Improved Brain Mapping Tool 20 Times More Powerful Than Previous Version

Posted on April 14th, 2016

A Salk team builds upon their rabies virus technology to better map neurons across large swaths of the nervous system. In a mouse brain section (thalamus), neurons providing monosynaptic inputs to cortical inhibitory neurons are traced via rabies (blue). Purple counterstaining shows surrounding cellular architecture. (Credit: The Salk Institute)

A Salk team builds upon their rabies virus technology to better map neurons across large swaths of the nervous system. In a mouse brain section (thalamus), neurons providing monosynaptic inputs to cortical inhibitory neurons are traced via rabies (blue). Purple counterstaining shows surrounding cellular architecture. (Credit: The Salk Institute)

LA JOLLA—Salk Institute scientists have developed a new reagent to map the brain’s complex network of connections that is 20 times more efficient than their previous version. This tool improves upon a technique called rabies virus tracing, which was originally developed in the Callaway lab at Salk and is commonly used to map neural connections.

Rabies viral tracing uses a modified version of the rabies virus that jumps between neurons, lighting up connections along the way. The illuminated map allows researchers to precisely trace which neurons connect to each other. Visualizing this neural circuitry can help scientists learn more about conditions ranging from motor diseases to neurodevelopmental disorders.

“To truly understand brain function, we have to understand how different types of neurons are connected to each other across many distant brain areas. The rabies tracing methods we have developed made that possible, but we were only labeling a fraction of all of the connections,” says Edward Callaway, a Salk professor and senior author of the new paper, published April 14, 2016 in the journal Cell Reports. Callaway is also an affiliate member of the Kavli Institute for Brain and Mind at UC San Diego.

He adds that such a dramatic improvement in a critical tool for neuroscience will help researchers illuminate aspects of brain disorders where connectivity and global processing goes awry, such as in autism and schizophrenia.

From left: Euiseok Kim, Edward Callaway, Tony Ito-Cole and Matthew Jacobs (Credit: The Salk Institute)

From left: Euiseok Kim, Edward Callaway, Tony Ito-Cole and Matthew Jacobs (Credit: The Salk Institute)

Long distance connections between neurons are key to what is called global processing in the brain. Imagine a ball sailing toward a catcher. The catcher’s visual circuits will process the information about the ball and send that information over to the brain’s motor circuits. The motor circuits then direct nerves in the catcher’s arm and hand to grab the ball. That global processing relies on long-distance neural circuits forming precise connections to specific neuron types; these circuits can be revealed with rabies viral tracers.

“With this new rabies tracer, we can visualize connectivity neuron by neuron, and across long distance input neurons better than with previous rabies tracers,” says Euiseok Kim, a Salk research associate and first author of the paper.

There are billions of neurons in the brain, and only a handful of technologies that can map the communication going on between them. Some imaging techniques such as functional MRIs can visualize broad scale communication across the brain, but do not focus on the cellular level. Electrophysiology and electron microscopy can track cell-to-cell connectivity, but aren’t suited to mapping neural circuits across the whole brain.

Tracing methods using neurotropic viruses, like rabies, have long been utilized to trace connections across neural pathways. But these viruses spread widely throughout the brain across multiple circuits, making it difficult to determine which neurons are directly connected. In 2007, Callaway’s lab pioneered a new approach based on genetically modified rabies virus. This approach allowed the viral infection to be targeted to specific types of neurons and also allowed the spread of the virus to be controlled. The result is that this system illuminates neurons across the entire brain, but labels only those that are directly connected to neurons of interest.

To control how far the virus travels, scientists ensure the rabies virus can only infect a select group of neurons. First scientists remove and replace the crucial outer-coat of the rabies virus, called glycoproteins. The virus needs this coat of glycoproteins to enter and infect cells, but the replacement glycoprotein prevents the virus from infecting normal neurons. Scientists then alter a group of neurons in mice to become so-called “starter cells” that are uniquely susceptible to infection with the modified glycoprotein. Starter cells are also programmed to provide the rabies glycoproteins so that once a starter cell is infected, new copies of the rabies tracer can spread across the starter cell’s synapses into connected neurons. However, once the rabies viral tracer is in the next set of neurons, it won’t find the glycoprotein it needs to continue to spread, and so the trail of infection across neural circuits ends.

Although the original rabies viral tracer accurately traces circuits, it was only crossing a fraction of the starter cell’s synapses. The Salk research team went about engineering a more efficient rabies viral tracer. First, the researchers took pieces from various rabies strains to create new chimeric glycoproteins and then tested the versions in by counting labeled cells in known circuits.

The winning chimeric glycoprotein was further genetically modified with a technique called codon optimization to increase levels of the glycoprotein produced in starter cells. Compared to the original rabies tracer, the new codon-optimized tracer increased the tracing efficiency for long distance input neurons by up to 20 fold.

“Although this improved version is much better, there are still opportunities to improve the rabies tracer further as we continue to examine other rabies strains,” says Kim.

 

(Originally published by The Salk Institute)

Derailed Train of Thought? Brain’s Stopping System May Be at Fault

Posted on April 14th, 2016

Have you had the experience of being just on the verge of saying something when the phone rang? Did you then forget what it is you were going to say? A study of the brain’s electrical activity offers a new explanation of how that happens.

Published in Nature Communications, the study comes from the lab of neuroscientist Adam Aron at the University of California San Diego, together with collaborators at Oxford University in the UK, and was led by first author Jan Wessel, while a post-doctoral scholar in the Aron Lab. The researchers suggest that the same brain system that is involved in interrupting, or stopping, movement in our bodies also interrupts cognition – which, in the example of the phone ringing, derails your train of thought.

The findings may give insights into Parkinson’s disease, said Aron, a professor of psychology in the UC San Diego Division of Social Sciences and a member of the Kavli Institute for Brain and Mind, and Wessel, now an assistant professor of psychology and neurology at the University of Iowa. The disease can cause muscle tremors as well as slowed-down movement and facial expression. Parkinson’s patients may also present as the “opposite of distractible,” often with a thought stream so stable that it can seem hard to interrupt. The same brain system that is implicated in “over-stopping” motor activity in these patients, Aron said, might also be keeping them over-focused.

The current study focuses particularly on one part of the brain’s stopping system – the subthalamic nucleus (STN). This is a small lens-shaped cluster of densely packed neurons in the midbrain and is part of the basal ganglia system.

Adam Aron

Adam Aron, professor of psychology in the UC San Diego Division of Social Sciences (Credit: Nathalie Belanger)

Earlier research by Aron and colleagues had shown that the STN is engaged when action stopping is required. Specifically, it may be important, Aron said, for a “broad stop.” A broad stop is the sort of whole-body jolt we experience when, for example, we’re just about to exit an elevator and suddenly see that there’s another person standing right there on the other side of the doors.

The study analyzes signals from the scalp in 20 healthy subjects as well as signals from electrode implants in the STN of seven people with Parkinson’s disease. (The STN is the main target for therapeutic deep brain stimulation in Parkinson’s disease.)

All the volunteers were given a working memory task. On each trial, they were asked to hold in mind a string of letters, and then tested for recall. Most of the time, while they were maintaining the letters in mind, and before the recall test, they were played a simple, single-frequency tone. On a minority of trials, this sound was replaced by a birdsong segment – which is not startling like a “bang!” but is unexpected and surprising, like a cell phone chirping suddenly. The volunteers’ brain activity was recorded, as well as their accuracy in recalling the letters they’d been shown.

Jan Wessel

Jan Wessel, now at the University of Iowa. (Credit: Jan Wessel)

The results show, the researchers write, that unexpected events manifest the same brain signature as outright stopping of the body. They also recruit the STN. And the more the STN was engaged – or the more that part of the brain responded to the unexpected sound – the more it affected the subjects’ working memory and the more they lost hold of what they were trying to keep in mind.

“For now,” said Wessel, “we’ve shown that unexpected, or surprising, events recruit the same brain system we use to actively stop our actions, which, in turn, appears to influence the degree to which such surprising events affect our ongoing trains of thought.”

A role for the STN in stopping the body and interrupting working memory does fit anatomical models of how the nucleus is situated within circuitry in the brain. Yet more research is needed, the researchers write, to determine if there’s a causal link between the activity observed in the STN and the loss in working memory.

“An unexpected event appears to clear out what you were thinking,” Aron said. “The radically new idea is that just as the brain’s stopping mechanism is involved in stopping what we’re doing with our bodies it might also be responsible for interrupting and flushing out our thoughts.”

EEG

The study analyzes signals from the scalp in healthy volunteers as well as signals from electrode implants in the brains of people with Parkinson’s disease. (Credit: Nathalie Belanger)

A possible future line of investigation, Aron said, is to see if the STN and associated circuitry plays a role in conditions characterized by distractibility, like Attention Deficit Hyperactivity Disorder. “This is highly speculative,” he said, “but it could be fruitful to explore if the STN is more readily triggered in ADHD.”

Wessel added: “It might also be potentially interesting to see if this system could be engaged deliberately – and actively used to interrupt intrusive thoughts or unwanted memories.”

If further research bears out the connection suggested by the current study, between the STN and losing your train of thought following an unexpected event, the researchers say it might be that it is an adaptive feature of the brain, something we evolved long ago as a way to clear our cognition and re-focus on something new. Aron suggests this example: You’re walking along one morning on the African Savannah, going to gather firewood. You’re daydreaming about the meal you’re going to prepare when you hear a rustle in the grass. You make a sudden stop – and all thoughts of dinner are gone as you shift your focus to figure out what might be in the grass. In this case, it’s a good thing to forget what you had been thinking about.

 

(Originally published by UC San Diego)

Distinguished KIBM Neuroscientist Wins Thon Prize

Posted on March 31st, 2016

Jean-Pierre Changeux receives the Thon Prize in honor of his pioneering work in the fields of molecular biology and brain research.

Jean-Pierre Changeux receives the Thon Prize in honor of his pioneering work in the fields of molecular biology and brain research.

Jean-Pierre Changeux, an eminent neuroscientist from France and a distinguished international faculty member at UC San Diego’s Kavli Institute for Brain and Mind, has been awarded the prestigious Thon Prize, given by Norway’s Olav Thon Foundation.

Changeux, a professor at the Institut Pasteur in Paris who spends January through March every year conducting research at KIBM, received the Thon Prize’s international research award, equivalent to $500,000 U.S. dollars, “for his pioneering work in the fields of molecular biology and brain research.”

“Changeux is one of very few living researchers who has been able to leave his mark on several branches of science,” according to his citation. “Many of the concepts that drive modern science forward can be traced back to Changeux and his original discoveries.”

The prize committee said he “has linked a deep understanding of molecules and their regulation to new insight into the function and diseases of the brain. This insight has already led to new approaches to the treatment of neurological disorders and will continue to inspire scientists for decades to come.”

“Changeux’s research findings are central to our understanding of the formation of synapses and the plasticity of the synapses over time and during the ageing process, but also of cultural learning (such as reading and writing) and mental disorders. At the same time, the findings shed new light on crucial factors associated with child development and education.

On the basis of Changeux’s research, clinical tests are now underway with nicotine-based drugs for Alzheimer’s disease, Parkinson’s disease, depression, schizophrenia, ADHD, pain and tobacco addiction.

Since the mid-1990s, Changeux (in collaboration with Stanislas Dehaene) has used computational modelling to understand the neurobiological basis of cognitive functions. This work has inspired new research on the effects of general anesthetics and drug addiction.”

More information on the award at: http://www.uio.no/english/about/news-and-events/news/2016/the-olav-thon-foundation.html

The Kavli Foundation and University Partners Commit $100 Million to Brain Research

Posted on October 1st, 2015

OCTOBER 1, 2015 (WASHINGTON, D.C.) – The Kavli Foundation and its university partners announced today the commitment of more than $100 million in new funds to enable research aimed at deepening our understanding of the brain and brain-related disorders, such as traumatic brain injuries (TBI), Alzheimer’s disease and Parkinson’s disease.

“We are delighted to announce this major commitment to promoting a sustained interdisciplinary effort to solve the mysteries of the brain,” said Rockell N. Hankin, Chairman of the Board of Directors at The Kavli Foundation. “By transcending the traditional boundaries of research, the new neuroscience institutes will make breakthrough discoveries possible.”

The majority of the funds will establish three new Kavli neuroscience institutes at the Johns Hopkins University (JHU), The Rockefeller University and the University of California, San Francisco (UCSF). These institutes will become part of an international network of seven Kavli Institutes carrying out fundamental research in neuroscience, and a broader network of 20 Kavli Institutes dedicated to astrophysics, nanoscience, neuroscience and theoretical physics.

The new funding will support research that moves forward the national Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, a public and private collaboration launched by President Obama in April 2013. At the time of the President’s announcement, The Kavli Foundation publicly pledged to spend $40 million in support of basic neuroscience research. “With this announcement, the Foundation more than meets this commitment,” said Robert W. Conn, President and CEO of The Kavli Foundation. “The establishment of three new institutes, along with the added investment in our existing neuroscience institutes, will further empower great scientists to help write the next chapter in neuroscience.”

The BRAIN Initiative is supported by federal agencies, including the National Institutes of Health, National Science Foundation, and the Defense Advanced Research Projects Agency, and private partners such as The Kavli Foundation.

“The President launched the BRAIN Initiative to help unlock the mysteries of the brain, to improve our treatment of conditions like Alzheimer’s and autism, and to deepen our understanding of how we think, learn, and remember. The Kavli Foundation is responding to the President’s call to action by making investments to advance the goals of the BRAIN Initiative. I hope this spurs other private, philanthropic, and academic institutions to support this important initiative,” said John P. Holdren, PhD, assistant to the President for Science and Technology, and director of the White House Office of Science and Technology Policy.

kavli funding

The three new institutes are the Kavli Neuroscience Discovery Institute at JHU, the Kavli Neural Systems Institute at The Rockefeller University and the Kavli Institute for Fundamental Neuroscience at UCSF. Each of the Institutes will receive a $20 million endowment supported equally by their universities and the Foundation, along with start-up funding. The Foundation is also partnering with four other universities to build their Kavli Institute endowments further. These Institutes are at Columbia University, the University of California, San Diego, Yale University and the Norwegian University of Science and Technology.

The BRAIN Initiative calls specifically for establishing new interdisciplinary collaborations aimed at creating novel new technologies for visualizing the brain at work.

“The cultivation of diverse partnerships, with government, big and small business, non-profits and academia, is a critical step on the path to unravel the mysteries of the brain,” National Science Foundation Director France Córdova, PhD, said. “Only through continued investments in collaborative, fundamental research will we develop the innovative tools and technologies needed to help us understand the brain, which is the ultimate goal of the BRAIN Initiative. Progress in this area will bolster America’s health, economy and security.”

In the spirit of the interdisciplinary charge of the BRAIN Initiative, the new Kavli Institutes each work across their universities and with outside partners:

  • The mission of the new Kavli Neuroscience Discovery Institute (Kavli NDI) at JHU is to bring together neuroscientists, engineers and data scientists to investigate neural development, neuronal plasticity, perception and cognition. “The challenges of tomorrow will not be confined to distinct disciplines, and neither will be the solutions we create,” said Johns Hopkins University President Ronald J. Daniels. “The Kavli Foundation award is a tremendous honor, because it allows Johns Hopkins to build on our history of pioneering neuroscience and catalyze new partnerships with engineers and data scienctists that will be essential to building a unified understanding of brain function.”
  • At The Rockefeller University, the Kavli Neural Systems Institute (Kavli NSI) will also promote interdisciplinary research and learning to tackle the biggest questions in neuroscience through high-risk, high-reward projects and the development of new research technologies. “Kavli’s investment in neuroscience at Rockefeller will enable us to create and share new research approaches and laboratory technologies to capture the possibilities of neuroscience from the micro to the macro level,” said Rockefeller President Marc Tessier-Lavigne, PhD. “For example, Rockefeller scientists are currently developing a number of tools to push neuroscience forward, including advanced neuronal recording capabilities, sophisticated three-dimensional imaging, and non-invasive activation of neural circuits, among others.”
  • The Kavli Institute for Fundamental Neuroscience (Kavli IFN) at UCSF will focus initially on understanding brain plasticity, the remarkable capacity of the brain to modify its structure and function. The Kavli IFN will partner with engineers at two San Francisco Bay-area national laboratories to develop new tools and approaches to brain research. “UCSF scientists have made some of the seminal discoveries in modern neuroscience,” said UCSF Chancellor Sam Hawgood, MBBS. “The Kavli Institute will sustain this rich tradition into the 21st Century.”

“While private funding should never supplant federal funding,” said Conn, “the scientific enterprise also depends on philanthropic giving to catalyze pioneering new directions and discoveries.”

“Understanding the complex language of brain circuits—and how they function in both health and disease—is one of the greatest challenges in science. This effort will be made possible by cooperation across disciplines to build the advanced tools necessary to probe the brain in fine detail. The commitment of both public and private organizations brings much needed firepower and interdisciplinary expertise to this endeavor,” said Walter Koroshetz, MD, director of the National Institute of Neurological Disorders and Stroke and the co-chair of the NIH BRAIN Initiative.