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,” says Sur, the 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, postdocs 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.”
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 says.
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.
Solving the mystery of the Arc
Having seen the new rule in effect, the researchers were
still eager to understand how neurons 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
says. “If something goes up, something must go down. That’s the major role of
Arc.”
Sur says 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 synapses 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.
Ania Majewska, associate professor of neuroscience in the
Center for Visual Science at the University of Rochester, says the study’s
advanced methods allowed the team to achieve and important set of new results.
“Because of the difficulty in monitoring and manipulating
the tiny and numerous synapses that connect neurons, most studies have been
carried out in reduced preparations with artificial stimuli making it unclear
how the mechanisms identified are actually implemented in the complicated
circuits that function inside a brain reacting to its environment,” Majewska says.
“This new study from the Sur lab has great impact because it combines cutting
edge imaging and genetic tools to beautifully monitor the function of
individual synapses inside a brain that is responding to behaviorally-relevant
stimuli that elicit changes in neuronal responses.
“Given the results from this tour de force approach, we can
now say that, in the intact brain, synapses that lie in close proximity to one
another interact during changes in circuit function through a mechanism that
involves a molecular cascade in which arc plays a critical role,” she said.
“This information allows us to understand not only how neuronal circuits
develop and remodel in a physiological setting, but provides clues that will be
important in identifying how these processes go awry in various neurological
diseases.”
In addition to Sur, El-Boustani and Ip, the paper’s other
authors are Vincent Breton-Provencher, Ghraham Knott, Hiroyuki Okuno and
Haruhiko Bito.
http://news.mit.edu/2018/mit-scientists-discover-fundamental-rule-of-brain-plasticity-0622
Courtesy of Doximity
El-Boustani S, Ip JPK, Breton-Provencher V, Knott GW, Okuno
H, Bito H, Sur M.
Abstract
Plasticity of cortical responses in vivo involves
activity-dependent changes at synapses, but the manner in which different forms
of synaptic plasticity act together to create functional changes in neurons
remains unknown. We found that spike timing-induced receptive field plasticity
of visual cortex neurons in mice is anchored by increases in the synaptic
strength of identified spines. This is accompanied by a decrease in the strength
of adjacent spines on a slower time scale. The locally coordinated potentiation
and depression of spines involves prominent AMPA receptor redistribution via
targeted expression of the immediate early gene product Arc. Hebbian
strengthening of activated synapses and heterosynaptic weakening of adjacent
synapses thus cooperatively orchestrate cell-wide plasticity of functional
neuronal responses.
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