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New brain mapping tools showcased by the Kavli Institute

May 16, 2014
by Lindsay Borthwick

A suite of remarkable tools are allowing neuroscientists to see the brain in new ways, and to ask—and answer—questions they could only dream about just a few years ago. These new tools, with names like CLARITY, optogenetics and ArcLight, were on display recently at two events hosted by the Kavli Institute for Neuroscience at Yale: The Goldman-Rakic NARSAD Distinguished Lecture and the 2014 Kavli Workshop.

Goldman-Rakic NARSAD Distinguished Lecture

The first event brought to campus Stanford neuroscientist Karl Deisseroth, who, last year, unveiled CLARITY, a technique that renders brain tissue transparent. A feat of chemical engineering, CLARITY creates a three-dimensional brain with all its wiring intact and visible, and may help neuroscientists develop a detailed map of the nervous system. Deisseroth also helped develop optogenetics, a powerful cell manipulation technique that allows researchers to control the activity of individual nerve cells using a beam of light.

Last October, Deisseroth was awarded the 2013 Goldman-Rakic Prize in Cognitive Neuroscience Research, which was established to honor the pioneering Yale neurobiologist Patricia Goldman-Rakic, who died in 2003. He spoke to an audience of 300 at the Yale School of Medicine about the development of CLARITY, and his laboratory’s efforts to develop better ways to image “clarified” tissue and manage the “data explosion” such whole-brain imaging tools generate. He also introduced the audience to a technique for monitoring the activity of long-range neural projections, which underlie complex behaviors, in live mice. He calls the new method “fiber photometry” because it uses photons to track neural activity.

The lecture was followed by a working dinner at the home of the Kavli Institute's director, Pasko Rakic, with Deisseroth and a group of Kavli investigators. After dinner, Deisseroth gave an informal overview of President Obama’s BRAIN Initiative, a large-scale brain-mapping project, to which he is an advisor. This stimulated a lively discussion among the guests about the specific goals of the Initiative and how it may impact the future of neuroscience.

2014 Kavli Workshop

The next day, the Kavli Workshop on Multicellular Monitoring and Manipulation brought together five Yale neuroscientists who are developing and using new methods to study the activity of large groups of neurons.

“We need an intermediate level of neuroscience,” said David McCormick, vice-director of the Kavli Institute, who introduced the workshop to an audience of graduate students, post-doctoral fellows and neuroscientists from across the university. “Between single cells and broad cortical networks lies neuronal assemblies. Multineuronal monitoring will allow scientists to observe these assemblies in real-time.”

McCormick, who later presented results from his laboratory, predicted that there will be many “stunning success stories and stunning failures” over the next 25 years as researchers make the technological leap to capturing the activity of groups of neurons and linking their activity to specific behaviors. Such technological advances are beginning to emerge and may reveal a new level of organization in the brain, both when it functions normally and when it malfunctions in psychiatric and neurological disorders, he said.

Highlights from the Kavli Workshop included:

Vincent Pieribone, PhD, James B. Pierce professor of cellular and molecular physiology and neurobiology talked about his efforts, over the past 10 years, to develop probes that can sense the electrical activity of neurons.

“The molecular revolution had left us neurophysiologists behind. We were still using electrodes, the same tools people had been using for decades,” he said. “I thought there must be a better way to do this.”

He proved the field right. After testing more than 600 candidate probes, in 2012, he published the discovery of ArcLight, a fluorescent protein-based voltage sensor derived from a common sea squirt. ArcLight can monitor changes in activity in individual neurons and dendrites, the signal-receiving branches of neurons, and is more sensitive than existing probes.

A deep-sea diver, Pieribone will be scouring the South Pacific ocean in July in a submersible, looking for species that may harbor proteins that can be exploited for brain research. He’s particularly interesting in finding bioluminescent organisms, which generate their own light and may harbor proteins that offer advantages over existing fluorescence-based sensors.

Michael Nitabach, PhD, JD, associate professor of cellular and molecular physiology and genetics and a Kavli member, has collaborated with Vincent Pieribone to study the brains of the fruit fly Drosophila melanogaster using ArcLight.

“ArcLight worked in the very first fly we recorded from, a sign that it was a really robust recorder of electrical activity in the fly brain,” he told the audience. He went on to describe the power of ArcLight, which has allowed him to image and record from multiple brain cells simultaneously.

Nitabach also presented ongoing research into the neural circuits underlying the regulation of sleep and associative learning in fruit flies. His laboratory is currently combining modern tools of genetics, physiology, imaging and behavior to understand how a simple circuit in the mushroom body, a brain region that is analogous to the mammalian cortex, operates at the cellular and synaptic level.

The long-term goal is to apply this knowledge to more complex vertebrate nervous systems.

Kavli member Michael Crair, PhD, professor of neurobiology and of opthalmology and visual science, studies the development, structure and function of the mammalian visual system. At the workshop, he discussed a technique he developed to image retinal ganglion cells—neurons that line the retina and receive and relay visual input to the brain—in newborn mice.

More than 20 years ago, researchers noticed that in mice—which are blind at birth—retinal ganglion neurons are spontaneously active, and that this electrical activity propagates across the retina in waves. (The same is true in other developing mammals.) But they didn’t know why.

With the help of calcium-sensitive dyes and, more recently, a genetically encoded calcium indicator, both of which monitor neural activity, Crair has shown that in mice these retinal waves coordinate the development of the neural circuits that support vision. Using optogenetics, he can manipulate the timing or extent of these waves and alter the development of these circuits. This spontaneous activity may be essential to wiring up the brain in developing mammals, he said.

Jessica Cardin, PhD, assistant professor of neurobiology and a Kavli member, described how she uses tetrodes, a bundle of four electrodes, to record the activity of multiple neurons at once, in awake, behaving mice. By combining this technique with optogenetics, which allows her to identify the individual brain cells she is recording from, she can track the role of excitatory and inhibitory neurons in local circuits—and how circuits are disrupted in mouse models of psychiatric diseases, such as schizophrenia and autism.

Her overall aim is to use these techniques to understand how brain circuits maintain their “functional flexibility”:

“Your brain is capable of dealing with the almost infinite number of environments that you encounter throughout life. Your brain circuits are able to adapt and be flexible and deal with all of these inputs,” she said. “But what are the mechanisms by which these circuits become flexible—capable of responding to different contexts or different behavioral states in different ways—and also what happens when they lose some of that flexibility?”

David McCormick, PhD, vice-director of the Kavli Institute and professor of neurobiology, presented results from an ongoing project on the function of circuits in the auditory cortex of mice. His laboratory is exploring how these circuits are capable of responding so rapidly to changes in the animal’s acoustic environment. They aim to use genetically encoded calcium sensors to record the activity of groups of neurons in this brain region.

However, they first needed to find a way to monitor the animal’s behavioral state during an experiment—not just whether it is still or moving but whether or not it is alert and paying attention to a given task. They’ve shown that without understanding the animal’s state, the meaning of data recorded from the animal’s brain is difficult to interpret. The solution? Track the diameter of the animal’s pupil. The pupil turns out to be a window into the animal’s mind that researchers can use to know if it’s doing its homework.

Submitted by YSM Web Group on May 15, 2014