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2016 Phillip A. Sharp Lecture in Neural Circuits

Anne Trafton |

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!

Anne Trafton |

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

Anne Trafton |

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

Anne Trafton |

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).

Diagnosing depression before it starts

Anne Trafton |

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

Anne Trafton |

“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

Anne Trafton |

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.

Study finds altered brain chemistry in people with autism

Anne Trafton |

MIT and Harvard University neuroscientists have found a link between a behavioral symptom of autism and reduced activity of a neurotransmitter whose job is to dampen neuron excitation. The findings suggest that drugs that boost the action of this neurotransmitter, known as GABA, may improve some of the symptoms of autism, the researchers say.

Brain activity is controlled by a constant interplay of inhibition and excitation, which is mediated by different neurotransmitters. GABA is one of the most important inhibitory neurotransmitters, and studies of animals with autism-like symptoms have found reduced GABA activity in the brain. However, until now, there has been no direct evidence for such a link in humans.

“This is the first connection in humans between a neurotransmitter in the brain and an autistic behavioral symptom,” says Caroline Robertson, a postdoc at MIT’s McGovern Institute for Brain Research and a junior fellow of the Harvard Society of Fellows. “It’s possible that increasing GABA would help to ameliorate some of the symptoms of autism, but more work needs to be done.”

Robertson is the lead author of the study, which appears in the Dec. 17 online edition of Current Biology. The paper’s senior author is Nancy Kanwisher, the Walter A. Rosenblith Professor of Brain and Cognitive Sciences and a member of the McGovern Institute. Eva-Maria Ratai, an assistant professor of radiology at Massachusetts General Hospital, also contributed to the research.

Too little inhibition

Many symptoms of autism arise from hypersensitivity to sensory input. For example, children with autism are often very sensitive to things that wouldn’t bother other children as much, such as someone talking elsewhere in the room, or a scratchy sweater. Scientists have speculated that reduced brain inhibition might underlie this hypersensitivity by making it harder to tune out distracting sensations.

In this study, the researchers explored a visual task known as binocular rivalry, which requires brain inhibition and has been shown to be more difficult for people with autism. During the task, researchers show each participant two different images, one to each eye. To see the images, the brain must switch back and forth between input from the right and left eyes.

For the participant, it looks as though the two images are fading in and out, as input from each eye takes its turn inhibiting the input coming in from the other eye.

“Everybody has a different rate at which the brain naturally oscillates between these two images, and that rate is thought to map onto the strength of the inhibitory circuitry between these two populations of cells,” Robertson says.

She found that nonautistic adults switched back and forth between the images nine times per minute, on average, and one of the images fully suppressed the other about 70 percent of the time. However, autistic adults switched back and forth only half as often as nonautistic subjects, and one of the images fully suppressed the other only about 50 percent of the time.

Performance on this task was also linked to patients’ scores on a clinical evaluation of communication and social interaction used to diagnose autism: Worse symptoms correlated with weaker inhibition during the visual task.

The researchers then measured GABA activity using a technique known as magnetic resonance spectroscopy, as autistic and typical subjects performed the binocular rivalry task. In nonautistic participants, higher levels of GABA correlated with a better ability to suppress the nondominant image. But in autistic subjects, there was no relationship between performance and GABA levels. This suggests that GABA is present in the brain but is not performing its usual function in autistic individuals, Robertson says.

“GABA is not reduced in the autistic brain, but the action of this inhibitory pathway is reduced,” she says. “The next step is figuring out which part of the pathway is disrupted.”

“This is a really great piece of work,” says Richard Edden, an associate professor of radiology at the Johns Hopkins University School of Medicine. “The role of inhibitory dysfunction in autism is strongly debated, with different camps arguing for elevated and reduced inhibition. This kind of study, which seeks to relate measures of inhibition directly to quantitative measures of function, is what we really to need to tease things out.”

Early diagnosis

In addition to offering a possible new drug target, the new finding may also help researchers develop better diagnostic tools for autism, which is now diagnosed by evaluating children’s social interactions. To that end, Robertson is investigating the possibility of using EEG scans to measure brain responses during the binocular rivalry task.

“If autism does trace back on some level to circuitry differences that affect the visual cortex, you can measure those things in a kid who’s even nonverbal, as long as he can see,” she says. “We’d like it to move toward being useful for early diagnostic screenings.”

Music in the brain

Anne Trafton |

Scientists have long wondered if the human brain contains neural mechanisms specific to music perception. Now, for the first time, MIT neuroscientists have identified a neural population in the human auditory cortex that responds selectively to sounds that people typically categorize as music, but not to speech or other environmental sounds.