Fundamental rule of brain plasticity
June 21, 2018
Science Daily/Picower Institute at MIT
A series of complex experiments in the visual cortex of mice has yielded a simple rule about plasticity: When a synapse strengthens, others immediately nearby weaken.
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."
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, 3D 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 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 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.
https://www.sciencedaily.com/releases/2018/06/180621141027.htm
Longer, intense rehabilitation boosts recovery after brain injury
February 22, 2016
Science Daily/University of California, San Diego Health Sciences
Cognitive and functional recovery after a stroke or traumatic injury requires intense rehabilitative therapy to help the brain repair and restructure itself. New findings report that not only is rehabilitation vital but that a longer, even more intense period of rehabilitation may produce even greater benefit.
"This has implications for medical practice and medical insurance," said senior study author Mark Tuszynski, MD, PhD, professor in the Department of Neurosciences and director of the Center for Neural Repair at UC San Diego School of Medicine, and a neurologist with the VA San Diego Healthcare System. "Typically, insurance supports brief periods of rehab to teach people to get good enough to go home. These findings suggest that if insurance would pay for longer and more intensive rehab, patients might actually recover more function."
The findings are published in the February 22 online early edition of PNAS.
In recent years, numerous studies have documented the surprising plasticity or ability of the adult central nervous system to recover from injury. The emerging question has been how to best encourage the repair and regrowth of damaged nerve cells and connections.
To better understand what happens at the molecular and cellular levels and how rehabilitation might be made more effective after brain injury, researchers studied rats relearning skills and physical abilities. They found rats that received intensive therapy for an extended period of time showed significant restructuring of the brain around the damage site: Surviving neurons sprouted greater numbers of dendritic spines, which made more connections with other neurons. The result, said Tuszynski, was a dramatic 50 percent recovery of function.
Animals that did not undergo intensive rehabilitation did not rebuild brain structure or recover function.
Additionally, the researchers found that a key system in the brain -- the basal forebrain cholinergic system -- is critical to rehabilitation. Structures in this part of the brain, such as the nucleus basalis, produce acetylcholine, a chemical released by nerve cells to send signals to other cells. Specifically, motor neurons release acetylcholine to activate muscles.
Damage to the cholinergic system, which can occur naturally during aging, completely blocks brain plasticity mediated by rehabilitation and significantly reduces functional recovery. Tuszynski said the finding suggests that a class of drugs called cholinesterase inhibitors, which boost the levels and persistence of acetylcholine and are used in some treatments for Alzheimer's disease, might further improve functional outcomes after brain injury.
"We did not try to do this in our study," said Tuszynski, "but we did suggest future studies could be done to look at this possibility."
https://www.sciencedaily.com/releases/2016/02/160222155824.htm
Mindfulness meditation training changes brain structure in eight weeks
January 21, 2011
Science Daily/Massachusetts General Hospital
Participating in an 8-week mindfulness meditation program appears to make measurable changes in brain regions associated with memory, sense of self, empathy and stress. A new study is the first to document meditation-produced changes over time in the brain's gray matter.
"Although the practice of meditation is associated with a sense of peacefulness and physical relaxation, practitioners have long claimed that meditation also provides cognitive and psychological benefits that persist throughout the day," says Sara Lazar, PhD, of the MGH Psychiatric Neuroimaging Research Program, the study's senior author. "This study demonstrates that changes in brain structure may underlie some of these reported improvements and that people are not just feeling better because they are spending time relaxing."
Previous studies from Lazar's group and others found structural differences between the brains of experienced mediation practitioners and individuals with no history of meditation, observing thickening of the cerebral cortex in areas associated with attention and emotional integration. But those investigations could not document that those differences were actually produced by meditation.
"It is fascinating to see the brain's plasticity and that, by practicing meditation, we can play an active role in changing the brain and can increase our well-being and quality of life." says Britta Hölzel, PhD, first author of the paper and a research fellow at MGH and Giessen University in Germany. "Other studies in different patient populations have shown that meditation can make significant improvements in a variety of symptoms, and we are now investigating the underlying mechanisms in the brain that facilitate this change."
Amishi Jha, PhD, a University of Miami neuroscientist who investigates mindfulness-training's effects on individuals in high-stress situations, says, "These results shed light on the mechanisms of action of mindfulness-based training. They demonstrate that the first-person experience of stress can not only be reduced with an 8-week mindfulness training program but that this experiential change corresponds with structural changes in the amygdala, a finding that opens doors to many possibilities for further research on MBSR's potential to protect against stress-related disorders, such as post-traumatic stress disorder." Jha was not one of the study investigators.
http://www.sciencedaily.com/releases/2011/01/110121144007.htm
Mental training changes brain structure and reduces social stress
October 4, 2017
Science Daily/Max Planck Institute for Human Cognitive and Brain Sciences
Meditation can have positive effects on our health and well-being. However it has been unclear which mental practice has which effect, and what the underlying processes are. Researchers have discovered that different trainings affect either our attention or our social competencies and modify different brain networks. One mental technique was able to reduce the stress hormone cortisol. These results may influence the adaptation of mental trainings in clinics and education.
Meditation is beneficial for our well-being. This ancient wisdom has been supported by scientific studies focusing on the practice of mindfulness. However, the words "mindfulness" and "meditation" denote a variety of mental training techniques that aim at the cultivation of various different competencies. In other words, despite growing interest in meditation research, it remains unclear which type of mental practice is particularly useful for improving either attention and mindfulness or social competencies, such as compassion and perspective-taking.
Other open questions are, for example, whether such practices can induce structural brain plasticity and alter brain networks underlying the processing of such competencies, and which training methods are most effective in reducing social stress. To answer these questions, researchers from the Department of Social Neuroscience at the Max Planck Institute of Human Cognitive and Brain Sciences in Leipzig, Germany conducted the large-scale ReSource Project aiming at teasing apart the unique effects of different methods of mental training on the brain, body, and on social behaviour.
The ReSource Project consisted of three 3-month training modules, each focusing on a different competency. The first module trained mindfulness-based attention and interoception. Participants were instructed in classical meditation techniques similar to those taught in the 8-week Mindfulness-based Stress Reduction Program (MBSR), which requires one to focus attention on the breath (Breathing Meditation), on sensations in different parts of the body (Body Scan), or on visual or auditory cues in the environment. Both exercises were practised in solitude.
Training in the second module focused on socio-affective competencies, such as compassion, gratitude, and dealing with difficult emotions. In addition to classical meditation exercises, participants learnt a new technique requiring them to practise each day for 10 minutes in pairs. These partner exercises, or so-called "contemplative dyads," were characterised by a focused exchange of every-day life affective experiences aiming to train gratitude, dealing with difficult emotions, and empathic listening.
In the third module, participants trained socio-cognitive abilities, such as metacognition and perspective-taking on aspects of themselves and on the minds of others. Again, besides classical meditation exercises, this module also offered dyadic practices focusing on improving perspective-taking abilities. In pairs, participants learnt to mentally take the perspective of an "inner part" or aspect of their personality. Examples of inner parts were the "worried mother," the "curious child," or the "inner judge."
By reflecting on a recent experience from this perspective, the speaker in dyadic pair-exercise trained in perspective-taking on the self, thus gaining a more comprehensive understanding of his or her inner world. By trying to infer which inner part is speaking, the listener practices taking the perspective of the other.
All exercises were trained on six days a week for a total of 30 minutes a day. Researchers assessed a variety of measures such as psychological behavioural tests, brain measures by means of magnetic resonance-imaging (MRI), and stress markers such as cortisol release before and after each of the three three-month training modules.
"Depending on which mental training technique was practised over a period of three months, specific brain structures and related behavioural markers changed significantly in the participants. For example, after the training of mindfulness-based attention for three months, we observed changes in the cortex in areas previously shown to be related to attention and executive functioning.
Simultaneously, attention increased in computer-based tasks measuring executive aspects of attention, while performance in measures of compassion or perspective-taking had not increased significantly. These social abilities were only impacted in our participants during the other two more intersubjective modules," states Sofie Valk, first author of the publication, which has just been released by the journal Science Advances.
"In the two social modules, focusing either on socio-affective or socio-cognitive competencies, we were able to show selective behavioural improvements with regard to compassion and perspective-taking. These changes in behaviour corresponded with the degree of structural brain plasticity in specific regions in the cortex which support these capacities," according to Valk.
"Even though brain plasticity in general has long been studied in neuroscience, until now little was known about the plasticity of the social brain. Our results provide impressive evidence for brain plasticity in adults through brief and concentrated daily mental practice, leading to an increase in social intelligence. As empathy, compassion, and perspective-taking are crucial competencies for successful social interactions, conflict resolution, and cooperation, these findings are highly relevant to our educational systems as well as for clinical application," explains Prof. Tania Singer, principal investigator of the ReSource Project.
Besides differentially affecting brain plasticity, the different types of mental training also differentially affected the stress response. "We discovered that in participants subjected to a psychosocial stress test, the secretion of the stress hormone cortisol was diminished by up to 51%. However, this reduced stress sensitivity was dependent on the types of previously trained mental practice," says Dr Veronika Engert, first author of another publication from the ReSource Project, which describes the connection between mental training and the acute psychosocial stress response, also recently published in Science Advances. "Only the two modules focusing on social competencies significantly reduced cortisol release after a social stressor. We speculate that the cortisol stress response was affected particularly by the dyadic exercises practised in the social modules. The daily disclosure of personal information to a stranger coupled with the non-judgmental, empathic listening experience in the dyads may have "immunised" participants against the fear of social shame and judgment by others -- typically a salient trigger of social stress. The concentrated training of mindfulness-based attention and interoceptive awareness, on the other hand, had no dampening effect on the release of cortisol after experiencing a social stressor."
Interestingly, despite these differences on the level of stress physiology, each of the 3-month training modules reduced the subjective perception of stress. This means that although objective, physiological changes in social stress reactivity were only seen when participants engaged with others and trained their inter-subjective abilities, and participants felt subjectively less stressed after all mental training modules.
"The current results highlight not only that crucial social competencies necessary for successful social interaction and cooperation can still be improved in healthy adults and that such mental training leads to structural brain changes and to social stress reduction, but also that different methods of mental training have differential effects on the brain, on health, and behaviour. It matters what you train," suggests Prof. Singer. "Once we have understood which mental training techniques have which effects, we will be able to employ these techniques in a targeted way to support mental and physical health."
For example, many currently popular mindfulness programmes may be a valid method to foster attention and strengthen cognitive efficiency. However, if we as a society want to become less vulnerable to social stress or train social competencies, such as empathy, compassion, and perspective-taking, mental training techniques focusing more on the "we" and social connectedness among people may be a better choice.
https://www.sciencedaily.com/releases/2017/10/171004142653.htm