Scientists discover fundamental rule of brain plasticity

June 21, 2018, Picower Institute at MIT
A dendrite and its spines, reconstructed with electron microscopy (right) after it was imaged with two-photon microscopy in the intact brain (left). Credit: Mriganka Sur, et. al.

Our brains are famously flexible, or "plastic," because neurons can do new things by forging new or stronger connections with other neurons. But if some connections strengthen, neuroscientists have reasoned, neurons must compensate lest they become overwhelmed with input. In a new study in Science, researchers at the Picower Institute for Learning and Memory at MIT demonstrate for the first time how this balance is struck: when one connection, called a synapse, strengthens, immediately neighboring synapses weaken based on the action of a crucial protein called Arc.

Senior author Mriganka Sur said he was excited but not surprised that his team discovered a simple, fundamental rule at the core of such a complex system as the brain, where 100 billion neurons each have thousands of ever-changing synapses. He likens it to how a massive school of fish can suddenly change direction, en masse, so long as the lead fish turns and every other fish obeys the simple rule of following the fish right in front of it.

"Collective behaviors of complex systems always have simple rules," said Sur, Paul E. and Lilah Newton Professor of Neuroscience in the Picower Institute and the department of Brain and Cognitive Sciences at MIT. "When one synapse goes up, within 50 micrometers there is a decrease in the strength of other synapses using a well-defined molecular mechanism."

This finding, he said, provides an explanation of how synaptic strengthening and weakening combine in neurons to produce plasticity.

Multiple manipulations

Though the rule they found was simple, the experiments that revealed it were not. As they worked to activate plasticity in the visual cortex of mice and then track how synapses changed to make that happen, lead authors Sami El-Boustani and Jacque Pak Kan Ip, postdoctoral researchers in Sur's lab, accomplished several firsts.

In one key experiment, they invoked plasticity by changing a neuron's "receptive field," or the patch of the visual field it responds to. Neurons receive input through synapses on little spines of their branch-like dendrites. To change a neuron's receptive field, the scientists pinpointed the exact spine on the relevant dendrite of the neuron, and then closely monitored changes in its synapses as they showed the mouse a target in a particular place on a screen that differed from the neuron's original receptive field. Whenever the target was in the new receptive field position they wanted to induce, they reinforced the neuron's response by flashing a blue light inside the mouse's visual cortex, instigating extra activity just like another neuron might. The neuron had been genetically engineered to be activated by light flashes, a technique called "optogenetics."

A dendrite (a branch of a neuron) with round processes or spines, expressing a red fluorescent protein together with a green tag for the protein Arc, obtained with two-photon microscopy in an awake mouse. Credit: Sur, et. al.

The researchers did this over and over. Because the light stimulation correlated with each appearance of the target in the new position in the mouse's vision, this caused the neuron to strengthen a particular synapse on the spine, encoding the new receptive field.

"I think it's quite amazing that we are able to reprogram single neurons in the intact brain and witness in the living tissue the diversity of molecular mechanisms that allows these cells to integrate new functions through synaptic plasticity," El-Boustani said.

As the synapse for the new receptive field grew, the researchers could see under the two-photon microscope that nearby synapses also shrank. They did not observe these changes in experimental control neurons that lacked the optogenetic stimulation.

But then they went further to confirm their findings. Because synapses are so tiny, they are near the limit of the resolution of light microscopy. So after the experiments the team dissected the brain tissues containing the dendrites of manipulated and control neurons and shipped them to co-authors at the Ecole Polytechnique Federal de Lausanne in Switzerland. They performed a specialized, higher-resolution, 3-D electron microscope imaging, confirming that the structural differences seen under the two-photon microscope were valid.

"This is the longest length of dendrite ever reconstructed after being imaged in vivo," said Sur, who also directs the Simons Center for the Social Brain at MIT.

Of course, reprogramming a mouse's genetically engineered neuron with flashes of light is an unnatural manipulation, so the team did another more classic "monocular deprivation" experiment in which they temporarily closed one eye of a mouse. When that happens synapses in neurons related to the closed eye weaken and synapses related to the still open eye strengthen. Then when they reopened the previously closed eye, the synapses rearrange again. They tracked that action, too, and saw that as synapses strengthen, their immediate neighbors would weaken to compensate.

Two-photon imaging of a stretch of dendrite and its spines in the intact brain of a behaving mouse. A red fluorescent protein is used to visualize the structure of the dendrite, while calcium activity in individual spines is monitored with a green indicator. Branch-wide and spine-specific signals can be observed in response to visual stimuli. Credit: Sur, et. al.
Solving the mystery of the Arc

Having seen the new rule in effect, the researchers were still eager to understand how obey it. They used a chemical tag to watch how key "AMPA" receptors changed in the synapses and saw that synaptic enlargement and strengthening correlated with more AMPA receptor expression while shrinking and weakening correlated with less AMPA receptor expression.

The protein Arc regulates AMPA receptor expression, so the team realized they had to track Arc to fully understand what was going on. The problem, Sur said, is that no one had ever done that before in the brain of a live, behaving animal. So the team reached out to co-authors at the Kyoto University Graduate School of Medicine and the University of Tokyo, who invented a chemical tag that could do so.

Using the tag, the team could see that the strengthening synapses were surrounded with weakened synapses that had enriched Arc expression. Synapses with reduced amount of Arc were able to express more AMPA receptors whereas increased Arc in neighboring spines caused those synapses to express less AMPA receptors.

"We think Arc maintains a balance of synaptic resources," Ip said. "If something goes up, something must go down. That's the major role of Arc."

Sur said the study therefore solves a mystery of Arc: No one before had understood why Arc seemed to be upregulated in dendrites undergoing synaptic plasticity, even though it acts to weaken synapses, but now the answer was clear. Strengthening increase Arc to weaken their neighbors.

Sur added that the rule helps explain how learning and memory might work at the individual neuron level because it shows how a neuron adjusts to the repeated simulation of another.

Explore further: Repeated stimulation enlarges dendritic spines

More information: "Locally coordinated synaptic plasticity of visual cortex neurons in vivo" Science (2018). science.sciencemag.org/cgi/doi … 1126/science.aao0862

Related Stories

Repeated stimulation enlarges dendritic spines

June 8, 2018
Even in adult brains, new neurons are generated throughout a lifetime. In a publication in the scientific journal PNAS, a research group led by Goethe University describes plastic changes of adult-born neurons in the hippocampus, ...

Receptors key to strong memories

February 27, 2018
When we create a memory, a pattern of connections forms between neurons in the brain. New work from UC Davis shows how these connections can be strengthened or weakened at a molecular level. The study is published Feb. 27 ...

Key brain receptor sheds light on neurological conditions, researchers say

March 3, 2016
Researchers at the University of Colorado Anschutz Medical Campus have found that a key receptor in the brain, once thought to only strengthen synapses, can also weaken them, offering new insights into the mechanisms driving ...

Microglia pruning brain synapses captured on film for the first time

March 26, 2018
For the first time, EMBL researchers have captured microglia pruning synaptic connections between brain cells. Their findings show that the special glial cells help synapses grow and rearrange, demonstrating the essential ...

Scientists find brain plasticity assorted into functional networks

February 4, 2016
The brain still has a lot to learn about itself. Scientists at the Virginia Tech Carilion Research Institute have made a key finding of the striking differences in how the brain's cells can change through experience.

Study reveals reciprocal activity of brain proteins necessary for learning and memory

October 13, 2017
A UCLA team reports that a protein called IDOL targets and prevents overproduction of the synaptic protein ApoER2, an adjustment that allows connections between neurons to change during the learning process for humans and ...

Recommended for you

A 15-minute scan could help diagnose brain damage in newborns

November 14, 2018
A 15-minute scan could help diagnose brain damage in babies up to two years earlier than current methods.

Precision neuroengineering enables reproduction of complex brain-like functions in vitro

November 14, 2018
One of the most important and surprising traits of the brain is its ability to dynamically reconfigure the connections to process and respond properly to stimuli. Researchers from Tohoku University (Sendai, Japan) and the ...

New brain imaging research shows that when we expect something to hurt it does, even if the stimulus isn't so painful

November 14, 2018
Expect a shot to hurt and it probably will, even if the needle poke isn't really so painful. Brace for a second shot and you'll likely flinch again, even though—second time around—you should know better.

New clues to the origin and progression of multiple sclerosis

November 13, 2018
Mapping of a certain group of cells, known as oligodendrocytes, in the central nervous system of a mouse model of multiple sclerosis (MS), shows that they might have a significant role in the development of the disease. The ...

Mutations, CRISPR, and the biology behind movement disorders

November 12, 2018
Scientists at the RIKEN Center for Brain Science (CBS) in Japan have discovered how mutations related to a group of movement disorders produce their effects. Published in Proceedings of the National Academy of Sciences, the ...

In live brain function, researchers are finally seeing red

November 12, 2018
For years, green has been the most reliable hue for live brain imaging, but after using a new high-throughput screening method, researchers at the John B. Pierce Laboratory and the Yale School of Medicine, together with collaborators ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.