undone. Although this was not the main focus of the study, this research could have wide-ranging implications for studying emotional memory disorders, such as post-traumatic stress disorder (PTSD).

Building on Pavlov's work

The researchers trained mice in the study to associate a tone with a light foot shock. At the beginning of the experiment, mice had no reaction to the tone, but would freeze in place in response to the light shock. After pairing the tone and the light shock a few times, the tone alone was enough to cause the mice to freeze in place.

"You can think of this type of learning as a survival strategy," said Benjamin Grewe, lead author of the paper and former postdoctoral scholar in the Schnitzer lab. "We need that as humans, animals need that. When we associate certain stimuli with their possible dangerous outcomes, it helps us to avoid dangerous situations in the first place."

During the training, the researchers directly observed the activity of about 200 neurons in the amygdala. Using a miniature microscope - developed previously by the Schnitzer lab - to view neurons deep in the brain, they could observe activity of individual cells as well as of the entire ensemble. What they found was that, as the mice learned to associate the tone with the shock, the set of cells that responded to the tone began to resemble those that responded to the shock itself.

"The two stimuli are both eliciting fear responses," said Schnitzer, who is also a Howard Hughes Medical Institute investigator. "It's almost as if this part of the brain is blurring the lines between the two, in the sense that it's using the same cells to encode them."

The amount of change in how the group of neurons responded to the tone also predicted how much the mouse behavior would change. Mice whose amygdalas activated similarly in response to the tone and to the shock froze most consistently in response to the tone, by itself, 24 hours later.

"We managed, for the first time, to record the activity of a large network of neurons in the amygdala and did that with single cell resolution," Grewe said. "So we knew what every single cell was doing."

Lingering associations

As part of the experiments, the team also undid the conditioning so that the mice stopped freezing in reaction to the tone. During this phase the neural response never completely returned to its original state.

The experiment to reverse the association was not designed to represent any human diseases or disorders, but this finding could potentially inform research into problems with emotional memory, such as generalized anxiety disorder or PTSD, where people may have difficulty dissociating neutral stimuli from negative ones. That kind of application, however, would likely be some years in the future.

"We're just beginning this work," Schnitzer said, "but these findings give us a window into how the external world may be annotated for us in this brain structure."
-end-
Additional co-authors of this work include Lacey J. Kitch, Jerome A. Lecoq, Jesse D. Marshall, Margaret C. Larkin, Pablo E. Jercog, and Jin Zhong Li of Stanford University and Howard Hughes Medical Institute; Jan Gründemann and Francois Grenier of the Friedrich Miescher Institute for Biomedical Research; Jones G. Parker of Stanford University and Pfizer Neuroscience Research; and Andreas Lüthi of the Friedrich Miescher Institute for Biomedical Research and the University of Basel. Schnitzer is also a member of Stanford Bio-X and the Stanford Neurosciences Institute.

This work was funded by the Swiss National Science Foundation, the U.S. National Science Foundation, Stanford University, the Simons Foundation, the Helen Hay Whitney Foundation, the Novartis Research Foundation, Howard Hughes Medical Institute and DARPA.

Stanford University

Related Neurons Articles:

New tool to identify and control neurons
One of the big challenges in the Neuroscience field is to understand how connections and communications trigger our behavior.
Neurons that regenerate, neurons that die
In a new study published in Neuron, investigators report on a transcription factor that they have found that can help certain neurons regenerate, while simultaneously killing others.
How neurons use crowdsourcing to make decisions
When many individual neurons collect data, how do they reach a unanimous decision?
Neurons can learn temporal patterns
Individual neurons can learn not only single responses to a particular signal, but also a series of reactions at precisely timed intervals.
A turbo engine for tracing neurons
Putting a turbo engine into an old car gives it an entirely new life -- suddenly it can go further, faster.
Brain neurons help keep track of time
Turning the theory of how the human brain perceives time on its head, a novel analysis in mice reveals that dopamine neuron activity plays a key role in judgment of time, slowing down the internal clock.
During infancy, neurons are still finding their places
Researchers have identified a large population of previously unrecognized young neurons that migrate in the human brain during the first few months of life, contributing to the expansion of the frontal lobe, a region important for social behavior and executive function.
How many types of neurons are there in the brain?
For decades, scientists have struggled to develop a comprehensive census of cell types in the brain.
Molecular body guards for neurons
In the brain, patterns of neural activity are perfectly balanced.
Engineering researchers use laser to 'weld' neurons
University of Alberta researchers have developed a method of connecting neurons, using ultrashort laser pulses -- a breakthrough technique that opens the door to new medical research and treatment opportunities.

Related Neurons Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Anthropomorphic
Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#SB2 2019 Science Birthday Minisode: Mary Golda Ross
Our second annual Science Birthday is here, and this year we celebrate the wonderful Mary Golda Ross, born 9 August 1908. She died in 2008 at age 99, but left a lasting mark on the science of rocketry and space exploration as an early woman in engineering, and one of the first Native Americans in engineering. Join Rachelle and Bethany for this very special birthday minisode celebrating Mary and her achievements. Thanks to our Patreons who make this show possible! Read more about Mary G. Ross: Interview with Mary Ross on Lash Publications International, by Laurel Sheppard Meet Mary Golda...