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Optogenetics with SOUL

by Sabbi Lall |

Optogenetics has revolutionized neurobiology, allowing researchers to use light to activate or deactivate neurons that are genetically modified to express a light-sensitive channel. This ability to manipulate neuron activity has allowed causal testing of the function of specific neurons, and also has therapeutic potential to reduce symptoms in brain disorders. However, activating neurons deep within a given brain, especially a large primate brain but even a small mouse brain, is challenging and currently requires implanting fibers that could cause damage or inflammation.

McGovern Investigator Guoping Feng and colleagues have now overcome this challenge, developing optogenetic tools that allow non-invasive stimulation of neurons in the deep brain.

“Neuroscientists have dreamed of methods to turn neurons on and off, to understand the function of different neurons, but also to repair brain malfunctions that lead to psychiatric disorders, and optogenetics made this possible” explained Feng, the James W. (1963) and Patricia T. Poitras Professor in Brain and Cognitive Sciences. “We were trying to improve the light sensitivity of optogenetic tools to broaden applications.”

Engineering with light

In order to stimulate neurons with minimal invasiveness, Feng and colleagues engineered a new type of opsin. The original breakthrough optogenetics protocol used channelrhodopsin, a light-sensitive channel discovered in algae. By expressing this channel in neurons, light of the right wavelength can be used to activate the neuron in a dish or in vivo. However, in vivo application requires the implantation of optical fibers to deliver the light close to the specific brain region being stimulated, especially if the target region is in the deep brain. In addition, if the neuron being targeted is in the deep brain, it is hard for light to reach the region in the absence of invasive tools that can damage tissue and impact the behavior of the animal.

Our study creates a method that can activate any mouse brain region, independent of its location, non-invasively.

“Prior to our study, a few studies have contributed in various ways to the development of optogenetic stimulation methods that would be minimally invasive to the brain. However, all of these studies had various limitations in the extent of brain regions they could activate,” said co-senior study author Robert Desimone, director of the McGovern Institute and the Doris and Don Berkey Professor of Neuroscience at MIT.

Probing the brain with SOUL

Feng and colleagues turned instead to new opsins, in particular SOUL, a new type of opsin that is very sensitive to even low-level light. The Feng group engineered this opsin, based on SSFO a second generation optogenetics tool, to have increased light sensitivity, and took advantage of a second property: that SOUL is activated in multiple steps, and once activated, it stays active for longer than other commonly used opsins. This means that a burst of a few seconds of low-level light can cause neurons to stay active for 10-30 minutes.

In order to put SOUL through its paces, the Feng lab expressed this channel in the lateral hypothalamus of the mouse brain. This is a deep region, challenging to reach with light, but with neurons that have clear functions that will lead to changes in behavior. Feng’s group was able to turn on this region non-invasively with light from outside the skull, and cause changes in feeding behavior.

“We were really surprised that SOUL was able to activate one of the deepest areas in the mouse brain, the lateral hypothalamus, which is 6 mm deep,” explains Feng.

But there were more surprises. When the authors activated a region of the primate brain using SOUL, they saw oscillations, waves of synchronized neuronal activity coming together like a choir. Such waves are believed to be important for many brain functions, and this result suggests that the new opsin can manipulate these brain waves, allowing scientists to study their role in the brain.

The authors are planning to move the study in several directions, studying models of brain disorders to identify circuits that may be suitable targets for therapy, as well as moving the methodology so that it can be used beyond the superficial cortex in larger animals. While it is too early to discuss applying the system to humans, the research brings us one step closer to future treatment of neurological disorders.

Family members unite to fight COVID-19

by Sugandha Sharma |

Even before MIT sent out its first official announcement about the COVID-19 crisis, I had already asked permission from my supervisor and taken my computer home so that I could start working from home.

My first and foremost concern was my family and friends. I was born and brought up in India, and then immigrated to Canada, so I have a big and wonderful family spread across both those countries. These countries had a lower number of COVID-19 cases at the time, but I could see what would be coming their way. I was anxious, very anxious. In India, my dad being an anesthetist could be exposed while working in the hospital. In Canada, my uncle who is a physician could be exposed, and on top of that he lives in the same house as my grandparents who are even more vulnerable due to their age. I knew I had to do something.

We started having regular video calls as a family. My mom even led daily online yoga sessions, and the discussions that followed those sessions ensured that we didn’t feel lonely and gave us a sense of purpose. Together, we looked at the statistics in the data from China and Italy, and learned that we needed to flatten the curve due to the lack of medical resources required to meet the need of the hour. We could foresee that more infections would lead to more patients, thus raising the demand for medical resources beyond the amount we had available.

We had several discussions around developing products for helping medical professionals and the general public during this pandemic.

We learned that since no government has enough resources to cope at the time of pandemics, we have to be innovative in trying to make the best use of the limited resources available to us.

Through our discussions and experiences of some of us in the field, we came to the conclusion that the only way to effectively fight COVID-19 is prevention at source. Hence, we started working on a mobile app that uses AI and advanced data analytics to trace contact, determine the risk of infection, and thereby suggest precautions. Luckily we have engineers and computer scientists in our family (my own background is in electrical engineering), so it was easy for us to divide the work.  In our prototype, when people sign-up, they are asked to fill out a short self-assessment form that can be used to identify any symptoms of COVID-19. This data is then used to predict vulnerable areas and to give recommendations to people who might have taken a certain route as shown below.

Sharma’s mobile app showing heatmap of the vulnerable areas in a locality in Toronto, ON (left) and personalized recommendations based on the most recent route taken by an individual (right).

We ended up submitting our proposal and prototype to the COVID-19 challenge launched by Vale (a global mining company) and the winners will be announced in May.

Personally, to be completely honest, I had my times when I broke down due to everything that was going on in the world around me. It’s not easy to see people dying, and losing jobs. My way of staying strong was to make sure that I was doing my best to contribute.

I have set up a beautiful home office for myself and I am focusing on my PhD research, being grateful that I can still continue to do it from home. I have also restarted the joint MIT-Harvard computational neuroscience journal club meetings online, so that members can get access to this wonderful community once again! It was amazing to see from a poll we conducted that 92% of the members of the club wanted the meetings to be re-started online.

These times are unprecedented for my generation, my mom’s generation and even for my grandmother’s generation. I have never seen the world come together in a way I have seen during this pandemic. The kind of response we have seen from our societies and governments across the globe shows that we can make intelligent decisions for the collective good of humanity. For once, we’re all on the same side!

Sugandha (Su) Sharma is a graduate student in the labs of Ila Fiete and Josh Tenenbaum. When she’s not developing a mobile app to fight COVID-19, Su explores the computational and theoretical principles underlying higher level cognition and intelligence in the human brain.

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Saxe Lab examines social impact of COVID-19

by Julie Pryor |

After being forced to relocate from their MIT dorms during the COVID19 crisis, two members of the Saxe lab are now applying their psychology skills to study the impact of mandatory relocation and social isolation on mental health.

“When ‘social distancing’ measures hit MIT, we tried to process how the implementation of these policies would impact the landscape of our social lives,” explains graduate student Heather Kosakowski, who conceived of the study late one evening with undergraduate Michelle Hung.  This landscape is broad, examining the effects of being uprooted and physically relocated from a place, but also changes in social connections, including friendships and even dating life.

MIT undergrad Michelle Hung in the Saxe lab. Photo: Michelle Hung

“I started speculating about how my life and the lives of other MIT students would change,” says Hung. “I was overwhelmed, sad, and scared. But then we realized that we were actually equipped to find the answers to our questions by conducting a study.”

Together, Kosakowski and Hung developed a survey to measure how the social behavior of MIT students, postdocs, and staff is changing over the course of the pandemic. Survey questions were designed to measure loneliness and other aspects of mental health. The survey was sent to members of the MIT community and shared on social media in mid-March, when the pandemic hit the US, and MIT made the unprecedented decision to send students home, shift to online instruction, and dramatically ramp down operations on campus.

More than 500 people responded to the initial survey, ranging in age from 18 to 60, living in cities and countries around the world. Many but not all of those who responded were affiliated with MIT. Kosakowski and Hung are sending follow-up surveys to participants every two weeks and the team plans to collect data for the duration of the pandemic.

“Throwing myself into creating the survey was a way to cope with feeling sad about leaving a community I love,” explains Hung, who flew home to California in March and admits that she struggles with feelings of loneliness now that she’s off campus.

Although it is too soon to form any conclusions about their research, Hung predicts that feelings of loneliness may actually diminish over the course of the pandemic.

“Humans have an impressive ability to adapt to change,” she says. “And I think in this virtual world, people will find novel ways to stay connected that we couldn’t have predicted.”

Whether we find ourselves feeling more or less lonely as this COVID-19 crisis comes to an end, both Kosakowski and Hung agree that it will fundamentally change life as we know it.

The Saxe lab is looking for more survey participants. To learn more about this study or to participate in the survey, click here.

 

Learning from social isolation

by Heather Kosakowski |

“Livia Tomova, a postdoc in the Saxe Lab, recently completed a study about social isolation and its impact on the brain. Michelle Hung and I had a lot of exposure to her research in the lab. When “social distancing” measures hit MIT, we tried to process how the implementation of these policies would impact the landscape of our social lives.

We came up with some hypotheses and agreed that the coronavirus pandemic would fundamentally change life as we know it.

So we developed a survey to measure how the social behavior of MIT students, postdocs, and staff changes over the course of the pandemic. Our study is still in its very early stages, but it has been an incredibly fulfilling experience to be a part of Michelle’s development as a scientist.

Heather Kosakowski’s daughter in Woods Hole, Massachusetts. Photo: Heather Kosakowski

After the undergraduates left, graduate students were also strongly urged to leave graduate student housing. My daughter (age 11) and I live in a 28th-floor apartment and her school was canceled. One of my advisors, Nancy Kanwisher, had a vacant apartment in Woods Hole that she offered to let lab members stay in. As more and more resources for children were being closed or shut down, I decided to take her up on the offer. Wood’s Hole is my daughter’s absolute favorite place and I feel extremely lucky to have such a generous option. My daughter has been coping really well with all of these changes.

While my research is at an exciting stage, I miss being on campus with the students from my cohort and my lab mates and my weekly in-person meetings with my advisors. One way I’ve been coping with this reality is by listening to stories of other people’s experiences. We are all human and we are all in the midst of a pandemic but, we are all experiencing the pandemic in different ways. I find the diversity of our experience intriguing. I have been fortunate to have friends write stories about their experiences, so that I can post them on my blog. I only have a handful of stories right now but, it has been really fun for me to listen, and humbling for me to share each individual’s unique experience.”

Heather Kosakowski is a graduate student in the labs of Rebecca Saxe and Nancy Kanwisher where she studies the infant brain and the developmental origins of object recognition, language, and music. Heather is also a Marine Corps veteran and single mom who manages a blog that “ties together different aspects of my experience, past and present, with the hopes that it might make someone else out there feel less alone.”

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Three from MIT awarded 2020 Guggenheim Fellowships

by Julie Pryor |

MIT faculty members Sabine Iatridou, Jonathan Gruber, and Rebecca Saxe are among 175 scientists, artists, and scholars awarded 2020 fellowships from the John Simon Guggenheim Foundation. Appointed on the basis of prior achievement and exceptional promise, the 2020 Guggenheim Fellows were selected from almost 3,000 applicants.

“It’s exceptionally encouraging to be able to share such positive news at this terribly challenging time” says Edward Hirsch, president of the foundation. “A Guggenheim Fellowship has always offered practical assistance, helping fellows do their work, but for many of the new fellows, it may be a lifeline at a time of hardship, a survival tool as well as a creative one.”

Since 1925, the foundation has granted more the $375 million in fellowships to over 18,000 individuals, including Nobel laureates, Fields medalists, poets laureate, and winners of the Pulitzer Prize, among other internationally recognized honors. This year’s MIT recipients include a linguist, an economist, and a cognitive neuroscientist.

Rebecca Saxe is an associate investigator of the McGovern Institute and the John W. Jarve (1978) Professor in Brain and Cognitive Sciences. She studies human social cognition, using a combination of behavioral testing and brain imaging technologies. She is best known for her work on brain regions specialized for abstract concepts such as “theory of mind” tasks that involve understanding the mental states of other people. She also studies the development of the human brain during early infancy. She obtained her PhD from MIT and was a Harvard University junior fellow before joining the MIT faculty in 2006. Saxe was chosen in 2012 as a Young Global Leader by the World Economic Forum, and she received the 2014 Troland Award from the National Academy of Sciences. Her TED Talk, “How we read each other’s minds” has been viewed over 3 million times.

Jonathan Gruber is the Ford Professor of Economics at MIT, the director of the Health Care Program at the National Bureau of Economic Research, and the former president of the American Society of Health Economists. He has published more than 175 research articles, has edited six research volumes, and is the author of “Public Finance and Public Policy,” a leading undergraduate text; “Health Care Reform,” a graphic novel; and “Jump-Starting America: How Breakthrough Science Can Revive Economic Growth and the American Dream.” In 2006 he received the American Society of Health Economists Inaugural Medal for the best health economist in the nation aged 40 and under. He served as deputy sssistant secretary for economic policy at the U.S. Department of the Treasury. He was a key architect of Massachusetts’ ambitious health reform effort, and became an inaugural member of the Health Connector Board, the main implementing body for that effort. He served as a technical consultant to the Obama administration and worked with both the administration and Congress to help craft the Affordable Care Act. In 2011, he was named “One of the Top 25 Most Innovative and Practical Thinkers of Our Time” by Slate magazine.

Sabine Iatridou is professor of linguistics in MIT’s Department of Linguistics and Philosophy. Her work focuses on syntax and the syntax-semantics interface, as well as comparative linguistics. She is the author and coauthor of a series of innovative papers about tense and modality that opened up whole new domains of research for the field. Since those publications, she has made foundational contributions to many branches of linguistics that connect form with meaning. She is the recipient of the National Young Investigator Award (USA), of an honorary doctorate from the University of Crete in Greece, and of an award from the Royal Dutch Academy of Sciences. She was elected fellow of the Linguistic Society of America. She is co-founder and co-director of the CreteLing Summer School of Linguistics.

“As we grapple with the difficulties of the moment, it is also important to look to the future,” says Hirsch. “The artists, writers, scholars, and scientific researchers supported by the fellowship will help us understand and learn from what we are enduring individually and collectively, and it is an honor for the foundation to help them do their essential work.”

Researchers achieve remote control of hormone release

Anne Trafton |

Abnormal levels of stress hormones such as adrenaline and cortisol are linked to a variety of mental health disorders, including depression and posttraumatic stress disorder (PTSD). MIT researchers have now devised a way to remotely control the release of these hormones from the adrenal gland, using magnetic nanoparticles.

This approach could help scientists to learn more about how hormone release influences mental health, and could eventually offer a new way to treat hormone-linked disorders, the researchers say.

“We’re looking how can we study and eventually treat stress disorders by modulating peripheral organ function, rather than doing something highly invasive in the central nervous system,” says Polina Anikeeva, an MIT professor of materials science and engineering and of brain and cognitive sciences.

To achieve control over hormone release, Dekel Rosenfeld, an MIT-Technion postdoc in Anikeeva’s group, has developed specialized magnetic nanoparticles that can be injected into the adrenal gland. When exposed to a weak magnetic field, the particles heat up slightly, activating heat-responsive channels that trigger hormone release. This technique can be used to stimulate an organ deep in the body with minimal invasiveness.

Anikeeva and Alik Widge, an assistant professor of psychiatry at the University of Minnesota and a former research fellow at MIT’s Picower Institute for Learning and Memory, are the senior authors of the study. Rosenfeld is the lead author of the paper, which appears today in Science Advances.

Controlling hormones

Anikeeva’s lab has previously devised several novel magnetic nanomaterials, including particles that can release drugs at precise times in specific locations in the body.

In the new study, the research team wanted to explore the idea of treating disorders of the brain by manipulating organs that are outside the central nervous system but influence it through hormone release. One well-known example is the hypothalamic-pituitary-adrenal (HPA) axis, which regulates stress response in mammals. Hormones secreted by the adrenal gland, including cortisol and adrenaline, play important roles in depression, stress, and anxiety.

“Some disorders that we consider neurological may be treatable from the periphery, if we can learn to modulate those local circuits rather than going back to the global circuits in the central nervous system,” says Anikeeva, who is a member of MIT’s Research Laboratory of Electronics and McGovern Institute for Brain Research.

As a target to stimulate hormone release, the researchers decided on ion channels that control the flow of calcium into adrenal cells. Those ion channels can be activated by a variety of stimuli, including heat. When calcium flows through the open channels into adrenal cells, the cells begin pumping out hormones. “If we want to modulate the release of those hormones, we need to be able to essentially modulate the influx of calcium into adrenal cells,” Rosenfeld says.

Unlike previous research in Anikeeva’s group, in this study magnetothermal stimulation was applied to modulate the function of cells without artificially introducing any genes.

To stimulate these heat-sensitive channels, which naturally occur in adrenal cells, the researchers designed nanoparticles made of magnetite, a type of iron oxide that forms tiny magnetic crystals about 1/5000 the thickness of a human hair. In rats, they found these particles could be injected directly into the adrenal glands and remain there for at least six months. When the rats were exposed to a weak magnetic field — about 50 millitesla, 100 times weaker than the fields used for magnetic resonance imaging (MRI) — the particles heated up by about 6 degrees Celsius, enough to trigger the calcium channels to open without damaging any surrounding tissue.

The heat-sensitive channel that they targeted, known as TRPV1, is found in many sensory neurons throughout the body, including pain receptors. TRPV1 channels can be activated by capsaicin, the organic compound that gives chili peppers their heat, as well as by temperature. They are found across mammalian species, and belong to a family of many other channels that are also sensitive to heat.

This stimulation triggered a hormone rush — doubling cortisol production and boosting noradrenaline by about 25 percent. That led to a measurable increase in the animals’ heart rates.

Treating stress and pain

The researchers now plan to use this approach to study how hormone release affects PTSD and other disorders, and they say that eventually it could be adapted for treating such disorders. This method would offer a much less invasive alternative to potential treatments that involve implanting a medical device to electrically stimulate hormone release, which is not feasible in organs such as the adrenal glands that are soft and highly vascularized, the researchers say.

Another area where this strategy could hold promise is in the treatment of pain, because heat-sensitive ion channels are often found in pain receptors.

“Being able to modulate pain receptors with this technique potentially will allow us to study pain, control pain, and have some clinical applications in the future, which hopefully may offer an alternative to medications or implants for chronic pain,” Anikeeva says. With further investigation of the existence of TRPV1 in other organs, the technique can potentially be extended to other peripheral organs such as the digestive system and the pancreas.

The research was funded by the U.S. Defense Advance Research Projects Agency ElectRx Program, a Bose Research Grant, the National Institutes of Health BRAIN Initiative, and a MIT-Technion fellowship.

Perspectives from a COVID-19 “essential worker”

by Steve Shannon |

“Overall, a big portion of my job has been to support our fantastic researchers during the rampdown period, so the transition has been tough. We supported the wind-down period and ensured those who did scan before the shutdown, were taking every precaution to keep all researchers and study participants safe.

I was out of the office during the first week of rampdown with an oscillating fever I kept wondering, do I have the coronavirus? I also played the “is it allergies or coronavirus” game. I struggled with my mood and motivation. My son is a nurse at the Montreal Children’s Hospital emergency room so I have also been deeply concerned about his well-being.

“I am one of the few people permitted to enter Building 46 to check on our imaging center equipment – and the experience has been surreal.”

Knowing that the McGovern Institute and MIT is doing so much to assist us with our mental well-being is comforting and very much appreciated.

Now, I am just trying to keep to a regular routine. I am one of the few people permitted to enter Building 46 to do equipment checks. Recently, our original magnet (MRI scanner) had a spontaneous quench, or loss of liquid helium, so I am working with engineers to get current flowing back to the magnet.

I have entered the building three times in two weeks, and each time there has been zero traffic. The parking garage is almost empty and there is parking available on the street – which never happens in Cambridge! When I see someone on the street, we look at each other in disbelief and shock. Our building is clearly in lockdown; all the doors are locked and I rarely see another person.

When this crisis is over, I most look forward to seeing people smile again — or maybe I just look forward to seeing people!

Steve Shannon has been working at the McGovern Institute since 2006, serving as operations manager of the Martinos Imaging Center for more than fourteen years.​

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Finding connections during social isolation

by Halie Olson |

“It’s been really heartening to see the compassion that’s emerged during this situation. People are looking out for each other, and thinking about each other, and checking in with each other.

Usually our social interactions are just built into the day, and now we need to be more deliberate.

The need for human connection has become so apparent these last few weeks as we’ve all been physically distancing. Usually our social interactions are just built into the day, and now we need to be more deliberate.

I’ve started writing a letter to a different person every day – something that I never took the time to do before! Especially as scientists, communication and collaboration are central to what we do. I’ve been amazed at how quickly we’re adapting to this situation and finding ways to keep connecting with each other – whether it’s virtual conferences or Zoom lab meetings or Slack channels. Plus seeing other people’s pets has been a bonus!

Overall I’ve just been really grateful and awed to see people come together, and support each other, and keep things moving forward during a tough time.”

Halie Olson, a graduate student in the labs of John Gabrieli and Rebecca Saxe, studies how early life experiences and environments impact brain development.

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Bridging the gap between clinicians and engineers

by MJ Antonini |

“Two weeks ago I joined the Greater Boston Pandemic Fabrication group (PanFab) which is coordinated by the Harvard MIT Center for Regulatory Science and has close connections with Brigham and Women’s Hospital.

My motivation for joining the PanFab group stemmed from my growing frustration with not being able to help with the current pandemic.

While following the various volunteers’ initiatives that aim to address the shortage of personal protective equipment (PPE), I felt that my training in medical engineering and medical physics in the Harvard-MIT Program in Health Sciences and Technology would be useful for interfacing clinicians at the hospital and engineers and hobbyists designing replacement solutions.

PanFab was established to meet urgent demands for medical supplies and equipment arising from the COVID19 pandemic. We have several initiatives ongoing such as 3d-printed nasopharyngeal swabs, face-shield for healthcare workers, and investigation of multiple PPE sterilization methods.

Personally, I focus on the face-shield project and am leading its production scale-up, and dissemination to local hospitals.

If anyone would like to volunteer their skills with us, send an email to panfabteam@gmail.com, we are always looking for new volunteers!”

McGovern Graduate Fellow MJ Antonini works on the improvement of polymer fibers for neural recording and stimulation in the lab of Polina Anikeeva. 

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Finding balance with physical exercise

by Anna Ivanova |

“I was never good at working out. Every time I was about to go to the gym, I would always come up with an excuse to postpone the workout. Last winter break, however, my sister introduced me to some YouTube fitness classes, and I actually had fun doing them with her. I realized that, to me, working out in my living room was much more enjoyable that dragging my feet to the gym.

Just like in the lab, [my advisor] encourages us to do our very best but is always respectful of our limits.

When COVID hit, I knew I had to do something to keep me in shape, now that I was spending all my days on the couch. I signed up for Wellbeats,  an online class platform that MIT offers [as part of its virtual fitness offerings]. Soon, I was doing their online workouts almost every day. Some of the time, I am joined by my roommates. The workouts provide a great way for us to bond, take a break from work, and relieve some of the stress that tends to build up so quickly these days.

More recently, my advisor Ev Fedorenko has started to lead her own workouts for the lab over Zoom. She carefully walks us through every exercise, showing how to do it correctly. Just like in the lab, she encourages us to do our very best but is always respectful of our limits. So, not only am I the most fit I’ve ever been in my life, but I’ve also been able to connect with my lab in a new and meaningful way.”

Anna Ivanova is a graduate student who studies how the brain processes language in the labs of Evelina Fedorenko and Nancy Kanwisher. She is also an editor and regular contributor to the MIT Grad Blog.

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