Research Area: Cellular & Molecular Neuroscience

​synapses, vesicles, electrophysiology, protein complexes, signaling, small molecules, disease-linked genes, dendrites, cell death, brain disorders, neurodevelopment

Ed Boyden wins premier Royal Society honor

by Sabbi Lall |

Edward S. Boyden, the Y. Eva Tan Professor in Neurotechnology at MIT, has been awarded the 2019 Croonian Medal and Lecture by the Royal Society. Twenty-four medals and awards are announced by the Royal Society each year, honoring exceptional researchers who are making outstanding contributions to science.

“The Royal Society gives an array of medals and awards to scientists who have done exceptional, ground-breaking work,” explained Sir Venki Ramakrishnan, President of the Royal Society. “This year, it is again a pleasure to see these awards bestowed on scientists who have made such distinguished and far-reaching contributions in their fields. I congratulate and thank them for their efforts.”

Boyden wins the medal and lecture in recognition of his research that is expanding our understanding of the brain. This includes his critical role in the development of optogenetics, a technique for controlling brain activity with light, and his invention of expansion microscopy. Croonian Medal laureates include notable luminaries of science and neurobiology.

“It is a great honor to be selected to receive this medal, especially
since it was also given to people such as Santiago Ramon y Cajal, the
founder of modern neuroscience,” says Boyden. “This award reflects the great work of many fantastic students, postdocs, and collaborators who I’ve had the privilege to work with over the years.”

The award includes an invitation to deliver the premier British lecture in the biological sciences, given annually at the Royal Society in London. At the lecture, the winner is awarded a medal and a gift of £10,000. This announcement comes shortly after Boyden was co-awarded the Warren Alpert Prize for his role in developing optogenetics.

History of the Croonian Medal and Lecture

William Croone, pictured, envisioned an annual lecture that is the premier biological sciences medal and lecture at the Royal Society
William Croone, FRS Photo credit: Royal College of Physicians, London

The lectureship was conceived by William Croone FRS, one of the original Fellows of the Society based in London. Among the papers left on his death in 1684 were plans to endow two lectureships, one at the Royal Society and the other at the Royal College of Physicians. His widow later bequeathed the means to carry out the scheme. The lecture series began in 1738.

 

 

Ed Boyden holds the titles of Investigator, McGovern Institute; Y. Eva Tan Professor in Neurotechnology at MIT; Leader, Synthetic Neurobiology Group, MIT Media Lab; Professor, Biological Engineering, Brain and Cognitive Sciences, MIT Media Lab; Co-Director, MIT Center for Neurobiological Engineering; Member, MIT Center for Environmental Health Sciences, Computational and Systems Biology Initiative, and Koch Institute.

Ed Boyden receives 2019 Warren Alpert Prize

by Sabbi Lall |

The 2019 Warren Alpert Foundation Prize has been awarded to four scientists, including Ed Boyden, for pioneering work that launched the field of optogenetics, a technique that uses light-sensitive channels and pumps to control the activity of neurons in the brain with a flick of a switch. He receives the prize alongside Karl Deisseroth, Peter Hegemann, and Gero Miesenböck, as outlined by The Warren Alpert Foundation in their announcement.

Harnessing light and genetics, the approach illuminates and modulates the activity of neurons, enables study of brain function and behavior, and helps reveal activity patterns that can overcome brain diseases.

Boyden’s work was key to envisioning and developing optogenetics, now a core method in neuroscience. The method allows brain circuits linked to complex behavioral processes, such as those involved in decision-making, feeding, and sleep, to be unraveled in genetic models. It is also helping to elucidate the mechanisms underlying neuropsychiatric disorders, and has the potential to inspire new strategies to overcome brain disorders.

“It is truly an honor to be included among the extremely distinguished list of winners of the Alpert Award,” says Boyden, the Y. Eva Tan Professor in Neurotechnology at the McGovern Institute, MIT. “To me personally, it is exciting to see the relatively new field of neurotechnology recognized. The brain implements our thoughts and feelings. It makes us who we are. This mysteries and challenge requires new technologies to make the brain understandable and repairable. It is a great honor that our technology of optogenetics is being thus recognized.”

While they were students, Boyden, and fellow awardee Karl Deisseroth, brainstormed about how microbial opsins could be used to mediate optical control of neural activity. In mid-2004, the pair collaborated to show that microbial opsins can be used to optically control neural activity. Upon launching his lab at MIT, Boyden’s team developed the first optogenetic silencing tool, the first effective optogenetic silencing in live mammals, noninvasive optogenetic silencing, and single-cell optogenetic control.

“The discoveries made by this year’s four honorees have fundamentally changed the landscape of neuroscience,” said George Q. Daley, dean of Harvard Medical School. “Their work has enabled scientists to see, understand and manipulate neurons, providing the foundation for understanding the ultimate enigma—the human brain.”

Beyond optogenetics, Boyden has pioneered transformative technologies that image, record, and manipulate complex systems, including expansion microscopy, robotic patch clamping, and even shrinking objects to the nanoscale. He was elected this year to the ranks of the National Academy of Sciences, and selected as an HHMI Investigator. Boyden has received numerous awards for this work, including the 2018 Gairdner International Prize and the 2016 Breakthrough Prize in Life Sciences.

The Warren Alpert Foundation, in association with Harvard Medical School, honors scientists whose work has improved the understanding, prevention, treatment or cure of human disease. Prize recipients are selected by the foundation’s scientific advisory board, which is composed of distinguished biomedical scientists and chaired by the dean of Harvard Medical School. The honorees will share a $500,000 prize and will be recognized at a daylong symposium on Oct. 3 at Harvard Medical School.

Ed Boyden holds the titles of Investigator, McGovern Institute; Y. Eva Tan Professor in Neurotechnology at MIT; Leader, Synthetic Neurobiology Group, Media Lab; Associate Professor, Biological Engineering, Brain and Cognitive Sciences, Media Lab; Co-Director, MIT Center for Neurobiological Engineering; Member, MIT Center for Environmental Health Sciences, Computational and Systems Biology Initiative, and Koch Institute.

Mark Harnett receives a 2019 McKnight Scholar Award

Anne Trafton |

McGovern Institute investigator Mark Harnett is one of six young researchers selected to receive a prestigious 2019 McKnight Scholar Award. The award supports his research “studying how dendrites, the antenna-like input structures of neurons, contribute to computation in neural networks.”

Harnett examines the biophysical properties of single neurons, ultimately aiming to understand how these relate to the complex computations that underlie behavior. His lab was the first to examine the biophysical properties of human dendrites. The Harnett lab found that human neurons have distinct properties, including increased dendritic compartmentalization that could allow more complex computations within single neurons. His lab recently discovered that such dendritic computations are not rare, or confined to specific behaviors, but are a widespread and general feature of neuronal activity.

“As a young investigator, it is hard to prioritize so many exciting directions and ideas,” explains Harnett. “I really want to thank the McKnight Foundation, both for the support, but also for the hard work the award committee puts into carefully thinking about and giving feedback on proposals. It means a lot to get this type of endorsement from a seriously committed and distinguished committee, and their support gives even stronger impetus to pursue this research direction.”

The McKnight Foundation has supported neuroscience research since 1977, and provides three prominent awards, with the Scholar award aimed at supporting young scientists, and drawing applications from the strongest young neuroscience faculty across the US. William L. McKnight (1887-1979) was an early leader of the 3M Company and had a personal interest in memory and brain diseases. The McKnight Foundation was established with this focus in mind, and the Scholar Award provides $75,000 per year for three years to support cutting edge neuroscience research.

 

A chemical approach to imaging cells from the inside

by Karen Zusi |

A team of researchers at the McGovern Institute and Broad Institute of MIT and Harvard have developed a new technique for mapping cells. The approach, called DNA microscopy, shows how biomolecules such as DNA and RNA are organized in cells and tissues, revealing spatial and molecular information that is not easily accessible through other microscopy methods. DNA microscopy also does not require specialized equipment, enabling large numbers of samples to be processed simultaneously.

“DNA microscopy is an entirely new way of visualizing cells that captures both spatial and genetic information simultaneously from a single specimen,” says first author Joshua Weinstein, a postdoctoral associate at the Broad Institute. “It will allow us to see how genetically unique cells — those comprising the immune system, cancer, or the gut, for instance — interact with one another and give rise to complex multicellular life.”

The new technique is described in Cell. Aviv Regev, core institute member and director of the Klarman Cell Observatory at the Broad Institute and professor of biology at MIT, and Feng Zhang, core institute member of the Broad Institute, investigator at the McGovern Institute for Brain Research at MIT, and the James and Patricia Poitras Professor of Neuroscience at MIT, are co-authors. Regev and Zhang are also Howard Hughes Medical Institute Investigators.

The evolution of biological imaging

In recent decades, researchers have developed tools to collect molecular information from tissue samples, data that cannot be captured by either light or electron microscopes. However, attempts to couple this molecular information with spatial data — to see how it is naturally arranged in a sample — are often machinery-intensive, with limited scalability.

DNA microscopy takes a new approach to combining molecular information with spatial data, using DNA itself as a tool.

To visualize a tissue sample, researchers first add small synthetic DNA tags, which latch on to molecules of genetic material inside cells. The tags are then replicated, diffusing in “clouds” across cells and chemically reacting with each other, further combining and creating more unique DNA labels. The labeled biomolecules are collected, sequenced, and computationally decoded to reconstruct their relative positions and a physical image of the sample.

The interactions between these DNA tags enable researchers to calculate the locations of the different molecules — somewhat analogous to cell phone towers triangulating the locations of different cell phones in their vicinity. Because the process only requires standard lab tools, it is efficient and scalable.

In this study, the authors demonstrate the ability to molecularly map the locations of individual human cancer cells in a sample by tagging RNA molecules. DNA microscopy could be used to map any group of molecules that will interact with the synthetic DNA tags, including cellular genomes, RNA, or proteins with DNA-labeled antibodies, according to the team.

“DNA microscopy gives us microscopic information without a microscope-defined coordinate system,” says Weinstein. “We’ve used DNA in a way that’s mathematically similar to photons in light microscopy. This allows us to visualize biology as cells see it and not as the human eye does. We’re excited to use this tool in expanding our understanding of genetic and molecular complexity.”

Funding for this study was provided by the Simons Foundation, Klarman Cell Observatory, NIH (R01HG009276, 1R01- HG009761, 1R01- MH110049, and 1DP1-HL141201), New York Stem Cell Foundation, Simons Foundation, Paul G. Allen Family Foundation, Vallee Foundation, the Poitras Center for Affective Disorders Research at MIT, the Hock E. Tan and K. Lisa Yang Center for Autism Research at MIT, J. and P. Poitras, and R. Metcalfe. 

The authors have applied for a patent on this technology.

McGovern neuroscientists develop a new model for autism

Anne Trafton |

Using the genome-editing system CRISPR, researchers at MIT and in China have engineered macaque monkeys to express a gene mutation linked to autism and other neurodevelopmental disorders in humans. These monkeys show some behavioral traits and brain connectivity patterns similar to those seen in humans with these conditions.

Mouse studies of autism and other neurodevelopmental disorders have yielded drug candidates that have been tested in clinical trials, but none of them have succeeded. Many pharmaceutical companies have given up on testing such drugs because of the poor track record so far.

The new type of model, however, could help scientists to develop better treatment options for some neurodevelopmental disorders, says Guoping Feng, who is the James W. and Patricia Poitras Professor of Neuroscience, a member of MIT’s McGovern Institute for Brain Research, and one of the senior authors of the study.

“Our goal is to generate a model to help us better understand the neural biological mechanism of autism, and ultimately to discover treatment options that will be much more translatable to humans,” says Feng, who is also an institute member of the Broad Institute of MIT and Harvard and a senior scientist in the Broad’s Stanley Center for Psychiatric Research.

“We urgently need new treatment options for autism spectrum disorder, and treatments developed in mice have so far been disappointing. While the mouse research remains very important, we believe that primate genetic models will help us to develop better medicines and possibly even gene therapies for some severe forms of autism,” says Robert Desimone, the director of MIT’s McGovern Institute for Brain Research, the Doris and Don Berkey Professor of Neuroscience, and an author of the paper.

Huihui Zhou of the Shenzhen Institutes of Advanced Technology, Andy Peng Xiang of Sun Yat-Sen University, and Shihua Yang of South China Agricultural University are also senior authors of the study, which appears in the June 12 online edition of Nature. The paper’s lead authors are former MIT postdoc Yang Zhou, MIT research scientist Jitendra Sharma, Broad Institute group leader Rogier Landman, and Qiong Ke of Sun Yat-Sen University. The research team also includes Mriganka Sur, the Paul and Lilah E. Newton Professor in the Department of Brain and Cognitive Sciences and a member of MIT’s Picower Institute for Learning and Memory.

Gene variants

Scientists have identified hundreds of genetic variants associated with autism spectrum disorder, many of which individually confer only a small degree of risk. In this study, the researchers focused on one gene with a strong association, known as SHANK3. In addition to its link with autism, mutations or deletions of SHANK3 can also cause a related rare disorder called Phelan-McDermid Syndrome, whose most common characteristics include intellectual disability, impaired speech and sleep, and repetitive behaviors. The majority of these individuals are also diagnosed with autism spectrum disorder, as many of the symptoms overlap.

The protein encoded by SHANK3 is found in synapses — the junctions between brain cells that allow them to communicate with each other. It is particularly active in a part of the brain called the striatum, which is involved in motor planning, motivation, and habitual behavior. Feng and his colleagues have previously studied mice with Shank3 mutations and found that they show some of the traits associated with autism, including avoidance of social interaction and obsessive, repetitive behavior.

Although mouse studies can provide a great deal of information on the molecular underpinnings of disease, there are drawbacks to using them to study neurodevelopmental disorders, Feng says. In particular, mice lack the highly developed prefrontal cortex that is the seat of many uniquely primate traits, such as making decisions, sustaining focused attention, and interpreting social cues, which are often affected by brain disorders.

The recent development of the CRISPR genome-editing technique offered a way to engineer gene variants into macaque monkeys, which has previously been very difficult to do. CRISPR consists of a DNA-cutting enzyme called Cas9 and a short RNA sequence that guides the enzyme to a specific area of the genome. It can be used to disrupt genes or to introduce new genetic sequences at a particular location.

Members of the research team based in China, where primate reproductive technology is much more advanced than in the United States, injected the CRISPR components into fertilized macaque eggs, producing embryos that carried the Shank3 mutation.

Researchers at MIT, where much of the data was analyzed, found that the macaques with Shank3 mutations showed behavioral patterns similar to those seen in humans with the mutated gene. They tended to wake up frequently during the night, and they showed repetitive behaviors. They also engaged in fewer social interactions than other macaques.

Magnetic resonance imaging (MRI) scans also revealed similar patterns to humans with autism spectrum disorder. Neurons showed reduced functional connectivity in the striatum as well as the thalamus, which relays sensory and motor signals and is also involved in sleep regulation. Meanwhile, connectivity was strengthened in other regions, including the sensory cortex.

Michael Platt, a professor of neuroscience and psychology at the University of Pennsylvania, says the macaque models should help to overcome some of the limitations of studying neurological disorders in mice, whose behavioral symptoms and underlying neurobiology are often different from those seen in humans.

“Because the macaque model shows a much more complete recapitulation of the human behavioral phenotype, I think we should stand a much greater chance of identifying the degree to which any particular therapy, whether it’s a drug or any other intervention, addresses the core symptoms,” says Platt, who was not involved in the study.

Drug development

Within the next year, the researchers hope to begin testing treatments that may affect autism-related symptoms. They also hope to identify biomarkers, such as the distinctive functional brain connectivity patterns seen in MRI scans, that would help them to evaluate whether drug treatments are having an effect.

A similar approach could also be useful for studying other types of neurological disorders caused by well-characterized genetic mutations, such as Rett Syndrome and Fragile X Syndrome. Fragile X is the most common inherited form of intellectual disability in the world, affecting about 1 in 4,000 males and 1 in 8,000 females. Rett Syndrome, which is more rare and almost exclusively affects girls, produces severe impairments in language and motor skills and can also cause seizures and breathing problems.

“Given the limitations of mouse models, patients really need this kind of advance to bring them hope,” Feng says. “We don’t know whether this will succeed in developing treatments, but we will see in the next few years how this can help us to translate some of the findings from the lab to the clinic.”

The research was funded, in part, by the Shenzhen Overseas Innovation Team Project, the Guangdong Innovative and Entrepreneurial Research Team Program, the National Key R&D Program of China, the External Cooperation Program of the Chinese Academy of Sciences, the Patrick J. McGovern Foundation, the National Natural Science Foundation of China, the Shenzhen Science, Technology Commission, the James and Patricia Poitras Center for Psychiatric Disorders Research at the McGovern Institute at MIT, the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, and the Hock E. Tan and K. Lisa Yang Center for Autism Research at the McGovern Institute at MIT. The research facilities in China where the primate work was conducted are accredited by AAALAC International, a private, nonprofit organization that promotes the humane treatment of animals in science through voluntary accreditation and assessment programs.

McGovern Institute postcard collection

by Julie Pryor |

A collection of 13 postcards arranged in columns.
The McGovern Institute postcard collection, 2023.

The McGovern Institute may be best known for its scientific breakthroughs, but a captivating series of brain-themed postcards developed by McGovern researchers and staff now reveals the institute’s artistic side.

What began in 2017 with a series of brain anatomy postcards inspired by the U.S. Works Projects Administration’s iconic national parks posters, has grown into a collection of twelve different prints, each featuring a unique fusion of neuroscience and art.

More information about each series in the McGovern Institute postcard collection, including the color-your-own mindfulness postcards, can be found below.

Mindfulness Postcard Series, 2023

In winter 2023, the institute released its mindfulness postcard series, a collection of four different neuroscience-themed illustrations that can be colored in with pencils, markers, or paint. The postcard series was inspired by research conducted in John Gabrieli’s lab, which found that practicing mindfulness reduced children’s stress levels and negative emotions during the pandemic. These findings contribute to a growing body of evidence that practicing mindfulness — focusing awareness on the present, typically through meditation, but also through coloring — can change patterns of brain activity associated with emotions and mental health.

Download and color your own postcards.

Genes

The McGovern Institute is at the cutting edge of applications based on CRISPR, a genome editing tool pioneered by McGovern Investigator Feng Zhang. Hidden within this DNA-themed postcard is a clam, virus, bacteriophage, snail, and the word CRISPR. Click the links to learn how these hidden elements relate to genetic engineering research at the McGovern Institute.

 

Line art showing strands of DNA and the McGovern Institute logo.
The McGovern Institute’s “mindfulness” postcard series includes this DNA-themed illustration containing five hidden design elements related to McGovern research. Image: Joseph Laney

Neurons

McGovern researchers probe the nanoscale and cellular processes that are critical to brain function, including the complex computations conducted in neurons, to the synapses and neurotransmitters that facilitate messaging between cells. Find the mouse, worm, and microscope — three critical elements related to cellular and molecular neuroscience research at the McGovern Institute — in the postcard below.

 

Line art showing multiple neurons and the McGovern Institute logo.
The McGovern Institute’s “mindfulness” postcard series includes this neuron-themed illustration containing three hidden design elements related to McGovern research. Image: Joseph Laney

Human Brain

Cognitive neuroscientists at the McGovern Institute examine the brain processes that come together to inform our thoughts and understanding of the world.​ Find the musical note, speech bubbles, and human face in this postcard and click on the links to learn more about how these hidden elements relate to brain research at the McGovern Institute.

 

Line art of a human brain and the McGovern Institute logo.
The McGovern Institute’s “mindfulness” postcard series includes this brain-themed illustration containing three hidden design elements related to McGovern research. Image: Joseph Laney

Artificial Intelligence

McGovern researchers develop machine learning systems that mimic human processing of visual and auditory cues and construct algorithms to help us understand the complex computations made by the brain. Find the speech bubbles, DNA, and cochlea (spiral) in this postcard and click on the links to learn more about how these hidden elements relate to computational neuroscience research at the McGovern Institute.

Line art showing an artificial neural network in the shape of the human brain and the McGovern Institute logo.
The McGovern Institute’s “mindfulness” postcard series includes this AI-themed illustration containing three hidden design elements related to McGovern research. Image: Joseph Laney

Neuron Postcard Series, 2019

In 2019, the McGovern Institute released a second series of postcards based on the anatomy of a neuron. Each postcard includes text on the back side that describes McGovern research related to that specific part of the neuron. The descriptive text for each postcard is shown beloSynapse

Synapse

Snow melting off the branch of a bush at the water's edge creates a ripple effect in the pool of water below. Words at the bottom of the image say "It All Begins at the SYNAPSE"Signals flow through the nervous system from one neuron to the next across synapses.

Synapses are exquisitely organized molecular machines that control the transmission of information.

McGovern researchers are studying how disruptions in synapse function can lead to brain disorders like autism.

Image: Joseph Laney

Axon

Illustration of three bears hunting for fish in a flowing river with the words: "Axon: Where Action Finds Potential"The axon is the long, thin neural cable that carries electrical impulses called action potentials from the soma to synaptic terminals at downstream neurons.

Researchers at the McGovern Institute are developing and using tracers that label axons to reveal the elaborate circuit architecture of the brain.

Image: Joseph Laney

Soma

An elk stands on a rocky outcropping overlooking a large lake with an island in the center. Words at the top read: "Collect Your Thoughts at the Soma"The soma, or cell body, is the control center of the neuron, where the nucleus is located.

It connects the dendrites to the axon, which sends information to other neurons.

At the McGovern Institute, neuroscientists are targeting the soma with proteins that can activate single neurons and map connections in the brain.

Image: Joseph Laney

Dendrites

A mountain lake at sunset with colorful fish and snow from a distant mountaintop melting into the lake. Words say "DENDRITIC ARBOR"Long branching neuronal processes called dendrites receive synaptic inputs from thousands of other neurons and carry those signals to the cell body.

McGovern neuroscientists have discovered that human dendrites have different electrical properties from those of other species, which may contribute to the enhanced computing power of the human brain.

Image: Joseph Laney

Brain Anatomy Postcard Series, 2017

The original brain anatomy-themed postcard series, developed in 2017, was inspired by the U.S. Works Projects Administration’s iconic national parks posters created in the 1930s and 1940s. Each postcard includes text on the back side that describes McGovern research related to that specific part of the neuron. The descriptive text for each postcard is shown below.

Sylvian Fissure

Illustration of explorer in cave labeled with temporal and parietal letters
The Sylvian fissure is a prominent groove on the right side of the brain that separates the frontal and parietal lobes from the temporal lobe. McGovern researchers are studying a region near the right Sylvian fissure, called the rTPJ, which is involved in thinking about what another person is thinking.

Hippocampus

The hippocampus, named after its resemblance to the seahorse, plays an important role in memory. McGovern researchers are studying how changes in the strength of synapses (connections between neurons) in the hippocampus contribute to the formation and retention of memories.

Basal Ganglia

The basal ganglia are a group of deep brain structures best known for their control of movement. McGovern researchers are studying how the connections between the cerebral cortex and a part of the basal ganglia known as the striatum play a role in emotional decision making and motivation.

 

 

 

The arcuate fasciculus is a bundle of axons in the brain that connects Broca’s area, involved in speech production, and Wernicke’s area, involved in understanding language. McGovern researchers have found a correlation between the size of this structure and the risk of dyslexia in children.

 

 

Order and Share

To order your own McGovern brain postcards, contact our colleagues at the MIT Museum, where proceeds will support current and future exhibitions at the growing museum.

Please share a photo of yourself in your own lab (or natural habitat) with one of our cards on social media. Tell us what you’re studying and don’t forget to tag us @mcgovernmit using the hashtag #McGovernPostcards.

Antenna-like inputs unexpectedly active in neural computation

Anne Trafton |

Most neurons have many branching extensions called dendrites that receive input from thousands of other neurons. Dendrites aren’t just passive information-carriers, however. According to a new study from MIT, they appear to play a surprisingly large role in neurons’ ability to translate incoming signals into electrical activity.

Neuroscientists had previously suspected that dendrites might be active only rarely, under specific circumstances, but the MIT team found that dendrites are nearly always active when the main cell body of the neuron is active.

“It seems like dendritic spikes are an intrinsic feature of how neurons in our brain can compute information. They’re not a rare event,” says Lou Beaulieu-Laroche, an MIT graduate student and the lead author of the study. “All the neurons that we looked at had these dendritic spikes, and they had dendritic spikes very frequently.”

The findings suggest that the role of dendrites in the brain’s computational ability is much larger than had previously been thought, says Mark Harnett, who is the Fred and Carole Middleton Career Development Assistant Professor of Brain and Cognitive Sciences, a member of the McGovern Institute for Brain Research, and the senior author of the paper.

“It’s really quite different than how the field had been thinking about this,” he says. “This is evidence that dendrites are actively engaged in producing and shaping the outputs of neurons.”

Graduate student Enrique Toloza and technical associate Norma Brown are also authors of the paper, which appears in Neuron on June 6.

“A far-flung antenna”

Dendrites receive input from many other neurons and carry those signals to the cell body, also called the soma. If stimulated enough, a neuron fires an action potential — an electrical impulse that spreads to other neurons. Large networks of these neurons communicate with each other to perform complex cognitive tasks such as producing speech.

Through imaging and electrical recording, neuroscientists have learned a great deal about the anatomical and functional differences between different types of neurons in the brain’s cortex, but little is known about how they incorporate dendritic inputs and decide whether to fire an action potential. Dendrites give neurons their characteristic branching tree shape, and the size of the “dendritic arbor” far exceeds the size of the soma.

“It’s an enormous, far-flung antenna that’s listening to thousands of synaptic inputs distributed in space along that branching structure from all the other neurons in the network,” Harnett says.

Some neuroscientists have hypothesized that dendrites are active only rarely, while others thought it possible that dendrites play a more central role in neurons’ overall activity. Until now, it has been difficult to test which of these ideas is more accurate, Harnett says.

To explore dendrites’ role in neural computation, the MIT team used calcium imaging to simultaneously measure activity in both the soma and dendrites of individual neurons in the visual cortex of the brain. Calcium flows into neurons when they are electrically active, so this measurement allowed the researchers to compare the activity of dendrites and soma of the same neuron. The imaging was done while mice performed simple tasks such as running on a treadmill or watching a movie.

Unexpectedly, the researchers found that activity in the soma was highly correlated with dendrite activity. That is, when the soma of a particular neuron was active, the dendrites of that neuron were also active most of the time. This was particularly surprising because the animals weren’t performing any kind of cognitively demanding task, Harnett says.

“They weren’t engaged in a task where they had to really perform and call upon cognitive processes or memory. This is pretty simple, low-level processing, and already we have evidence for active dendritic processing in almost all the neurons,” he says. “We were really surprised to see that.”

Evolving patterns

The researchers don’t yet know precisely how dendritic input contributes to neurons’ overall activity, or what exactly the neurons they studied are doing.

“We know that some of those neurons respond to some visual stimuli, but we don’t necessarily know what those individual neurons are representing. All we can say is that whatever the neuron is representing, the dendrites are actively participating in that,” Beaulieu-Laroche says.

While more work remains to determine exactly how the activity in the dendrites and the soma are linked, “it is these tour-de-force in vivo measurements that are critical for explicitly testing hypotheses regarding electrical signaling in neurons,” says Marla Feller, a professor of neurobiology at the University of California at Berkeley, who was not involved in the research.

The MIT team now plans to investigate how dendritic activity contributes to overall neuronal function by manipulating dendrite activity and then measuring how it affects the activity of the cell body, Harnett says. They also plan to study whether the activity patterns they observed evolve as animals learn a new task.

“One hypothesis is that dendritic activity will actually sharpen up for representing features of a task you taught the animals, and all the other dendritic activity, and all the other somatic activity, is going to get dampened down in the rest of the cortical cells that are not involved,” Harnett says.

The research was funded by the Natural Sciences and Engineering Research Council of Canada and the U.S. National Institutes of Health.

Ed Boyden elected to National Academy of Sciences

by Sabbi Lall |

Ed Boyden has been elected to join the National Academy of Sciences (NAS). The organization, established by an act of Congress during the height of the Civil War, was founded to provide independent and objective advice on scientific matters to the nation, and is actively engaged in furthering science in the United States. Each year NAS members recognize fellow scientists through election to the academy based on their distinguished and continuing achievements in original research.

“I’m very honored and grateful to have been elected to the NAS,” says Boyden. “This is a testament to the work of many graduate students, postdoctoral scholars, research scientists, and staff at MIT who have worked with me over the years, and many collaborators and friends at MIT and around the world who have helped our group on this mission to advance neuroscience through new tools and ways of thinking.”

Boyden’s research creates and applies technologies that aim to expand our understanding of the brain. He notably co-invented optogenetics as an independent side collaboration, conducted in parallel to his PhD studies, a game-changing technology that has revolutionized neurobiology. This technology uses targeted expression of light-sensitive channels and pumps to activate or suppress neuronal activity in vivo using light. Optogenetics quickly swept the field of neurobiology and has been leveraged to understand how specific neurons and brain regions contribute to behavior and to disease.

His research since has an overarching focus on understanding the brain. To this end, he and his lab have the ambitious goal of developing technologies that can map, record, and manipulate the brain. This has led, as selected examples, to the invention of expansion microscopy, a super-resolution imaging technology that can capture neuron’s microstructures and reveal their complex connections, even across large-scale neural circuits; voltage-sensitive fluorescent reporters that allow neural activity to be monitored in vivo; and temporal interference stimulation, a non-invasive brain stimulation technique that allows selective activation of subcortical brain regions.

“We are all incredibly happy to see Ed being elected to the academy,” says Robert Desimone, director of the McGovern Institute for Brain Research at MIT. “He has been consistently innovative, inventing new ways of manipulating and observing neurons that are revolutionizing the field of neuroscience.”

This year the NAS, an organization that includes over 500 Nobel Laureates, elected 100 new members and 25 foreign associates. Three MIT professors were elected this year, with Paula T. Hammond (David H. Koch (1962) Professor of Engineering and Department Head, Chemical Engineering) and Aviv Regev (HHMI Investigator and Professor in the Department of Biology) being elected alongside Boyden. Boyden becomes the seventh member of the McGovern Institute faculty to join the National Academy of Sciences.

The formal induction ceremony for new NAS members, during which they sign the ledger whose first signatory is Abraham Lincoln, will be held at the Academy’s annual meeting in Washington D.C. next spring.

 

 

 

 

 

 

 

 

Alumnus gives MIT $4.5 million to study effects of cannabis on the brain

by MIT School of Science |

The following news is adapted from a press release issued in conjunction with Harvard Medical School.

Charles R. Broderick, an alumnus of MIT and Harvard University, has made gifts to both alma maters to support fundamental research into the effects of cannabis on the brain and behavior.

The gifts, totaling $9 million, represent the largest donation to date to support independent research on the science of cannabinoids. The donation will allow experts in the fields of neuroscience and biomedicine at MIT and Harvard Medical School to conduct research that may ultimately help unravel the biology of cannabinoids, illuminate their effects on the human brain, catalyze treatments, and inform evidence-based clinical guidelines, societal policies, and regulation of cannabis.

Lagging behind legislation

With the increasing use of cannabis both for medicinal and recreational purposes, there is a growing concern about critical gaps in knowledge.

In 2017, the National Academies of Sciences, Engineering, and Medicine issued a report calling upon philanthropic organizations, private companies, public agencies and others to develop a “comprehensive evidence base” on the short- and long-term health effects — both beneficial and harmful — of cannabis use.

“Our desire is to fill the research void that currently exists in the science of cannabis,” says Broderick, who was an early investor in Canada’s medical marijuana market.

Broderick is the founder of Uji Capital LLC, a family office focused on quantitative opportunities in global equity capital markets. Identifying the growth of the Canadian legal cannabis market as a strategic investment opportunity, Broderick took equity positions in Tweed Marijuana Inc. and Aphria Inc., which have since grown into two of North America’s most successful cannabis companies. Subsequently, Broderick made a private investment in and served as a board member for Tokyo Smoke, a cannabis brand portfolio, which merged in 2017 to create Hiku Brands, where he served as chairman. Hiku Brands was acquired by Canopy Growth Corp. in 2018.

Through the Broderick gifts to Harvard Medical School and MIT’s School of Science through the Picower Institute for Learning and Memory and the McGovern Institute for Brain Research, the Broderick funds will support independent studies of the neurobiology of cannabis; its effects on brain development, various organ systems and overall health, including treatment and therapeutic contexts; and cognitive, behavioral and social ramifications.

“I want to destigmatize the conversation around cannabis — and, in part, that means providing facts to the medical community, as well as the general public,” says Broderick, who argues that independent research needs to form the basis for policy discussions, regardless of whether it is good for business. “Then we’re all working from the same information. We need to replace rhetoric with research.”

MIT: Focused on brain health and function

The gift to MIT from Broderick will provide $4.5 million over three years to support independent research for four scientists at the McGovern and Picower institutes.

Two of these researchers — John Gabrieli, the Grover Hermann Professor of Health Sciences and Technology, a professor of brain and cognitive sciences, and a member of MIT’s McGovern Institute for Brain Research; and Myriam Heiman, the Latham Family Associate Professor of Neuroscience at the Picower Institute — will separately explore the relationship between cannabis and schizophrenia.

Gabrieli, who directs the Martinos Imaging Center at MIT, will monitor any potential therapeutic value of cannabis for adults with schizophrenia using fMRI scans and behavioral studies.

“The ultimate goal is to improve brain health and wellbeing,” says Gabrieli. “And we have to make informed decisions on the way to this goal, wherever the science leads us. We need more data.”

Heiman, who is a molecular neuroscientist, will study how chronic exposure to phytocannabinoid molecules THC and CBD may alter the developmental molecular trajectories of cell types implicated in schizophrenia.

“Our lab’s research may provide insight into why several emerging lines of evidence suggest that adolescent cannabis use can be associated with adverse outcomes not seen in adults,” says Heiman.

In addition to these studies, Gabrieli also hopes to investigate whether cannabis can have therapeutic value for autism spectrum disorders, and Heiman plans to look at whether cannabis can have therapeutic value for Huntington’s disease.

MIT Institute Professor Ann Graybiel has proposed to study the cannabinoid 1 (CB1) receptor, which mediates many of the effects of cannabinoids. Her team recently found that CB1 receptors are tightly linked to dopamine — a neurotransmitter that affects both mood and motivation. Graybiel, who is also a member of the McGovern Institute, will examine how CB1 receptors in the striatum, a deep brain structure implicated in learning and habit formation, may influence dopamine release in the brain. These findings will be important for understanding the effects of cannabis on casual users, as well as its relationship to addictive states and neuropsychiatric disorders.

Earl Miller, Picower Professor of Neuroscience at the Picower Institute, will study effects of cannabinoids on both attention and working memory. His lab has recently formulated a model of working memory and unlocked how anesthetics reduce consciousness, showing in both cases a key role in the brain’s frontal cortex for brain rhythms, or the synchronous firing of neurons. He will observe how these rhythms may be affected by cannabis use — findings that may be able to shed light on tasks like driving where maintenance of attention is especially crucial.

Harvard Medical School: Mobilizing basic scientists and clinicians to solve an acute biomedical challenge 

The Broderick gift provides $4.5 million to establish the Charles R. Broderick Phytocannabinoid Research Initiative at Harvard Medical School, funding basic, translational and clinical research across the HMS community to generate fundamental insights about the effects of cannabinoids on brain function, various organ systems, and overall health.

The research initiative will span basic science and clinical disciplines, ranging from neurobiology and immunology to psychiatry and neurology, taking advantage of the combined expertise of some 30 basic scientists and clinicians across the school and its affiliated hospitals.

The epicenter of these research efforts will be the Department of Neurobiology under the leadership of Bruce Bean and Wade Regehr.

“I am excited by Bob’s commitment to cannabinoid science,” says Regehr, professor of neurobiology in the Blavatnik Institute at Harvard Medical School. “The research efforts enabled by Bob’s vision set the stage for unraveling some of the most confounding mysteries of cannabinoids and their effects on the brain and various organ systems.”

Bean, Regehr, and fellow neurobiologists Rachel Wilson and Bernardo Sabatini, for example, focus on understanding the basic biology of the cannabinoid system, which includes hundreds of plant and synthetic compounds as well as naturally occurring cannabinoids made in the brain.

Cannabinoid compounds activate a variety of brain receptors, and the downstream biological effects of this activation are astoundingly complex, varying by age and sex, and complicated by a person’s physiologic condition and overall health. This complexity and high degree of variability in individual biology has hampered scientific understanding of the positive and negative effects of cannabis on the human body. Bean, Regehr, and colleagues have already made critical insights showing how cannabinoids influence cell-to-cell communication in the brain.

“Even though cannabis products are now widely available, and some used clinically, we still understand remarkably little about how they influence brain function and neuronal circuits in the brain,” says Bean, the Robert Winthrop Professor of Neurobiology in the Blavatnik Institute at HMS. “This gift will allow us to conduct critical research into the neurobiology of cannabinoids, which may ultimately inform new approaches for the treatment of pain, epilepsy, sleep and mood disorders, and more.”

To propel research findings from lab to clinic, basic scientists from HMS will partner with clinicians from Harvard-affiliated hospitals, bringing together clinicians and scientists from disciplines including cardiology, vascular medicine, neurology, and immunology in an effort to glean a deeper and more nuanced understanding of cannabinoids’ effects on various organ systems and the body as a whole, rather than just on isolated organs.

For example, Bean and colleague Gary Yellen, who are studying the mechanisms of action of antiepileptic drugs, have become interested in the effects of cannabinoids on epilepsy, an interest they share with Elizabeth Thiele, director of the pediatric epilepsy program at Massachusetts General Hospital. Thiele is a pioneer in the use of cannabidiol for the treatment of drug-resistant forms of epilepsy. Despite proven clinical efficacy and recent FDA approval for rare childhood epilepsies, researchers still do not know exactly how cannabidiol quiets the misfiring brain cells of patients with the seizure disorder. Understanding its mechanism of action could help in developing new agents for treating other forms of epilepsy and other neurologic disorders.

Neuroscientists reverse some behavioral symptoms of Williams Syndrome

by Anne Trafton |

Williams Syndrome, a rare neurodevelopmental disorder that affects about 1 in 10,000 babies born in the United States, produces a range of symptoms including cognitive impairments, cardiovascular problems, and extreme friendliness, or hypersociability.

In a study of mice, MIT neuroscientists have garnered new insight into the molecular mechanisms that underlie this hypersociability. They found that loss of one of the genes linked to Williams Syndrome leads to a thinning of the fatty layer that insulates neurons and helps them conduct electrical signals in the brain.

The researchers also showed that they could reverse the symptoms by boosting production of this coating, known as myelin. This is significant, because while Williams Syndrome is rare, many other neurodevelopmental disorders and neurological conditions have been linked to myelination deficits, says Guoping Feng, the James W. and Patricia Poitras Professor of Neuroscience and a member of MIT’s McGovern Institute for Brain Research.

“The importance is not only for Williams Syndrome,” says Feng, who is one of the senior authors of the study. “In other neurodevelopmental disorders, especially in some of the autism spectrum disorders, this could be potentially a new direction to look into, not only the pathology but also potential treatments.”

Zhigang He, a professor of neurology and ophthalmology at Harvard Medical School, is also a senior author of the paper, which appears in the April 22 issue of Nature Neuroscience. Former MIT postdoc Boaz Barak, currently a principal investigator at Tel Aviv University in Israel, is the lead author and a senior author of the paper.

Impaired myelination

Williams Syndrome, which is caused by the loss of one of the two copies of a segment of chromosome 7, can produce learning impairments, especially for tasks that require visual and motor skills, such as solving a jigsaw puzzle. Some people with the disorder also exhibit poor concentration and hyperactivity, and they are more likely to experience phobias.

In this study, the researchers decided to focus on one of the 25 genes in that segment, known as Gtf2i. Based on studies of patients with a smaller subset of the genes deleted, scientists have linked the Gtf2i gene to the hypersociability seen in Williams Syndrome.

Working with a mouse model, the researchers devised a way to knock out the gene specifically from excitatory neurons in the forebrain, which includes the cortex, the hippocampus, and the amygdala (a region important for processing emotions). They found that these mice did show increased levels of social behavior, measured by how much time they spent interacting with other mice. The mice also showed deficits in fine motor skills and increased nonsocial related anxiety, which are also symptoms of Williams Syndrome.

Next, the researchers sequenced the messenger RNA from the cortex of the mice to see which genes were affected by loss of Gtf2i. Gtf2i encodes a transcription factor, so it controls the expression of many other genes. The researchers found that about 70 percent of the genes with significantly reduced expression levels were involved in the process of myelination.

“Myelin is the insulation layer that wraps the axons that extend from the cell bodies of neurons,” Barak says. “When they don’t have the right properties, it will lead to faster or slower electrical signal transduction, which affects the synchronicity of brain activity.”

Further studies revealed that the mice had only about half the normal number of mature oligodendrocytes — the brain cells that produce myelin. However, the number of oligodendrocyte precursor cells was normal, so the researchers suspect that the maturation and differentiation processes of these cells are somehow impaired when Gtf2i is missing in the neurons.

This was surprising because Gtf2i was not knocked out in oligodendrocytes or their precursors. Thus, knocking out the gene in neurons may somehow influence the maturation process of oligodendrocytes, the researchers suggest. It is still unknown how this interaction might work.

“That’s a question we are interested in, but we don’t know whether it’s a secreted factor, or another kind of signal or activity,” Feng says.

In addition, the researchers found that the myelin surrounding axons of the forebrain was significantly thinner than in normal mice. Furthermore, electrical signals were smaller, and took more time to cross the brain in mice with Gtf2i missing.

The study is an example of pioneering research into the contribution of glial cells, which include oligodendrocytes, to neuropsychiatric disorders, says Doug Fields, chief of the nervous system development and plasticity section of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

“Traditionally myelin was only considered in the context of diseases that destroy myelin, such as multiple sclerosis, which prevents transmission of neural impulses. More recently it has become apparent that more subtle defects in myelin can impair neural circuit function, by causing delays in communication between neurons,” says Fields, who was not involved in the research.

Symptom reversal

It remains to be discovered precisely how this reduction in myelination leads to hypersociability. The researchers suspect that the lack of myelin affects brain circuits that normally inhibit social behaviors, making the mice more eager to interact with others.

“That’s probably the explanation, but exactly which circuits and how does it work, we still don’t know,” Feng says.

The researchers also found that they could reverse the symptoms by treating the mice with drugs that improve myelination. One of these drugs, an FDA-approved antihistamine called clemastine fumarate, is now in clinical trials to treat multiple sclerosis, which affects myelination of neurons in the brain and spinal cord. The researchers believe it would be worthwhile to test these drugs in Williams Syndrome patients because they found thinner myelin and reduced numbers of mature oligodendrocytes in brain samples from human subjects who had Williams Syndrome, compared to typical human brain samples.

“Mice are not humans, but the pathology is similar in this case, which means this could be translatable,” Feng says. “It could be that in these patients, if you improve their myelination early on, it could at least improve some of the conditions. That’s our hope.”

Such drugs would likely help mainly the social and fine-motor issues caused by Williams Syndrome, not the symptoms that are produced by deletion of other genes, the researchers say. They may also help treat other disorders, such as autism spectrum disorders, in which myelination is impaired in some cases, Feng says.

“We think this can be expanded into autism and other neurodevelopmental disorders. For these conditions, improved myelination may be a major factor in treatment,” he says. “We are now checking other animal models of neurodevelopmental disorders to see whether they have myelination defects, and whether improved myelination can improve some of the pathology of the defects.”

The research was funded by the Simons Foundation, the Poitras Center for Affective Disorders Research at MIT, the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, and the Simons Center for the Social Brain at MIT.