jeff-lichtman

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Brainbow is the process by which individual neurons in the brain can be distinguished from neighboring neurons using fluorescent proteins. By randomly expressing different ratios of red, green, and blue derivatives of green fluorescent protein individual neurons, it is possible to flag each neuron with a distinctive color. 

This process has been a major contribution to the field of connectomics, or the study of neural connections in the brain. The technique was originally developed in the spring of 2007 by a team led by Jeff W. Lichtman and Joshua R. Sanes, both professors of Molecular & Cellular Biology at Harvard University. (Source)

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Meandering memories

When I saw Camillo Gogli’s 1894 drawing of the principal cells of the hippocampus (top), I was immediately struck by how strongly they reminded me of some gorgeous images I’d encountered weeks before. The 1944 maps by Harold N. Fisk (bottom) trace the shifting course of the Mississippi River over time. Their curlicues evoke the winding curves of the hippocampus where memories are made in the brain.

I also find it worthy of notice that Golgi’s 1894 drawing is so similar to a photomicrograph of the hippocampus made in 2005 by Tamily Weissman, Jeff Lichtman, and Joshua Sanes. Those images are 111 years apart. It’s easy to recognize that one is the ancestor of the other.

Turning science on its head

Harvard neuroscientists have made a discovery that turns 160 years of neuroanatomy on its head.

Myelin, the electrical insulating material in the body long known to be essential for the fast transmission of impulses along the axons of nerve cells, is not as ubiquitous as thought, according to new work led by Professor Paola Arlotta of the Harvard Stem Cell Institute (HSCI) and the University’s Department of Stem Cell and Regenerative Biology, in collaboration with Professor Jeff Lichtman of Harvard’s Department of Molecular and Cellular Biology.

“Myelin is a relatively recent invention during evolution,” says Arlotta. “It’s thought that myelin allowed the brain to communicate really fast to the far reaches of the body, and that it has endowed the brain with the capacity to compute higher-level functions.”

In fact, loss of myelin is a feature in a number of devastating diseases, including multiple sclerosis and schizophrenia.

But the new research shows that despite myelin’s essential roles in the brain, “some of the most evolved, most complex neurons of the nervous system have less myelin than older, more ancestral ones,” said Arlotta, co-director of the HSCI neuroscience program.

What this means, she said, is that the higher one looks in the cerebral cortex — closer to the top of the brain, which is its most evolved part — the less myelin one finds.  Not only that, but “neurons in this part of the brain display a brand-new way of positioning myelin along their axons that has not been previously seen. They have ‘intermittent myelin’ with long axon tracts that lack myelin interspersed among myelin-rich segments.”

“Contrary to the common assumptions that neurons use a universal profile of myelin distribution on their axons, the work indicates that different neurons choose to myelinate their axons differently,” Arlotta said. “In classic neurobiology textbooks, myelin is represented on axons as a sequence of myelinated segments separated by very short nodes that lack myelin. This distribution of myelin was tacitly assumed to be always the same, on every neuron, from the beginning to the end of the axon. This new work finds this not to be the case.”

The results of the research by Arlotta and postdoctoral fellow Giulio Srubek Tomassy, the first author on the report, are published in the latest edition of the journal Science.

The paper is accompanied by a “perspective” by R. Douglas Fields of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, who said that Arlotta and Tomassy’s findings raise important questions about the purpose of myelin, and “are likely to spark new concepts about how information is transmitted and integrated in the brain.”

Arlotta and Tomassy collaborated closely on the new work with postdoctoral fellow Daniel Berger of the Lichtman lab, which generated one of the two massive electron microscopy databases that made the work possible.

“The fact that it is the most evolved neurons, the ones that have expanded dramatically in humans, suggest that what we’re seeing might be the ‘future.’ As neuronal diversity increases and the brain needs to process more and more complex information, neurons change the way they use myelin to achieve more,” said Arlotta.

Tomassy said it is possible that these profiles of myelination “may be giving neurons an opportunity to branch out and ‘talk’ to neighboring neurons.” For example, because axons cannot make synaptic contacts when they are myelinated, one possibility is that these long myelin gaps may be needed to increase neuronal communication and synchronize responses across different neurons. He and Arlotta postulate that the intermittent myelin may be intended to fine-tune the electrical impulses traveling along the axons, in order to allow the emergence of highly complex neuronal behaviors.

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Connectomics

Finding Turns Neuroanatomy on Its Head

Harvard researchers present new view of myelin.

Harvard neuroscientists have made a discovery that turns 160 years of neuroanatomy on its head.

Myelin, the electrical insulating material long known to be essential for the fast transmission of impulses along the axons of nerve cells, is not as ubiquitous as thought, according to a new work lead by Professor Paola Arlotta of the Harvard Stem Cell Institute (HSCI) and the University’s Department of Stem Cell and Regenerative Biology, in collaboration with Professor Jeff Lichtman, of Harvard’s Department of Molecular and Cellular Biology.

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Take a trip through the brain

A new imaging tool developed by Boston scientists could do for the brain what the telescope did for space exploration. In the first demonstration of how the technology works, published July 30 in the journal Cell, the researchers look inside the brain of an adult mouse at a scale previously unachievable, generating images at a nanoscale resolution. The inventors’ long-term goal is to make the resource available to the scientific community in the form of a national brain observatory.

“I’m a strong believer in bottom up-science, which is a way of saying that I would prefer to generate a hypothesis from the data and test it,” says senior study author Jeff Lichtman, of Harvard University. “For people who are imagers, being able to see all of these details is wonderful and we’re getting an opportunity to peer into something that has remained somewhat intractable for so long. It’s about time we did this, and it is what people should be doing about things we don’t understand.”

The researchers have begun the process of mining their imaging data by looking first at an area of the brain that receives sensory information from mouse whiskers, which help the animals orient themselves and are even more sensitive than human fingertips. The scientists used a program called VAST, developed by co-author Daniel Berger of Harvard and the Massachusetts Institute of Technology, to assign different colors and piece apart each individual “object” (e.g., neuron, glial cell, blood vessel cell, etc.).

“The complexity of the brain is much more than what we had ever imagined,” says study first author Narayanan “Bobby” Kasthuri, of the Boston University School of Medicine. “We had this clean idea of how there’s a really nice order to how neurons connect with each other, but if you actually look at the material it’s not like that. The connections are so messy that it’s hard to imagine a plan to it, but we checked and there’s clearly a pattern that cannot be explained by randomness.”

The researchers see great potential in the tool’s ability to answer questions about what a neurological disorder actually looks like in the brain, as well as what makes the human brain different from other animals and different between individuals. Who we become is very much a product of the connections our neurons make in response to various life experiences. To be able to compare the physical neuron-to-neuron connections in an infant, a mathematical genius, and someone with schizophrenia would be a leap in our understanding of how our brains shape who we are (or vice versa).

The cost and data storage demands for this type of research are still high, but the researchers expect expenses to drop over time (as has been the case with genome sequencing). To facilitate data sharing, the scientists are now partnering with Argonne National Laboratory with the hopes of creating a national brain laboratory that neuroscientists around the world can access within the next few years.

“It’s bittersweet that there are many scientists who think this is a total waste of time as well as a big investment in money and effort that could be better spent answering questions that are more proximal,” Lichtman says. “As long as data is showing you things that are unexpected, then you’re definitely doing the right thing. And we are certainly far from being out of the surprise element. There’s never a time when we look at this data that we don’t see something that we’ve never seen before.”