Brace yourself Chicago, it’s here! This weekend marks the start of Neuroscience 2015, the annual mega-conference of the Society for Neuroscience, world’s largest organization of scientists and physicians devoted to understanding the brain. Around 30,000 neuroscientists will spend the next five days sharing and discussing the latest in neuroscience research, turning the city of big shoulders into the city of big brains.
As always, the University of Chicago is well represented, with scientists and students presenting almost 150 posters or symposium talks. Don’t miss the UChicago SfN Social on Sunday, October 18, from 8pm – 10pm at the Shedd Aquarium, or minisymposia like “Different Brains, Common Circuits: Visual Decision Making in Rodents and Primates,” chaired by associate professor of neurobiology David Freedman, PhD.
For a deeper look at how some UChicago neuroscientists are working to decipher the brain, ScienceLife presents the second part of a story excerpted from the spring issue of Medicine on the Midway, which features the efforts of Mark Histed, PhD, research associate and assistant professor, and John Maunsell, PhD, the Albert D. Lasker professor in the Department of Neurobiology and director of the Grossman Institute for Neuroscience, Quantitative Biology and Human Behavior, as they build a window into the brain.
A window into the brain
“It’s clear that neuroscience is at a turning point,” says John Maunsell, PhD, director of the University of Chicago’s new Grossman Institute for Neuroscience, Quantitative Biology and Human Behavior. “An unprecedented number of new tools and approaches are enabling rapid progress on every front. It’s not one specific question or one specific area or one animal model. The floodgates of data are going to open, and the understanding will follow. The payoffs could be enormous.”
Established to spur the discovery of fundamental insights about the brain and human behavior, the Grossman Institute spans boundaries and coordinates neuroscience research across the University of Chicago. It opened its doors in 2014, occupying 22,000 square feet of open laboratory and office space on the fourth floor of the Surgery Brain Research Institute building.
Maunsell, Albert D. Lasker Professor of neurobiology, is still unpacking. A renowned neuroscientist who has made fundamental discoveries about the mechanisms that underlie vision, attention and perception, and former editor-in-chief of the prestigious Journal of Neuroscience, he joined the University of Chicago in 2014 from Harvard Medical School. While he juggles a myriad of tasks —establishing programs to foster collaborations and new exchanges of ideas, recruiting new faculty, developing new student programs and more — he manages the transition of his own laboratory to this new space.
Tucked in a corner of the Grossman Institute, in one of the few areas behind closed doors, Maunsell’s lab is strewn with pieces of complex equipment, computers, oscilloscopes and boxes full of random wires and parts. His collaborator, Mark Histed, PhD, research associate and assistant professor of neurobiology, walks through this space and points to an open area.
“That’s where we’re going to build the laser,” he says nonchalantly. “We’re just making sure the floor is capable of handling it.”
In a project funded by the BRAIN Initiative — a nationwide research effort to uncover fundamental insights about the brain, announced by President Obama in 2014 — Maunsell and Histed, along with international colleagues, are working to quite literally shed light on how the brain creates behavior and makes decisions.
One of the greatest recent revolutions in neuroscience is the field of optogenetics, a method that enables control over neural activity with light. It involves genetically engineering neurons to express a light-sensitive protein first discovered in algae. These neurons can then be activated or inhibited with a flash of light, reacting with precise timing — incredibly important when a change of a few milliseconds can alter the activity of entire networks.
For Maunsell and Histed, the real potential of optogenetics emerges when combined with other tools. The first are techniques to study behaviors in mice and measure their cognitive states. An example: a well-trained mouse holds down a lever while watching a video screen. When it notices a change in brightness, color, or whatever measure the researchers are interested in, it releases the lever. In doing so, the animal effectively reports a shift in its perception, and any associated changes in its neural patterns can be measured. This may sound simple, but these behavioral models, broadly known as psychophysics, have only recently been refined in mice. This is particularly significant because of numerous advantages to the mouse animal model, including the availability of optogenetic mice.
The second tool is a custom-designed microscope that uses a principle known as two-photon excitation — basically a powerful laser that targets cells with femtosecond pulses of light (a femtosecond is to a second as a second is to about 32 million years). The laser can be shined deep into living brain tissue, through a clear window surgically implanted in the skull. By stimulating fluorescent dyes or indicators, the laser lights up neurons that fire. This allows clear visualization of hundreds of neurons at once in an awake, healthy animal that is performing behavioral tasks. Even more impressively, this can be used to precisely control the activity of optogenetically modified neurons to see how behavior is affected.
“We will be able to perturb specific patterns of neural activity for the first time,” Histed says. “If we look at an area of a brain while we present a sensory stimulus, those neurons would fire in some complex way. If we change the activity of a few cells and see what results, we can begin to describe features of neural patterns that are most important for behavior. This is the key aspect of brain function that we don’t yet understand.”
For now, the hard work of designing and building the equipment, writing and debugging software code, and a myriad of other tasks remain. Impressively, much of this is done by hand, as no commercial versions have the specifications the team requires. For example, the team is assembling the two-photon microscope, which includes the femtosecond laser, piece by piece – effectively hand-building the clockwork network of lenses, mirrors and detectors that make up a microscope, but spread out all over a heavy table cushioned by air so that building vibrations don’t knock anything out of alignment.Maunsell and Histed plan to begin gathering data this fall.
“We don’t know how long it will take before questions like these are answered,” says Maunsell, “But they will all be approachable. It’s a great time to be in neuroscience and there’s no question that there will be enormous returns on this kind of investment.”
It is because of the sheer complexity of the brain that so many of its functions are mysterious, and so few cures and treatments exist for when things go wrong. Despite the proliferation of new and powerful tools in neuroscience, much, much more remains unknown than known. But these tools are enabling the development of strategies to that begin to address questions — from basic mechanisms to translational therapeutics —that could not even have been asked a few years ago.
“Neuroscience is at a stage like biology before Watson and Crick,” Histed says. “How do you go from these patterns to understanding how the brain works? That’s the enterprise upon which we’re embarking. There are thousands of labs across the country that are working on these issues, and it’s only a matter of time before someone figures out the most important principles.”