Brain disorders, climate change, clean energy, cancer – these are examples of problems which are difficult to solve because we don’t know what we would need to know to solve them. Edward Boyden, Associate Professor at Massachusetts Institute of Technology, teaches students how to think about approaching intractable problems. In this presentation for the World Economic Forum, he explains strategies such as valuing interdisciplinary expertise and being willing to leave comfort zones.
Category: Uncategorized
McGovern neuroscientists reverse autism symptoms
Autism has diverse genetic causes, most of which are still unknown. About 1 percent of people with autism are missing a gene called Shank3, which is critical for brain development. Without this gene, individuals develop typical autism symptoms including repetitive behavior and avoidance of social interactions.
In a study of mice, MIT researchers have now shown that they can reverse some of those behavioral symptoms by turning the gene back on later in life, allowing the brain to properly rewire itself.
“This suggests that even in the adult brain we have profound plasticity to some degree,” says Guoping Feng, an MIT professor of brain and cognitive sciences. “There is more and more evidence showing that some of the defects are indeed reversible, giving hope that we can develop treatment for autistic patients in the future.”
Feng, who is the James W. and Patricia Poitras Professor of Neuroscience and a member of MIT’s McGovern Institute for Brain Research and the Stanley Center for Psychiatric Research at the Broad Institute, is the senior author of the study, which appears in the Feb. 17 issue of Nature. The paper’s lead authors are former MIT graduate student Yuan Mei and former Broad Institute visiting graduate student Patricia Monteiro, now at the University of Coimbra in Portugal.
Boosting communication
The Shank3 protein is found in synapses — the connections that allow neurons to communicate with each other. As a scaffold protein, Shank3 helps to organize the hundreds of other proteins that are necessary to coordinate a neuron’s response to incoming signals.
Studying rare cases of defective Shank3 can help scientists gain insight into the neurobiological mechanisms of autism. Missing or defective Shank3 leads to synaptic disruptions that can produce autism-like symptoms in mice, including compulsive behavior, avoidance of social interaction, and anxiety, Feng has previously found. He has also shown that some synapses in these mice, especially in a part of the brain called the striatum, have a greatly reduced density of dendritic spines — small buds on neurons’ surfaces that help with the transmission of synaptic signals.
In the new study, Feng and colleagues genetically engineered mice so that their Shank3 gene was turned off during embryonic development but could be turned back on by adding tamoxifen to the mice’s diet.
When the researchers turned on Shank3 in young adult mice (two to four and a half months after birth), they were able to eliminate the mice’s repetitive behavior and their tendency to avoid social interaction. At the cellular level, the team found that the density of dendritic spines dramatically increased in the striatum of treated mice, demonstrating the structural plasticity in the adult brain.
However, the mice’s anxiety and some motor coordination symptoms did not disappear. Feng suspects that these behaviors probably rely on circuits that were irreversibly formed during early development.
When the researchers turned on Shank3 earlier in life, only 20 days after birth, the mice’s anxiety and motor coordination did improve. The researchers are now working on defining the critical periods for the formation of these circuits, which could help them determine the best time to try to intervene.
“Some circuits are more plastic than others,” Feng says. “Once we understand which circuits control each behavior and understand what exactly changed at the structural level, we can study what leads to these permanent defects, and how we can prevent them from happening.”
Gordon Fishell, a professor of neuroscience at New York University School of Medicine, praises the study’s “elegant approach” and says it represents a major advance in understanding the circuitry and cellular physiology that underlie autism. “The combination of behavior, circuits, physiology, and genetics is state-of-the art,” says Fishell, who was not involved in the research. “Moreover, Dr. Feng’s demonstration that restoration of Shank3 function reverses autism symptoms in adult mice suggests that gene therapy may ultimately prove an effective therapy for this disease.”
Early intervention
For the small population of people with Shank3 mutations, the findings suggest that new genome-editing techniques could in theory be used to repair the defective Shank3 gene and improve these individuals’ symptoms, even later in life. These techniques are not yet ready for use in humans, however.
Feng believes that scientists may also be able to develop more general approaches that would apply to a larger population. For example, if the researchers can identify defective circuits that are specific for certain behavioral abnormalities in some autism patients, and figure out how to modulate those circuits’ activity, that could also help other people who may have defects in the same circuits even though the problem arose from a different genetic mutation.
“That’s why it’s important in the future to identify what subtype of neurons are defective and what genes are expressed in these neurons, so we can use them as a target without affecting the whole brain,” Feng says.
2016 Phillip A. Sharp Lecture in Neural Circuits
Title: “Neural computations in the retina: from photons to behavior”
Speaker: Markus Meister, Caltech
Date + Time: March 8, 2016 @ 4pm
Location: 46-3002 (Singleton Auditorium)
Abstract:
The retina is touted as the brain’s window upon the world, but unlike a glass pane, the retina performs a great deal of visual processing. Its intricate circuits use ~70 different types of neuron. The output signals in the optic nerve are carried by 20 different types of retinal ganglion cell, each of which completely tiles the visual field. Thus the eye communicates twenty parallel representations of the visual scene. This raises several questions: What is being computed here, can we understand the visual feature reported by each type of ganglion cell? How is this feature computed by the circuit of neurons and synapses that leads to that ganglion cell type? And finally, why are these particular features getting computed, rather than some other set? In recent years, all these research areas have been turbocharged by modern genetic tools, especially the ability to visualize and modify select neuron types within a circuit. Some general insights are:
What? The various ganglion cell types fit on a spectrum from simple “pixel encoders” to “feature detectors”. A few types encode a very simple function of the image, like the local contrast, with a continuously varying firing rate. However, most types fire quite rarely and report specific features, for example differential motion between the foreground and the background. Some ganglion cells seem to play an alarm function; they are silent except under very specific stimulus conditions associated with threats.
How? It has emerged that dramatically different computations can result from circuits using the same kinds of neuronal elements, but arranged in a different sequence or combinations. In fact many of the twenty circuits in the retina share the same elements. On at least one occasion the same neuron is used to transfer signals in both directions! An important source of nonlinearity on which the computations are based is the sharp thresholding of signals at the bipolar cell synapse, which has emerged as a very versatile circuit element.
Why? It has been proposed that each of the twenty ganglion cell types of the retina is Evolution’s answer to a specific behavioral need that is served by the visual system. If so, then the selective silencing of one type of ganglion cell should affect only selected visual behaviors. Early experiments suggest this is a promising avenue of research.
Happy Chinese New Year!
In the Chinese calendar, 2016 is the Year of the Monkey. We wish all of our friends and colleagues a happy, healthy and inventive new year!
How maternal inflammation might lead to autism-like behavior
In 2010, a large study in Denmark found that women who suffered an infection severe enough to require hospitalization while pregnant were much more likely to have a child with autism (even though the overall risk of delivering a child with autism remained low).
Now research from MIT, the University of Massachusetts Medical School, the University of Colorado, and New York University Langone Medical Center reveals a possible mechanism for how this occurs. In a study of mice, the researchers found that immune cells activated in the mother during severe inflammation produce an immune effector molecule called IL-17 that appears to interfere with brain development.
The researchers also found that blocking this signal could restore normal behavior and brain structure.
“In the mice, we could treat the mother with antibodies that block IL-17 after inflammation had set in, and that could ameliorate some of the behavioral symptoms that were observed in the offspring. However, we don’t know yet how much of that could be translated into humans,” says Gloria Choi, an assistant professor of brain and cognitive sciences, a member of MIT’s McGovern Institute for Brain Research, and the lead author of the study, which appears in the Jan. 28 online edition of Science.
Finding the link
In the 2010 study, which included all children born in Denmark between 1980 and 2005, severe infections (requiring hospitalization) that correlated with autism risk included influenza, viral gastroenteritis, and urinary tract infections. Severe viral infections during the first trimester translated to a threefold risk for autism, and serious bacterial infections during the second trimester were linked with a 1.5-fold increase in risk.
Choi and her husband, Jun Huh, were graduate students at Caltech when they first heard about this study during a lecture by Caltech professor emeritus Paul Patterson, who had discovered that an immune signaling molecule called IL-6 plays a role in the link between infection and autism-like behaviors in rodents.
Huh, now an assistant professor at the University of Massachusetts Medical School and one of the paper’s senior authors, was studying immune cells called Th17 cells, which are well known for contributing to autoimmune disorders such as multiple sclerosis, inflammatory bowel diseases, and rheumatoid arthritis. He knew that Th17 cells are activated by IL-6, so he wondered if these cells might also be involved in cases of animal models of autism associated with maternal infection.
“We wanted to find the link,” Choi says. “How do you go all the way from the immune system in the mother to the child’s brain?”
Choi and Huh launched the study as postdocs at Columbia University and New York University School of Medicine, respectively. Working with Dan Littman, a professor of molecular immunology at NYU and one of the paper’s senior authors, they began by injecting pregnant mice with a synthetic analog of double-stranded RNA, which activates the immune system in a similar way to viruses.
Confirming the results of previous studies in mice, the researchers found behavioral abnormalities in the offspring of the infected mothers, including deficits in sociability, repetitive behaviors, and abnormal communication. They then disabled Th17 cells in the mothers before inducing inflammation and found that the offspring mice did not show those behavioral abnormalities. The abnormalities also disappeared when the researchers gave the infected mothers an antibody that blocks IL-17, which is produced by Th17 cells.
The researchers next asked how IL-17 might affect the developing fetus. They found that brain cells in the fetuses of mothers experiencing inflammation express receptors for IL-17, and they believe that exposure to the chemical provokes cells to produce even more receptors for IL-17, amplifying its effects.
In the developing mice, the researchers found irregularities in the normally well-defined layers of cells in the brain’s cortex, where most cognition and sensory processing take place. These patches of irregular structure appeared in approximately the same cortical regions in all of the affected offspring, but they did not occur when the mothers’ Th17 cells were blocked.
Disorganized cortical layers have also been found in studies of human patients with autism.
Preventing autism
The researchers are now investigating whether and how these cortical patches produce the behavioral abnormalities seen in the offspring.
“We’ve shown correlation between these cortical patches and behavioral abnormalities, but we don’t know whether the cortical patches actually are responsible for the behavioral abnormalities,” Choi says. “And if it is responsible, what is being dysregulated within this patch to produce this behavior?”
The researchers hope their work may lead to a way to reduce the chances of autism developing in the children of women who experience severe infections during pregnancy. They also plan to investigate whether genetic makeup influences mice’s susceptibility to maternal inflammation, because autism is known to have a very strong genetic component.
Charles Hoeffer, a professor of integrative physiology at the University of Colorado, is a senior author of the paper, and other authors include MIT postdoc Yeong Yim, NYU graduate student Helen Wong, UMass Medical School visiting scholars Sangdoo Kim and Hyunju Kim, and NYU postdoc Sangwon Kim.
Edward Boyden wins BBVA Foundation Frontiers of Knowledge Award
Edward S. Boyden, a professor of media arts and sciences, biological engineering, and brain and cognitive sciences at MIT, has won the BBVA Foundation Frontiers of Knowledge Award in Biomedicine for his role in the development of optogenetics, a technique for controlling brain activity with light. Gero Miesenböck of the University of Oxford and Karl Deisseroth of Stanford University were also honored with the prize for their role in developing and refining the technique.
The BBVA Foundation Frontiers of Knowledge Awards are given annually for “outstanding contributions and radical advances in a broad range of scientific, technological and artistic areas.” The €400.000 prize in the category of biomedicine will be shared among the three neuroscientists.
“If we imagine the brain as a computer, optogenetics is a keyboard that allows us to send extremely precise commands,” says Boyden, a a faculty member at the MIT Media Lab with a joint appointment at MIT’s McGovern Institute for Brain Research. “It is a tool whereby we can control the brain with exquisite precision.”
Boyden joins an illustrious list of prize laureates including physicist Stephen Hawking and artificial intelligence pioneer Marvin Minsky of MIT, who died on January 24.
The BBVA Foundation will host the winners at an awards ceremony on June 21, 2016 at the foundation’s headquarters in Madrid, Spain.
About the BBVA Foundation Frontiers of Knowledge Awards
The BBVA Foundation promotes, funds and disseminates world-class scientific research and artistic creation, in the conviction that science, culture and knowledge hold the key to better opportunities for all world citizens. The Foundation designs and implements its programs in partnership with some of the leading scientific and cultural organizations in Spain and abroad, striving to identify and prioritize those projects with the power to significantly advance the frontiers of the known world.
The juries in each of eight categories are made up of leading international experts in their respective fields, who arrive at their decisions in a wholly independent manner, applying internationally recognized metrics of excellence. The BBVA Foundation is aided in the organization of the awards by the Spanish National Research Council (CSIC).
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Diagnosing depression before it starts
A new brain imaging study from MIT and Harvard Medical School may lead to a screen that could identify children at high risk of developing depression later in life.
In the study, the researchers found distinctive brain differences in children known to be at high risk because of family history of depression. The finding suggests that this type of scan could be used to identify children whose risk was previously unknown, allowing them to undergo treatment before developing depression, says John Gabrieli, the Grover M. Hermann Professor in Health Sciences and Technology and a professor of brain and cognitive sciences at MIT.
“We’d like to develop the tools to be able to identify people at true risk, independent of why they got there, with the ultimate goal of maybe intervening early and not waiting for depression to strike the person,” says Gabrieli, an author of the study, which appears in the journal Biological Psychiatry.
Early intervention is important because once a person suffers from an episode of depression, they become more likely to have another. “If you can avoid that first bout, maybe it would put the person on a different trajectory,” says Gabrieli, who is a member of MIT’s McGovern Institute for Brain Research.
The paper’s lead author is McGovern Institute postdoc Xiaoqian Chai, and the senior author is Susan Whitfield-Gabrieli, a research scientist at the McGovern Institute.
Distinctive patterns
The study also helps to answer a key question about the brain structures of depressed patients. Previous imaging studies have revealed two brain regions that often show abnormal activity in these patients: the subgenual anterior cingulate cortex (sgACC) and the amygdala. However, it was unclear if those differences caused depression or if the brain changed as the result of a depressive episode.
To address that issue, the researchers decided to scan brains of children who were not depressed, according to their scores on a commonly used diagnostic questionnaire, but had a parent who had suffered from the disorder. Such children are three times more likely to become depressed later in life, usually between the ages of 15 and 30.
Gabrieli and colleagues studied 27 high-risk children, ranging in age from eight to 14, and compared them with a group of 16 children with no known family history of depression.
Using functional magnetic resonance imaging (fMRI), the researchers measured synchronization of activity between different brain regions. Synchronization patterns that emerge when a person is not performing any particular task allow scientists to determine which regions naturally communicate with each other.
The researchers identified several distinctive patterns in the at-risk children. The strongest of these links was between the sgACC and the default mode network — a set of brain regions that is most active when the mind is unfocused. This abnormally high synchronization has also been seen in the brains of depressed adults.
The researchers also found hyperactive connections between the amygdala, which is important for processing emotion, and the inferior frontal gyrus, which is involved in language processing. Within areas of the frontal and parietal cortex, which are important for thinking and decision-making, they found lower than normal connectivity.
Cause and effect
These patterns are strikingly similar to those found in depressed adults, suggesting that these differences arise before depression occurs and may contribute to the development of the disorder, says Ian Gotlib, a professor of psychology at Stanford University.
“The findings are consistent with an explanation that this is contributing to the onset of the disease,” says Gotlib, who was not involved in the research. “The patterns are there before the depressive episode and are not due to the disorder.”
The MIT team is continuing to track the at-risk children and plans to investigate whether early treatment might prevent episodes of depression. They also hope to study how some children who are at high risk manage to avoid the disorder without treatment.
Other authors of the paper are Dina Hirshfeld-Becker, an associate professor of psychiatry at Harvard Medical School; Joseph Biederman, director of pediatric psychopharmacology at Massachusetts General Hospital (MGH); Mai Uchida, an assistant professor of psychiatry at Harvard Medical School; former MIT postdoc Oliver Doehrmann; MIT graduate student Julia Leonard; John Salvatore, a former McGovern technical assistant; MGH research assistants Tara Kenworthy and Elana Kagan; Harvard Medical School postdoc Ariel Brown; and former MIT technical assistant Carlo de los Angeles.
Stanley Center & Poitras Center Translational Neuroscience Joint Seminar: Deanna M. Barch
“Connectomics and Psychopathology: A Tale of Many Regions”
Abstract: A growing body of research clearly indicates that both functional and structural connectivity within and between core brain systems is a critical determinant of cognitive and affective function in both health and disease. This talk will first briefly overview the state of the art methods for assessing human brain connectivity. Next this talk will illustrate the ways in which variation in brain connectivity relates to variation in cognitive and affective functions in healthy individuals, as well as how impairments in functional brain connectivity relate to impaired cognitive and affective function associated with risk for psychopathology and manifest illness.
Special Seminar: Gordon Fishell, PhD
Gordon Fishell, PhD
Julius Raynes Professor of Neuroscience, Associate Director of the NYU Neuroscience Institute
My laboratory is interested in the developmental steps that allow the startling repertoire of interneurons to develop and integrate into the developing nervous system. This process begins with their specification during which genetic programs initiated within progenitors relegate interneurons into specific cardinal classes. Subsequent to this neuronal activity is fundamental for both the laminar positioning, as well as the dendritic and axonal arborization of at least some interneuron subtypes. These results suggest that sensory information complements earlier established genetic programs to shape the way interneuronal subtypes integrate into nascent cortical circuits. The challenge moving forward is to understand how genetically similar interneuron subtypes are able to incorporate into diverse circuitries as different as the inhibitory circuitry that makes up the basal ganglia versus the excitatory circuits that make up the cerebral cortex.