TAG: "Neuroscience"

Study puts more natural movement for artificial limbs within reach


Providing simple neural signals to brain implants could stand in for body’s own feedback system.

By Pete Farley, UC San Francisco

In new research that brings natural movement by artificial limbs closer to reality, UC San Francisco scientists have shown that monkeys can learn simple brain-stimulation patterns that represent their hand and arm position, and can then make use of this information to precisely execute reaching maneuvers.

Goal-directed arm movements involving multiple joints, such as those we employ to extend and flex the arm and hand to pick up a coffee cup, are guided both by vision and by proprioception — the sensory feedback system that provides information on the body’s overall position in three-dimensional space. Previous research has shown that movement is impaired when either of these sources of information is compromised.

The most sophisticated artificial limbs, which are controlled via brain-machine interfaces (BMIs) that transmit neural commands to robotic mechanisms, rely on users’ visual guidance and do not yet incorporate proprioceptive feedback. These devices, though impressive, lack the fluidity and accuracy of skilled natural reaching movements, said Philip Sabes, Ph.D., senior author of the new study, published today (Nov. 24) in the Advance Online Edition of Nature Neuroscience.

“State-of-the-art BMIs generate movements that are slow and labored — they veer around a lot, with many corrections,” said Sabes, whose research to improve prosthetics has been funded by the REPAIR (Reorganization and Plasticity to Accelerate Injury Recovery) initiative of the Defense Advanced Projects Research Agency (DARPA). “Achieving smooth, purposeful movements will require proprioceptive feedback.”

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Tolman, behavior and academic freedom


UC Berkeley day of talks honors pioneering professor.

In Tolman Hall, Seth Rosenfeld, author of "Subversives," connected the dots from Edward Tolman's stand against the UC loyalty oath to the Free Speech Movement. (Photo by Barry Bergman, UC Berkeley)

If you’ve ever been to Tolman Hall, you probably reached it not by rigid adherence to a series of mechanical steps — start at West Circle, go up Hilgard Way, first right to the end of Morgan Hall, then first left and voila — but by navigating via the map in your head. That is, you pictured its location, and figured out a suitable route.

If you’d made the trip Monday, you would have learned it was the man who lent the aging psychology building his name, longtime UC Berkeley professor Edward Tolman, whose pre-World War II work with rats in mazes changed how we think about how we think. His groundbreaking insights laid the foundation for the discovery of what’s been called “the brain’s GPS” — the underlying neural machinery of the cognitive map — and this year’s Nobel Prize in Physiology or Medicine.

Edward Moser, who shared the 2014 Nobel with his wife, May-Britt Moser, and John O’Keefe, gave the keynote address at Monday’s daylong celebration of Tolman’s legacy. While Moser and fellow neuroscientist David Foster, of Johns Hopkins University, gave technical presentations on their clinical research — with due credit to Tolman’s pioneering work in psychology — others highlighted his role as a pioneer in the realm of academic freedom.

In 1949, as McCarthyism raged, Tolman took a high-profile stand against the special “loyalty oath” demanded of UC employees by President Robert Gordon Sproul and the Board of Regents. Although he was fired, he not only won back his faculty position but was instrumental in winning the fight against the oath, which was ultimately found to be unconstitutional.

“The issue I am concerned with involves not communists but liberals,” explained Tolman, reading a letter to Sproul at a meeting of the Academic Senate. “For, when one reads the second part of the oath again, one discovers certain ambiguities of statement and meaning which would make it very difficult for many of us liberals to be certain just what we were being asked to commit ourselves to.”

He further objected that because only individuals can “believe,” it was dangerous to require faculty to disavow membership in organizations that “believe in” the overthrow of the U.S. government. This, he said, was “neither good psychology nor good civil rights.”

In 1963, the year before the Free Speech Movement — whose support from the Berkeley faculty, said author and journalist (and one-time Daily Cal reporter) Seth Rosenfeld, was an extension of the loyalty-oath fight — Berkeley’s new psychology building was dedicated in his name.

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UCSF professor awarded Ralph W. Gerard Prize in Neuroscience


Roger Nicoll receives Society for Neuroscience’s highest award.

Roger Nicoll, UC San Francisco

UC San Francisco neuroscientist Roger Nicoll, M.D., has received the Society for Neuroscience’s (SfN) highest award, the Ralph W. Gerard Prize in Neuroscience. He and Richard W. Tsien, D.Phil., of New York University, will share the $25,000 prize.

The prize honors outstanding scientists who have made significant contributions to neuroscience throughout their careers. The Gerard Prize was established in the name of Ralph W. Gerard, who was instrumental in establishing SfN and served as honorary president from 1970 until his death in 1974.

“It is a pleasure to award the 2014 Gerard Prize jointly to Drs. Nicoll and Tsien. They have performed seminal work that has transformed our understanding of the mechanisms that the mammalian brain uses to transmit and store information,” SfN President Carol Mason said. “In addition to their many scientific accomplishments, Nicoll and Tsien have played a crucial role as mentors in the field of synaptic physiology and biophysics.”

Nicoll’s research has guided new understandings of the basic mechanisms underlying synaptic transmission, the process by which neurons communicate using chemicals called neurotransmitters. Specifically, he pioneered understanding of slow synaptic transmission, in which neurotransmitters communicate by initiating a series of chemical changes in target neurons.

Nicoll’s research also revealed new information about synaptic plasticity, particularly long-term potentiation (LTP), the strengthening of the synapses (connections) between nerve cells related to learning and memory. By using a combination of electrophysiological and molecular techniques, Nicoll’s lab has uncovered the role of several families of synaptic proteins involved in LTP and is currently exploring how LTP is stabilized and maintained. Nicoll will deliver the Grass Lecture on his work at Neuroscience 2014.

Nicoll also shared the 2014 Warren Alpert Foundation Prize with Oleh Hornykiewicz of the Medical University of Vienna and the University of Toronto; and Solomon Snyder of the Johns Hopkins University. They were honored for their pioneering research into neurotransmission and neurodegeneration. The three recipients shared an unrestricted prize of $250,000 and were honored at a special symposium at Harvard Medical School on Oct. 2.

Nicoll earned his M.D. from University of Rochester School of Medicine and is currently a professor in the Department of Cellular and Molecular Pharmacology at UCSF.

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Evaluating cognitive growth in people with intellectual disability


Researchers to establish new tests to track improved thinking and problem-solving skills.

David Hessl, UC Davis

Researchers with the UC Davis MIND Institute will develop and evaluate tests designed to measure and track changes in the cognitive functioning of people who typically are difficult to assess accurately: those with an intellectual disability, formerly termed mental retardation. The research will be funded through a new, five-year, $3.2 million grant from the National Institutes of Health (NIH).

The effort will be paired with other research conducted at the MIND Institute and elsewhere, which seeks to evaluate the efficacy of new, investigational treatments for people with intellectual disability. The tests will eventually be used to ascertain the effectiveness of medications and other treatments, specifically for people with fragile X and Down syndromes and other intellectual disabilities. Fragile X and Down syndromes are among the leading causes of intellectual disability in the United States and around the world. Fragile X syndrome also is the leading single-gene cause of autism spectrum disorder.

At the MIND Institute, the research will be led by principal investigator David Hessl, professor in the Department of Psychiatry and Behavioral Sciences and director of the Translational Psychophysiology and Assessment Laboratory, and co-investigator Leonard Abbeduto, director of the MIND Institute and Tsakopoulos-Vismara Endowed Chair of Psychiatry and Behavioral Sciences.

“There are virtually no comprehensive and developmentally appropriate, well-validated and reliable cognitive measures suitable for tracking treatment responses in people with intellectual disability,” Hessl said, “but there are exciting new therapies being evaluated now and more on the horizon, which suggests that substantial gains in cognitive functioning are possible, even for adults with lifelong cognitive deficits.”

“Most currently available standardized tests have been developed mainly for the general population and are not well-suited for people with intellectual disabilities,” he said. “They just weren’t designed for people with the level of functioning we typically see in fragile X and Down syndromes. What we will be working to do is modify and then validate the NIH Toolbox Cognition Battery so that it works well for individuals with intellectual disability.”

The NIH Toolbox is a multidimensional set of brief measures assessing cognitive, emotional, motor and sensory function from ages 3 to 85, meeting the need for a standard set of measures that can be used as a common currency across diverse study designs and settings. The cognitive test battery used in the study is a computer-based set of tests tapping processing speed, memory, attention and language.

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Monkeying around: What monkeys can teach us about pitching in World Series


Even the most highly practiced expert movements are being continually relearned.

Storied baseball pitchers are renowned for consistently throwing strike after strike, even under the pressure of the World Series.

But even the seasoned pros are actually continually relearning their machine-like throwing movements, according to a new study by UC San Francisco neuroscientist Philip Sabes, Ph.D., about how the brain integrates motor learning.

Sabes studies sensory and motor learning in macaque monkeys, with a focus on reaching behavior. One goal of this work is designing better arm prostheses for amputees or victims of paralysis that will allow the user to “feel” the prosthetic limb’s position in space.

In the course of that work, he and colleagues noticed that even the most highly trained monkeys exhibit significant variability in their performance; even when completing well-practiced reaching movements, the monkeys’ movements showed drift. Not only that, but the researchers found this motor variability correlated with similar drifts in the average firing rate of motor neurons.

Contrary to notions of highly stable “motor memories,” the team thinks that this correlation suggests that even the most highly practiced expert movements are actually being continually relearned on a trial-by-trial basis.

To illustrate the relevance of these primate studies to human behavior, the group exploited Major League Baseball’s obsessive data collection, obtaining detailed quantitative information on each four-seam fastball thrown during the 2011 baseball season. They even found measurable drifts in fast pitches thrown by the notoriously consistent Los Angeles Dodgers’ Clayton Kershaw in a game against the New York Mets on May 8, 2011.

For Sabes, a diehard San Francisco Giants fan whose lab is just blocks from AT&T Park, settling on the Giants’ arch-nemesis Kershaw as an example of expert motor behavior, was a concession to first author and postdoctoral fellow Kris S. Chaisanguanthum, Ph.D., a lifelong Dodgers follower.

And it can’t be denied that the precision of Kershaw’s delivery is the stuff of legend – earlier this year, ESPN’s website ran a headline reading “Clayton Kershaw’s Consistency Is Mind-Numbing.”

In the Sept. 3 issue of The Journal of Neuroscience, however, Sabes, Chaisanguanthum and former UCSF graduate student Helen H. Shen, Ph.D., show that, however it might appear from the stands, even two-time Cy Young Award-winner Kershaw’s release of his fabled four-seamer is subject to precisely the sort of behavioral drift they’ve observed in the lab.

The Giants and Kansas City Royals could learn a few things from those monkeys as they face off this week.

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Researcher receives award from American Academy of Pediatrics


Randi Hagerman honored with one of most prestigious awards for pediatricians in U.S.

Randi Hagerman, UC Davis

Randi Jenssen Hagerman, medical director of the UC Davis MIND Institute, Distinguished Professor of Pediatrics and Endowed Chair in Fragile X Research and Treatment, has received the prestigious C. Anderson Aldrich Award in Child Development for her outstanding contributions in the field of child development from the American Academy of Pediatrics (AAP), the professional organization for pediatricians in the United States.

The award recognizes pediatricians and non-pediatricians for their respective contributions to the field of developmental and behavioral pediatrics. It was presented at the American Academy of Pediatrics Section on Developmental and Behavioral Pediatrics national conference in San Diego on Oct. 12.

I am greatly honored by this award, humbled  after reading the list of previous recipients, and pleased that the AAP recognizes the importance of targeted treatments for individuals with neurodevelopmental disorders,” Hagerman said.

Hagerman is an internationally recognized clinician/scientist, director of the clinical trials program and founder of the Fragile X Research and Treatment Center at the MIND Institute. In 2001, with her husband, Paul J. Hagerman, UC Davis Distinguished Professor of Biochemistry and Molecular Medicine, she discovered fragile X-associated tremor/ataxia syndrome (FXTAS), a neurological disorder that affects older carriers of the fragile X premutation. In 1984 she co-founded the National Fragile X Foundation.

“This award is well-deserved recognition for Dr. Hagerman’s lifelong commitment to children with fragile X syndrome and their families,” said Leonard Abbeduto, Tsakopoulos-Vismara Endowed Chair of psychiatry and behavioral sciences and director of the MIND Institute. “She has helped thousands of people directly through her clinical care, and countless more through her groundbreaking research on the causes, consequences and treatment of FMR1-related disorders.”

“She also has trained and mentored a generation of pediatricians who will carry the field forward for decades to come,” Abbeduto continued. “It is certainly fitting that Dr. Hagerman is added to the list of luminaries who have received this award before her.“

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UC will lead effort to create library of brain cell activity


NIH program will advance fight against ALS, other neurodegenerative diseases.

Leslie Thompson, UC Irvine

UC Irvine will receive $8 million from the National Institutes of Health to establish one of six national centers dedicated to creating a database of human cellular responses that will accelerate efforts to develop new therapies for many diseases.

Leslie M. Thompson, UCI professor of psychiatry & human behavior and neurobiology & behavior, will partner with researchers from Cedars-Sinai Medical Center’s Regenerative Medicine Institute, the Gladstone Institute of Neurological Disease, UC San Francisco, Johns Hopkins University and the Massachusetts Institute of Technology.

They will study brain cell activity in motor neuron disorders including ALS and build a detailed archive of these disease “signatures” that identifies cell targets for new drug treatments. ALS, or amyotrophic lateral sclerosis, also called Lou Gehrig’s disease, attacks motor neurons, cells that control the muscles.

Overall, the NIH is awarding $64 million to six research groups to establish centers that support the Library of Integrated Network-Based Cellular Signatures program. The UC Irvine-based center will be called NeuroLINCS.

The goal of the LINCS program is to utilize the latest cutting-edge technology and scientific methods to catalog and analyze cellular function and molecular activity in response to perturbing agents – such as drugs and genetic factors – that have specific effects on cells. LINCS researchers will measure the cells’ tiniest molecular and biochemical responses and use computer analyses to uncover common patterns – called signatures. LINCS data will be freely available to any scientist.

“Human brain cells are far less understood than other cells in the body,” said Thompson, who’s affiliated with the Sue & Bill Gross Stem Cell Research Center and UCI MIND. “The collective expertise of NeuroLINCS investigators provides a unique opportunity to increase our knowledge of what makes brain cells unique and what happens during neurodegenerative diseases – with a strong focus toward effective treatments. We feel this will have broad application to a number of human brain diseases.”

She and her colleagues will study the effects, or signatures, of perturbing agents on induced pluripotent stem cell-derived neurons and glial cells from “unaffected” cells and those exhibiting the pathology of motor neuron diseases.

At UC Irvine, Thompson will work closely with the UCI Genomics High-Throughput Facility to explore gene expression patterns in these brain cells, which is expected to yield novel insights into pathways and gene networks that guide the development of cell signatures.

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Researchers seek middle-aged and older men for aging study


UC Davis study will follow groups of men with and without the fragile X premutation.

David Hessl, UC Davis

How alterations in a single gene on the X chromosome affects neurological and psychological functioning in men as they age is the subject of a new study by UC Davis MIND Institute researchers.

The gene is FMR1 (fragile X mental retardation 1), and those with an alteration in this gene, known as a “premutation,” are at risk for a range of psychological and medical conditions including decreased cognitive capacity and anxiety. In older adults with the premutation it can cause fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder that has motor symptoms that are similar to Parkinson’s disease and dementia and psychiatric symptoms that are similar to Alzheimer’s disease.

Researchers with the MIND Institute’s Fragile X Research and Treatment Center are seeking individuals the fragile X premutation who will participate in the study over five years, allowing researchers to track their brain changes, motor functioning, thinking and memory skills, as well as their emotional well‐being. They also are seeking healthy men of the same age, who will act as controls.

The study is co‐led by David Hessl, professor of psychiatry and behavioral sciences, and Susan Rivera, professor in the Department of Psychology.

“This study will follow groups of men with and without the fragile X premutation. It will examine the trajectory of change in their cognitive and emotional functioning, and the structure and function of their brains, in an effort to determine which factors are important for predicting the disease process that will occur in some of these men,” Hessl said.

Healthy male control participants must be between 40 and 75 and live in Northern California. Fragile X premutation carriers of the same age may travel to the MIND Institute from their homes anywhere in North America. Participation involves three two‐day study visits over five years. Compensation of $200, as well as travel reimbursement, will be provided for each two-day visit.

Once enrolled, individuals will receive tests to assess their ability to think and their memory skills. They will be interviewed and fill out questionnaires about their health history. They also will be asked to provide blood samples and will have brain scans taken while engaged in a variety of tasks.

For further information, please contact Jessica Famula, recruitment coordinator, (916) 703‐0470 or email jessica.famula@ucdmc.ucdavis.edu.

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UC receives nearly a quarter of NIH brain research grants


14 projects are led by researchers from six UC campuses.

The National Institutes of Health awarded UC researchers nearly a quarter of the $46 million in grants announced today (Sept. 30) in support of President Barack Obama’s BRAIN Initiative.

UC scientists have long been at the frontline of efforts to understand the brain’s inner workings — a pre-eminence reflected by the grants: Of the 58 NIH awards, 14 are projects led by researchers from UC Berkeley, UC Davis, UC Irvine, UCLA, UC San Diego and UC San Francisco.

Collectively, UC researchers will receive more than $10 million of the $46 million that the NIH is awarding for 2014.

“The human brain is the most complicated biological structure in the known universe. We’ve only just scratched the surface in understanding how it works — or, unfortunately, doesn’t quite work when disorders and disease occur,” said NIH Director Dr. Francis S. Collins in a statement. “There’s a big gap between what we want to do in brain research and the technologies available to make exploration possible.”

The BRAIN Initiative was launched last year by Obama as a large-scale federal effort to help scientists develop new tools and technologies to gain a deeper understanding of how the brain functions and to accelerate the creation of new treatments for neurological disorders.

“These initial awards are part of a 12-year scientific plan focused on developing the tools and technologies needed to make the next leap in understanding the brain,” Collins said. “This is just the beginning of an ambitious journey and we’re excited about the possibilities.”

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‘Frenemy’ in Parkinson’s takes to crowdsourcing


Protein regulates neuronal communication by self-association.

The protein alpha-synuclein is a well-known player in Parkinson’s disease and other related neurological conditions, such as dementia with Lewy bodies. Its normal functions, however, have long remained unknown. An enticing mystery, say researchers, who contend that understanding the normal is critical in resolving the abnormal.

Alpha-synuclein typically resides at presynaptic terminals – the communication hubs of neurons where neurotransmitters are released to other neurons. In previous studies, Subhojit Roy, M.D., Ph.D., and colleagues at the UC San Diego School of Medicine had reported that alpha-synuclein diminishes neurotransmitter release, suppressing communication among neurons. The findings suggested that alpha-synuclein might be a kind of singular brake, helping to prevent unrestricted firing by neurons. Precisely how, though, was a mystery.

Then Harvard University researchers reported in a recent study that alpha-synuclein self-assembles multiple copies of itself inside neurons, upending an earlier notion that the protein worked alone. And in a new paper, published this month in Current Biology, Roy, a cell biologist and neuropathologist in the departments of pathology and neurosciences, and co-authors put two and two together, explaining how these aggregates of alpha-synuclein, known as multimers, might actually function normally inside neurons.

First, they confirmed that alpha-synuclein multimers do in fact congregate at synapses, where they help cluster synaptic vesicles and restrict their mobility. Synaptic vesicles are essentially tiny packages created by neurons and filled with neurotransmitters to be released. By clustering these vesicles at the synapse, alpha-synuclein fundamentally restricts neurotransmission. The effect is not unlike a traffic light – slowing traffic down by bunching cars at street corners to regulate the overall flow.

“In normal doses, alpha-synuclein is not a mechanism to impair communication, but rather to manage it. However it’s quite possible that in disease, abnormal elevations of alpha-synuclein levels lead to a heightened suppression of neurotransmission and synaptic toxicity,” said Roy.

“Though this is obviously not the only event contributing to overall disease neuropathology, it might be one of the very first triggers, nudging the synapse to a point of no return. As such, it may be a neuronal event of critical therapeutic relevance.”

Indeed, Roy noted that alpha-synuclein has become a major target for potential drug therapies attempting to reduce or modify its levels and activity.

Co-authors include Lina Wang, Utpal Das and Yong Tang, UC San Diego; David Scott, Massachusetts Institute of Technology; and Pamela J. McLean, Mayo Clinic-Jacksonville.

Funding support for this research came from National Institutes of Health (grant P50AG005131-project 2) and the UC San Diego Alzheimer’s Disease Research Center.

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Seeding innovations in brain research


UC Berkeley, UCSF, Berkeley Lab join forces on BRAINseed collaboration.

Michel Maharbiz of electrical engineering and computer science describes a project to probe more deeply into the cerebral cortex. (Photo by Roy Kaltschmidt, Berkeley Lab)

Two state-of-the-art research areas – nanotech and optogenetics – were the dominant theme last Thursday, Sept. 18, as six researchers from UC Berkeley, UC San Francisco and Lawrence Berkeley National Laboratory sketched out their teams’ bold plans to jump-start new brain research.

The rapid-fire talks kicked off a one-of-a-kind collaboration among the three institutions in which each put up $1.5 million over three years to seed innovative but risky research. Called BRAINseed, the partnership could yield discoveries that accelerate President Barack Obama’s national BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative and California’s own Cal-BRAIN Initiative.

“It’s clear to everybody that any attempt to understand how the brain works, or ultimately what we might mean by cognition, is so daunting and so large that no one institution could hope to be a stand-alone leader in such an effort,” said Graham Fleming, UC Berkeley vice chancellor for research. “The synergies between UCSF, Lawrence Berkeley National Lab and UC Berkeley are very strong, and we complement one another in very effective ways.”

“This tri-partnership is unprecedented in the history of our institutions,” noted Horst Simon, deputy director of Berkeley Lab. “We are putting money down to fund a real collaboration that makes people sit down together and address some of the most challenging questions today.”

“BRAINseed underscores the tremendous power embodied in the institutions in the Bay Area, and the potential for amazing things to happen if we can overcome the geographical separations,” said Keith Yamamoto, UCSF vice chancellor for research.

When Obama announced the federal BRAIN Initiative in April 2013, he allocated $110 million for fiscal year 2014. This funding is already supporting several projects at UC Berkeley. Obama has proposed even more funding in future years “to revolutionize our understanding of the human mind and uncover new ways to treat, prevent, and cure brain disorders like Alzheimer’s, schizophrenia, autism, epilepsy and traumatic brain injury.”

Similarly, Cal-BRAIN — short for California Blueprint for Research to Advance Innovations in Neuroscience — aims to “accelerate the development of brain mapping techniques, including the development of new technologies.” The initial appropriation in this year’s state budget was $2 million.

Both Cal-BRAIN and the national initiative are expected to spur new startups in the area of neurotechnology based on the tools and inventions created in research labs. The innovations developed through these initiatives could have broad applications in disease monitoring beyond the brain and even outside the health care field.

“What we want to do is build a climate of collaboration so that we are stronger competitors in the national brain program and Cal-BRAIN,” Fleming said. “We see BRAINseed as a model for future collaborations (among the three institutions).”

Probing deeper into the brain

The six winning projects of 17 proposals originally submitted focus on new methods of mapping the brain and studying neurons deeper in the brain than ever before.

Fiberless deep brain imaging: Using novel nanocrystals developed by Bruce Cohen at Lawrence Berkeley National Laboratory, and biosensing and bioactuating molecules synthesized by Chris Chang and Ehud Isacoff at UC Berkeley, researchers hope to probe cell-to-cell communication deeper in the brain than ever before. The technique takes advantage of the fact that near infrared (NIR) light with its shorter wavelengths penetrates deeper into the brain than does visible light. The nanocrystals from Cohen’s lab absorb the NIR light and convert it into visible light. The visible light can then trigger optogenetic photoswitches that turn neuron receptors on and off, as well as activate biosensors that record the release of neurotransmitters at the synapse. Coupled with techniques developed by Charly Craik and Robert Edwards at UCSF for targeting probes to specific cells, the researchers on this project hope to be able to study cell signaling in the many layers of the cortex.

Integrated nanosystems: Our senses of touch and hearing, as well as our ability to feel pain and detect the position of our body in space, are all made possible by a special class of proteins known as mechanoreceptors. Scientists studying this system in cell culture have traditionally used micropipettes to apply pressure to mechanoreceptors, while microelectrodes record the resulting neural activity. But small as they are, these devices are much too bulky to precisely stimulate single receptors or make accurate neural recordings. A team led by UCSF’s Young-wook Jun is devising a system to overcome these limitations. In the new setup, magnetic nanoparticles controlled by micromagnetic “tweezers” will have the capacity to stimulate individual mechanoreceptors, and high-resolution optical signals emitted by “quantum dots,” developed in the lab of Paul Alivisatos of UC Berkeley and Berkeley Lab, will offer a truer picture of neural activity in sensory neurons. They will collaborate with UCSF’s Yuh Nung Jan.

In vivo optogenetic mechanisms: We think of the action of neurotransmitters as rapid and localized, but the effects of acetylcholine (ACh) in the brain are actually quite diffuse and unfold slowly. The hormone-like characteristics of ACh make it difficult to understand through conventional neurophysiology experiments. As a result, ACh transmission, which plays a role in Alzheimer’s and Parkinson’s diseases and in addiction, is poorly understood despite decades of study. UC Berkeley’s Richard Kramer has devised a system that enables researchers to use light to switch ACh receptors on and off in animals. Using this system, Kramer and UCSF’s Michael P. Stryker will be able to study how ACh modulates behavior in a wholly new way.

Acousto-optic virtual waveguides: Optogenetics approaches to probe the brain’s grey matter, or cortex, work only as deep as the light can penetrate, typically only a fraction of a millimeter below the surface. UC Berkeley engineers have developed a novel way to channel light deeper – more than a millimeter deep – to probe cell-to-cell signaling. Engineer Michel Maharbiz proposes to use ultrasound to create ‘waveguides’ that can steer light below the surface of the cortex, stimulating photoswitches that enable the study of neurotransmitters. With light-sensitive probes developed at Berkeley Lab and cell-imaging techniques from UCSF, the technology would open new avenues for non-invasive in-vivo imaging and stimulation of local brain areas. Maharbiz’s collaborators are Jim Schuck of Berkeley Lab, Reza Alam of UC Berkeley and Vikaas Singh Sohal of UCSF.

Optical integrators of neuronal activity: One of the greatest challenges in understanding the brain is connecting what happens over large volumes and hundreds of thousands of neurons to the signals transmitted at the individual synapse, the connection between nerve cells where communication takes place. Because calcium is key to neuronal signaling, a team led by Evan Miller, UC Berkeley assistant professor of molecular and cell biology and of chemistry, plans to use probes developed in his lab that ‘remember’ calcium concentration. Along with co-collaborators Pam den Besten and Terumi Kohwi-Shigematsu at UCSF and Berkeley Lab, respectively, Miller plans to investigate neuronal activity in models of disease. They can then correlate this with what happens over a larger volume of the brain. The technique combines “click chemistry” pioneered at UC Berkeley with probes generated in the Department of Chemistry to integrate images over different scales. This technique is a vital first step in developing tools that remember neuronal activity and enable 3D reconstruction of activity across entire brain regions with cellular resolution.

Development of instrumentation and computational methods: Though great progress has been made in mapping the function of the human brain, researchers have been stymied by limitations in both recording devices and the ability to analyze and understand brain signals. UCSF’s Edward F. Chang, M.D., is leading a team that aims to achieve up to a thousandfold increase in the density and electronic sophistication of recording arrays. The vast amount of data collected by these arrays will be stored and analyzed by some of the world’s most powerful computers at the National Energy Research Scientific Computing Center (NERSC), enabling a new level of understanding of the brain in both health and disease. Chang’s collaborators are Peter Denes and Kristofer Bouchard of Berkeley Lab and Fritz Sommer of UC Berkeley.

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‘Dimmer switch’ discovered for mood disorders


UC San Diego study’s findings have implications for how to treat depression.

Basal ganglia neurons (green) feed into the brain and release glutamate (red) and GABA (blue) and sometimes a mix of both neurotransmitters (white).

Researchers at the UC San Diego School of Medicine have identified a control mechanism for an area of the brain that processes sensory and emotive information that humans experience as “disappointment.”

The discovery of what may effectively be a neurochemical antidote for feeling let-down is reported today (Sept. 18) in the online edition of Science.

“The idea that some people see the world as a glass half empty has a chemical basis in the brain,” said senior author Roberto Malinow, M.D., Ph.D., professor in the Department of Neurosciences and neurobiology section of the Division of Biological Sciences. “What we have found is a process that may dampen the brain’s sensitivity to negative life events.”

Because people struggling with depression are believed to register negative experiences more strongly than others, the study’s findings have implications for understanding not just why some people have a brain chemistry that predisposes them to depression but also how to treat it.

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