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Stanley Center & Poitras Center Translational Neuroscience Joint Seminar: Amy Arnsten, PhD

Anne Trafton |

Stanley Center & Poitras Center Translational Neuroscience Joint Seminar
Speaker: Amy Arnsten, Yale University
December 1, 2015

The newly evolved circuits of the primate dorsolateral prefrontal cortex (dlPFC) generate the mental representations needed for working memory, the foundation of abstract thought. These layer III dlPFC pyramidal cell microcircuits are a focus of pathology in cognitive disorders such as schizophrenia and Alzheimer’s Disease. Research in the Arnsten lab has found that these circuits are uniquely regulated at the molecular level in ways that facilitate mental flexibility but make them particularly vulnerable to atrophy and degeneration. For example, in contrast to the primary visual cortex where calcium-cAMP signaling strengthens connections and increases neuronal firing, increased calcium-cAMP signaling in layer III of dlPFC weakens connections and decreases neuronal firing by opening K+ channels near the synapse. Understanding these unique properties has led to the development of treatments for dlPFC cognitive disorders in humans, e.g. Intuniv™, illustrating the importance of translational research.

MIT, Broad scientists overcome key CRISPR-Cas9 genome editing hurdle

Anne Trafton |

Researchers at the Broad Institute of MIT and Harvard and the McGovern Institute for Brain Research at MIT have engineered changes to the revolutionary CRISPR-Cas9 genome editing system that significantly cut down on “off-target” editing errors. The refined technique addresses one of the major technical issues in the use of genome editing.

The CRISPR-Cas9 system works by making a precisely targeted modification in a cell’s DNA. The protein Cas9 alters the DNA at a location that is specified by a short RNA whose sequence matches that of the target site. While Cas9 is known to be highly efficient at cutting its target site, a major drawback of the system has been that, once inside a cell, it can bind to and cut additional sites that are not targeted. This has the potential to produce undesired edits that can alter gene expression or knock a gene out entirely, which might lead to the development of cancer or other problems. In a paper published today in Science, Feng Zhang and his colleagues report that changing three of the approximately 1,400 amino acids that make up the Cas9 enzyme from S. pyogenes dramatically reduced “off-target editing” to undetectable levels in the specific cases examined.

Zhang and his colleagues used knowledge about the structure of the Cas9 protein to decrease off-target cutting. DNA, which is negatively charged, binds to a groove in the Cas9 protein that is positively charged. Knowing the structure, the scientists were able to predict that replacing some of the positively charged amino acids with neutral ones would decrease the binding of “off target” sequences much more than “on target” sequences.

After experimenting with various possible changes, Zhang’s team found that mutations in three amino acids dramatically reduced “off-target” cuts. For the guide RNAs tested, “off-target” cutting was so low as to be undetectable.

The newly-engineered enzyme, which the team calls “enhanced” S. pyogenes Cas9, or eSpCas9, will be useful for genome editing applications that require a high level of specificity. The Zhang lab is immediately making the eSpCas9 enzyme available for researchers worldwide. The team believes the same charge-changing approach will work with other recently described RNA-guided DNA targeting enzymes, including Cpf1, C2C1, and C2C3, which Zhang and his collaborators reported on earlier this year.

The prospect of rapid and efficient genome editing raises many ethical and societal concerns, says Zhang, who is speaking this morning at the International Summit on Gene Editing in Washington, DC. “Many of the safety concerns are related to off-target effects,” he said. “We hope the development of eSpCas9 will help address some of those concerns, but we certainly don’t see this as a magic bullet. The field is advancing at a rapid pace, and there is still a lot to learn before we can consider applying this technology for clinical use.”

Singing in the brain

Anne Trafton |

Male zebra finches, small songbirds native to central Australia, learn their songs by copying what they hear from their fathers. These songs, often used as mating calls, develop early in life as juvenile birds experiment with mimicking the sounds they hear.

MIT neuroscientists have now uncovered the brain activity that supports this learning process. Sequences of neural activity that encode the birds’ first song syllable are duplicated and altered slightly, allowing the birds to produce several variations on the original syllable. Eventually these syllables are strung together into the bird’s signature song, which remains constant for life.

“The advantage here is that in order to learn new syllables, you don’t have to learn them from scratch. You can reuse what you’ve learned and modify it slightly. We think it’s an efficient way to learn various types of syllables,” says Tatsuo Okubo, a former MIT graduate student and lead author of the study, which appears in the Nov. 30 online edition of Nature.

Okubo and his colleagues believe that this type of neural sequence duplication may also underlie other types of motor learning. For example, the sequence used to swing a tennis racket might be repurposed for a similar motion such as playing Ping-Pong. “This seems like a way that sequences might be learned and reused for anything that involves timing,” says Emily Mackevicius, an MIT graduate student who is also an author of the paper.

The paper’s senior author is Michale Fee, a professor of brain and cognitive sciences at MIT and a member of the McGovern Institute for Brain Research.

Bursting into song

Previous studies from Fee’s lab have found that a part of the brain’s cortex known as the HVC is critical for song production.

Typically, each song lasts for about one second and consists of multiple syllables. Fee’s lab has found that in adult birds, individual HVC neurons show a very brief burst of activity — about 10 milliseconds or less — at one moment during the song. Different sets of neurons are active at different times, and collectively the song is represented by this sequence of bursts.

In the new Nature study, the researchers wanted to figure out how those neural patterns develop in newly hatched zebra finches. To do that, they recorded electrical activity in HVC neurons for up to three months after the birds hatched.

When zebra finches begin to sing, about 30 days after hatching, they produce only nonsense syllables known as subsong, similar to the babble of human babies. At first, the duration of these syllables is highly variable, but after a week or so they turn into more consistent sounds called protosyllables, which last about 100 milliseconds. Each bird learns one protosyllable that forms a scaffold for subsequent syllables.

The researchers found that within the HVC, neurons fire in a sequence of short bursts corresponding to the first protosyllable that each bird learns. Most of the neurons in the HVC participate in this original sequence, but as time goes by, some of these neurons are extracted from the original sequence and produce a new, very similar sequence. This chain of neural sequences can be repurposed to produce different syllables.

“From that short sequence it splits into new sequences for the next new syllables,” Mackevicius says. “It starts with that short chain that has a lot of redundancy in it, and splits off some neurons for syllable A and some neurons for syllable B.”

This splitting of neural sequences happens repeatedly until the birds can produce between three and seven different syllables, the researchers found. This entire process takes about two months, at which point each bird has settled on its final song.

Evolution by duplication

The researchers note that this process is similar to what is believed to drive the production of new genes and traits during evolution.

“If you duplicate a gene, then you could have separate mutations in both copies of the gene and they could eventually do different functions,” Okubo says. “It’s similar with motor programs. You can duplicate the sequence and then independently modify the two daughter motor programs so that they can now each do slightly different things.”

Mackevicius is now studying how input from sound-processing parts of the brain to the HVC contributes to the formation of these neural sequences.

Mother and Child

Anne Trafton |

“The Mother and Child is a powerful symbol of love and innocence, beauty and fertility. Although these maternal values, and the women who embody them, may be venerated, they are usually viewed in opposition to other values: inquiry and intellect, progress and power. But I am a neuroscientist, and I worked to create this image; and I am also the mother in it, curled up inside the tube with my infant son.” — Rebecca Saxe

This image appeared in the 2015 issue of Smithsonian Magazine.

Ed Boyden wins 2016 Breakthrough Prize in Life Sciences

Anne Trafton |

MIT researchers took home several awards last night at the 2016 Breakthrough Prize ceremony at NASA’s Ames Research Center in Mountain View, California.

Edward Boyden, an associate professor of media arts and sciences, biological engineering, and brain and cognitive sciences, was one of five scientists honored with the Breakthrough Prize in Life Sciences, given for “transformative advances toward understanding living systems and extending human life.” He will receive $3 million for the award.

MIT physicists also contributed to a project that won the Breakthrough Prize in Fundamental Physics. That prize went to five experiments investigating the oscillation of subatomic particles known as neutrinos. More than 1,300 contributing physicists will share in the recognition for their work, according to the award announcement. Those physicists include MIT associate professor of physics Joseph Formaggio and his team, as well as MIT assistant professor of physics Lindley Winslow.

Larry Guth, an MIT professor of mathematics, was honored with the New Horizons in Mathematics Prize, which is given to promising junior researchers who have already produced important work in mathematics. Liang Fu, an assistant professor of physics, was honored with the New Horizons in Physics Prize, which is awarded to promising junior researchers who have already produced important work in fundamental physics.

“By challenging conventional thinking and expanding knowledge over the long term, scientists can solve the biggest problems of our time,” said Mark Zuckerberg, chairman and CEO of Facebook, and one of the prizes’ founders. “The Breakthrough Prize honors achievements in science and math so we can encourage more pioneering research and celebrate scientists as the heroes they truly are.”

Optogenetics

Boyden was honored for the development and implementation of optogenetics, a technique in which scientists can control neurons by shining light on them. Karl Deisseroth, a Stanford University professor who worked with Boyden to pioneer the technique, was also honored with one of the life sciences prizes.

Optogenetics relies on light-sensitive proteins, originally isolated from bacteria and algae. About 10 years ago, Boyden and Deisseroth began engineering neurons to express these proteins, allowing them to selectively stimulate or silence them with pulses of light. More recently, Boyden has developed additional proteins that are even more sensitive to light and can respond to different colors.

Scientists around the world have used optogenetics to reveal the brain circuitry underlying normal neural function as well as neurological disorders such as autism, obsessive-compulsive disorder, and depression.

Boyden is a member of the MIT Media Lab and MIT’s McGovern Institute for Brain Research.

Neutrino oscillations

The Breakthrough Prize in Fundamental Physics was awarded to five research projects investigating the nature of neutrinos: Daya Bay (China); KamLAND (Japan); K2K/T2K (Japan); Sudbury Neutrino Observatory (Canada); and Super-Kamiokande (Japan). Researchers with these experiments were recognized “for the fundamental discovery of neutrino oscillations, revealing a new frontier beyond, and possibly far beyond, the standard model of particle physics.”

Formaggio and his team at MIT have been collaborating on the Sudbury Neutrino Observatory (SNO) project since 2005. Research at the observatory, 2 kilometers underground in a mine near Sudbury, Ontario, demonstrated that neutrinos change their type — or “flavor” — on their way to Earth from the sun.

Winslow has been a collaborator on KamLAND, located in a mine in Japan, since 2001. Using antineutrinos from nuclear reactors, this experiment demonstrated that the change in flavor was energy-dependent. The combination of these results solved the solar neutrino puzzle and proved that neutrinos have mass.

The MIT SNO group has participated heavily on the analysis of neutrino data, particularly during that experiment’s final measurement phase. The MIT KamLAND group is involved with the next phase, KamLAND-Zen, which is searching for a rare nuclear process that if observed, would make neutrinos their own antiparticles.

Reaching new horizons

Guth, who will receive a $100,000 prize, was honored for his “ingenious and surprising solutions to long standing open problems in symplectic geometry, Riemannian geometry, harmonic analysis, and combinatorial geometry.”

Guth’s work at MIT focuses on combinatorics, or the study of discrete structures, and how sets of lines intersect each other in space. He also works in the area of harmonic analysis, studying how sound waves interact with each other.

Guth’s father, MIT physicist Alan Guth, won the inaugural Breakthrough Prize in Fundamental Physics in 2015.

Fu will share a New Horizons in Physics Prize with two other researchers: B. Andrei Bernevig of Princeton University and Xiao-Liang Qi of Stanford University. The physicists were honored for their “outstanding contributions to condensed matter physics, especially involving the use of topology to understand new states of matter.”

Fu works on theories of topological insulators — a new class of materials whose surfaces can freely conduct electrons even though their interiors are electrical insulators — and topological superconductors. Such materials may provide insight into quantum physics and have possible applications in creating transistors based on the spin of particles rather than their charge.

Yesterday’s prize ceremony was hosted by producer/actor/director Seth MacFarlane; awards were presented by the prize sponsors and by celebrities including actors Russell Crowe, Hilary Swank, and Lily Collins. The Breakthrough Prizes were founded by Sergey Brin and Anne Wojcicki, Jack Ma and Cathy Zhang, Yuri and Julia Milner, and Mark Zuckerberg and Priscilla Chan.

“Breakthrough Prize laureates are making fundamental discoveries about the universe, life, and the mind,” Yuri Milner said. “These fields of investigation are advancing at an exponential pace, yet the biggest questions remain to be answered.”