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Neuroscience

Exploring the inner workings of the healthy brain

Max Planck researchers share insights into normal brain function, which is the foundation to ultimately cure diseased brains

Scientists working under the aegis of the Max Planck Society are in an enviable position. With a budget of more than €1.5 billion to fund more than 80 institutes, the Society gives its researchers freedom to explore the basic science area of their choice without the expectation of a "micro-economic return on investment," said Dr. Peter Gruss, president of the Munich, Germany-based research organization. "No one tells us what research we should do. We have no programs. We hire the best people, and they are free to do autonomous, creative work in structural units we call Max Planck Institutes."

That said, it's not always easy to convey the importance and relevance of basic research to the general public or, indeed, to other scientists. "We need to communicate better," Dr. Gruss acknowledged — and to this end, scientists from both the Max Planck Florida Institute for Neuroscience (MPFI)  in Jupiter, Florida, and two Max Planck Institutes (MPI) in Germany presented seven-minute snapshots of their work to members of the Science Writers of New York.

[caption align="alignnone"]Max Planck researchers from Germany and Florida gave science writers a glimpse of work that is transforming our understanding of the brain. Left to right: Tobias Bonhoeffer, PhD; David Fitzpatrick, PhD; Nils Brose, PhD; Ryohei Yasuda, PhD; Moritz Helmstaedter, PhD; Bert Sakmann, MD; Ron Winslow, Wall Street Journal — moderator. (Photos by Daphne Youree Photography)Max Planck researchers from Germany and Florida gave science writers a glimpse of work that is transforming our understanding of the brain. Left to right: Tobias Bonhoeffer, PhD; David Fitzpatrick, PhD; Nils Brose, PhD; Ryohei Yasuda, PhD; Moritz Helmstaedter, PhD; Bert Sakmann, MD; Ron Winslow, Wall Street Journal — moderator. (Photos by Daphne Youree Photography)[/caption]

Bert Sakmann, PhDThe event, "Understanding the Brain: New Technologies for Exploring Brain Structure, Function, and Development," was held at The Pierre Hotel in New York City in September. It explored three different topic areas, each addressed by one Max Planck scientist working in Florida and one working in Germany.

[pullquote align="right"]If you want to understand the diseased brain, you first have to understand the healthy brain — and we are far away from understanding how a healthy brain functions.[/pullquote]"If you want to understand the diseased brain, you first have to understand the healthy brain — and we are far away from understanding how a healthy brain, even a simple mouse brain, functions," said Dr. Bert Sakmann, a Nobel laureate and inaugural director at MPFI. "That is why we have to stick to clarifying the basics."

Although Dr. Sakmann and the other presenters reinforced Max Planck's famous quote, "insight must precede application"— emphasizing the value of pursuing "cutting-edge, strictly curiosity-driven" research in lieu of focusing primarily on clinical implications — they managed to make complex basic science come alive, and at times speculated on the potential connections between their work in animals and what it might mean for humans.

Mapping brain circuits to understand how we make decisions – and a new crowdsourced game

Dr. Sakmann, who discussed his efforts to reconstruct the brain circuits underlying decision making, observed that each person makes about 1,000 decisions a day, most of which depend on input from an external stimulus, like a sound or touch. "To understand decision making, the first thing to understand is how an external stimulus that triggers a decision is represented in the brain," he said. To do so, he uses an experimental rat whisker system; when a whisker touches something, the rat must make a decision whether to continue on the same path, perhaps by jumping across a gap, for example.  

Dr. Sakmann and colleagues are developing a database of 3D reconstructions that elucidate the various cellular components of that decision-making process. The reconstructions are enabling the establishment of a "functional wiring diagram" that includes how an external stimulus is represented in the rat's brain, where and how that stimulus travels in the brain and how it results in an action.

Moritz Helmstaedter, PhDIn related work, Dr. Moritz Helmstaedter, group leader at MPI for Neurobiology in Martinsried, is analyzing data from electron microscopes to map neuronal circuits in the mouse retina. But these microscopes reveal tremendous detail, making the mapping process difficult. "It's like we are flying through blood vessels and seeing almost all of the neurons in every piece of tissue," he said. 

To make sense of such voluminous amounts of data, he is using a combination of computer processing and people's brain power. For the initial work, the Institute hired 250 undergraduate students working with computers to pore through the data, resulting in the mapping of close to 1,000 neurons in a piece of mouse retina.

But that's just the starting point. "The goal is to recreate the entire communication network—to map the communication points, or synapses, between neurons and measure how strongly they talk to each other," Dr. Helmstaedter explained. Because a single neuron can talk to hundreds or thousands of other neurons, the full network is "massive." Taking the same approach as the initial work would require more than 30,000 students, which clearly is impractical. Instead, Dr. Helmstaedter is crowdsourcing the initiative. His team has created a soon-to-launch online game, Brain Flight, with the stated goal of creating "the world's first map of the cerebral cortex." Participants will select processes extending from nerve cells and see if they can follow those processes to their endpoints. Those who do will win points, as an incentive to keep going. The resulting map "could be compared with brain models of disease," and used to screen for potential treatments, he said.

Neural communications – and an accidental discovery about autism

Delving into another aspect of nerve cell communication, Dr. Ryohei Yasuda, scientific director at MPFI, explained how he is using optical tools to understand how the brain forms memories. Thousands of tiny protrusions called dendritic spines are key actors in this process. Dr. Yasuda showed a short video in which the structure of a dendritic spine changed, becoming much larger for a short period during memory formation, and then reverting to a smaller size.

That process is the result of biochemical reactions mediated by signaling networks made up close to 1,000 signaling proteins, and help determine whether memories are sustained or forgotten, he explained. To better understand the process, his group is developing sensors to identify and learn more about the function of every protein in the signaling network. "We are hopeful that this knowledge will eventually provide insights into diseases that affect memory, such as Alzheimer's," he said.

Nils Brose, PhDDr. Nils Brose, director at MPI for Molecular Neurobiology in Göttingen, is looking more deeply into the molecular mechanisms of synapse formation and function. Synapses are critical not only to memory formation — they are "the central information processing units in the vertebrate brain and the basis for all human behavior," Dr. Brose explained.

He and his colleagues are using a variety of biochemical, genetic, physiological and behavioral methods to better understand what happens when a sending and a receiving neuron connect.

What's known is that at the moment of connection, an electrical signal from one nerve cell is briefly transformed into a chemical signal, then retranslated into an electrical signal. "For this to work, dozens of different proteins must be recruited to the right location," Dr. Brose said. "You have to have the right proteins on the sending part of the synapse and the right proteins on the receiving part." That recruitment is accomplished by signaling molecules called neurexins and neuroligins, which essentially connect the two parts of the synapse together.

[pullquote align="right"](Synapses are) the central information processing units in the vertebrate brain and the basis for all human behavior.[/pullquote]While investigating the genes associated with these molecules in mice, his team made a "totally unexpected" discovery with clinical implications — namely that specific mutations in genes that encode neuroligins are "causally involved" in certain forms of autism. The finding was surprising, Dr. Brose said, because "these molecules have been studied for decades by us and others, and we had no idea of the medical implications."

These heritable forms of autism, which make up a very small percentage of cases, "are caused by mutations that disrupt the genes that encode neuroligins, so the synapses don't look or function normally anymore," he explained. The abnormal synapses were seen in mouse models that carry the same mutation as human patients, demonstrating that "things go wrong not only in our laboratory, but also in diseases," Dr. Brose said. Single-gene disorders such as Huntington's disease or forms of early-onset Alzheimer's disease may show similar physiological consequences, he speculated.

A window into the developing brain

David Fitzpatrick, PhDDr. David Fitzpatrick,Scientific Director and CEO at MPFI, and Dr. Tobias Bonhoeffer, director of the MPI for Neurobiology in Martinsried, Germany, closed the event with highlights of work elucidating the brain's plasticity, or ability to change and grow as a result of experience. Using advanced optical imaging techniques, Dr. Fitzpatrick is investigating the functional architecture of neural circuits in the visual cortex and the role that visual experience plays in the development of those circuits.

"Most of the neurons in your brain are born prior to birth, but most of the synapses are formed after your birth," he said. To underscore that point, he presented a slide that showed how the density of synapses in the human visual cortex increased during the first year of life. "So, if your son, daughter or grandchild is sitting seemingly gazing out into space, be aware that about 700 synapses per second are being formed in that brain."

That means the brain is unlike any other computational device — a cell phone, for example — that is completely formed and functional when you buy it and only needs to be switched on to work, Dr. Fitzpatrick said. "The brain is formed at a time when activity can influence it. Therefore, experience can affect how its circuits form."

[pullquote align="right"]We now have an interesting model system for exploring how experience shapes neural circuits.[/pullquote]This was demonstrated in Dr. Fitzpatrick's recent work on "directional selectivity," a property that allows animals (and people) to see motion—for instance, a bar moving back and forth — in the environment.  

"Neurons in the visual cortex respond selectively for the direction of motion," Dr. Fitzpatrick explained. If something is moving to the left, for example, "certain neurons will fire a lot of spikes for this direction, but not very many for the opposite direction. Other neurons signal motion to the right."

His work has shown that directional selectivity emerges early in life and can be changed by training — such as by repeated presentation of a single direction of motion. "We found that neurons that initially preferred one direction ended up responding much more strongly to the opposite direction after the training period," he said, "so we now have an interesting model system for exploring how experience shapes neural circuits."

Tobias Bonhoeffer, PhDDr. Bonhoeffer picked up where Dr. Fitzpatrick left off, moving from postnatal plasticity to plasticity of the adult brain, which is needed for learning and, as Dr. Yasuda also showed, for memory. "If you learn a new activity such as skiing, new connections are made quite literally, and your brain adapts to the requirements necessary to be able to ski," Dr. Bonhoeffer said. "And, hopefully, if you learn something tonight, you will change the connections in your brain, and when you walk out of this room, you will have a different brain from the one you walked in with," he quipped.

[pullquote align="right"]If we can understand how learning works at a basic level, it could affect society as a whole, from how children are taught in schools to how we learn about our culture.[/pullquote]By implanting a specialized chamber on the mouse's head and staining the neurons fluorescently, "we have a little window into the brain of an intact animal, and we can see whether it changes during learning," Dr. Bonhoeffer observed.

Using this method, he showed that when a mouse learns to navigate a new environment, specific structural changes occur in the dendritic spines — and when that mouse is put in the same environment many weeks later, it relearns to navigate that environment more quickly because the structural changes are still in place. This example of the "memory effect" could also explain why a person who learns an activity as a child finds it much easier to learn that activity again as an adult, compared with an adult learning that activity for the first time.

"This is a good example of how our work can have a translational effect on society without any clinical applications," Dr. Bonhoeffer emphasized. "If we can understand how learning works at a basic level, it could affect society as a whole, from how children are taught in schools to how we learn about our culture.

"By studying normal function, without studying disease, we can still have quite a strong impact," he concluded.

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The Author

Marilynn Larkin

Marilynn Larkin is an award-winning science writer and editor who develops content for medical, scientific and consumer audiences. She was a contributing editor to The Lancet and its affiliated medical journals for more than 10 years and a regular contributor to the New York Academy of Sciences' publications and Reuters Health's professional newsfeed. She also launched and served as editor for of Caring for the Ages, an official publication of theAmerican Medical Directors Association. Larkin's articles also have appeared in Consumer Reports,Vogue ,Woman's Day and many other consumer publications, and she is the author of five consumer health books.



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