TAG: "brain"

Neurobiologists restore youthful vigor to adult brains

Reactivated plasticity points to new treatments for developmental disorders.

UC Irvine neurobiologist Sunil Gandhi led the study that, in a sense, coaxed old brain processes to become young again. (Photo by Steve Zylius, UC Irvine)

By Tom Vasich, UC Irvine

They say you can’t teach an old dog new tricks. The same can be said of the adult brain. Its connections are hard to change, while in children, novel experiences rapidly mold new connections during critical periods of brain development.

UC Irvine neurobiologist Sunil Gandhi and colleagues wanted to know whether the flexibility of the juvenile brain could be restored to the adult brain. Apparently, it can: They’ve successfully re-created a critical juvenile period in the brains of adult mice. In other words, the researchers have reactivated brain plasticity – the rapid and robust changes in neural pathways and synapses as a result of learning and experience.

And in doing so, they’ve cleared a trail for further study that may lead to new treatments for developmental brain disorders such as autism and schizophrenia. Results of their study appear online in Neuron.

The scientists achieved this by transplanting a certain type of embryonic neuron into the brains of adult mice. The transplanted neurons express GABA, a chief inhibitory neurotransmitter that aids in motor control, vision and many other cortical functions.

Much like older muscles lose their youthful flexibility, older brains lose plasticity. But in the Gandhi study, the transplanted GABA neurons created a new period of heightened plasticity that allowed for vigorous rewiring of the adult brain. In a sense, old brain processes became young again.

In early life, normal visual experience is crucial to properly wire connections in the visual system. Impaired vision during this time leads to a long-lasting visual deficit called amblyopia. In an attempt to restore normal sight, the researchers transplanted GABA neurons into the visual cortex of adult amblyopic mice.

“Several weeks after transplantation, when the donor animal’s visual system would be going through its critical period, the amblyopic mice started to see with normal visual acuity,” said Melissa Davis, a postdoctoral fellow and lead author of the study.

These results raise hopes that GABA neuron transplantation might have future clinical applications. This line of research is also likely to shed light on the basic brain mechanisms that create critical periods.

“These experiments make clear that developmental mechanisms located within these GABA cells control the timing of the critical period,” said Gandhi, an assistant professor of neurobiology & behavior.

He added that the findings point to the use of GABA cell transplantation to enhance retraining of the adult brain after injury. Furthermore, this work sparks new questions as to how these transplanted GABA neurons reactivate plasticity, the answers to which might lead to therapies for currently incurable brain disorders.

Dario Figueroa Velez, Roblen Guevarra, Michael Yang, Mariyam Habeeb and Mathew Carathedathu of UCI contributed to the study, which was supported by a National Institutes of Health Director’s New Innovator Award (DP2 EY024504-01), a Searle Scholars award, a Klingenstein Fellowship and a postdoctoral training grant from the California Institute for Regenerative Medicine (TG2-01152).

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Measuring ‘brainstorms’

Researchers pioneer technique permitting peek inside neurons at activity of ion channels.

A team led by Peter Burke, UC Irvine professor of electrical engineering & computer science, developed a detector that offers a window into the inner workings of the brain and a brand-new tool for future research. (Photo by Steve Zylius, UC Irvine)

By Pat Brennan, UC Irvine

Like a gathering storm, tiny electrical pulses in a brain cell coalesce into a kind of explosion: the firing of a single neuron.

And the firing of billions of neurons provides each of us with the inner experiences that define our lives – seeing, hearing, thinking, even noting the passage of time between heartbeats.

In a feat of engineering that could extend the reach of both nanotechnology and neurobiology, UC Irvine researchers have found a way to peer inside a neuron and watch as the storm gathers.

Using carbon nanowires only a few atoms thick, the team – led by electrical engineering & computer science professor Peter Burke – managed to eavesdrop on the opening and closing of ion channels at the scale of a single brain cell.

Ions are charged particles that transmit electrical signals. The collective activity of thousands or millions of channels through which they flow is what causes a neuron to fire.

“When it rains, you get a weather report that tells how many inches of rain fell in a given period,” says Burke, whose work was published last month in Scientific Reports. “The weatherman doesn’t measure each drop.”

But the technique his team developed, he says, is the equivalent of “measuring each individual drop of rain.”

That’s a first. “No one has ever measured a single ion channel with a single nanowire before,” Burke says.

The method offers a window into the inner workings of the brain and a brand-new tool for future research.

And it could significantly advance the goals of President Barack Obama’s BRAIN Initiative, announced in 2013, which seeks to map brain functions and attack neurological disorders such as Alzheimer’s, epilepsy and autism.

The team began by creating an artificial cell. Its wall, like that of a real cell, is pockmarked with pores that open and close, allowing ions to flow in and out.

Next, the scientists installed nanowires just outside the artificial cell’s wall. The wires are capable of registering minuscule fluxes of energy and picked up the pelting of “raindrops” – in this case, the size of atoms – signaling the opening and closing of ion channels.

For now, the nanowire detector is confined to its carefully constructed laboratory setting. Asked to speculate, however, Burke sees a number of potentially revolutionary applications in the years and decades ahead.

A nanowire detector, for example, could be implanted in a living human brain, perhaps providing therapy for brain disorders or simply monitoring the organ itself and learning the submicroscopic details of information traffic among brain cells.

No one has yet developed a way to implant such a device, Burke notes, and doing so might be difficult. One possible avenue: attach the detector to a free-floating “nano radio” that could broadcast data about the state of ion channels.

“So many processes in life, in biology, are using electricity,” Burke says. “The cell, in a sense, is converting some physical phenomenon into an electrical signal. It all involves these ion channels.”

All our senses, from vision to smell, rely on these channels, he says, adding that in the future “you could have an artificial nose, an artificial eye.”

Electricity is critical to coordinate the beating of our hearts and other life-or-death bodily functions, such as the release of insulin in response to sugar in the blood. So the new detectors could, for instance, lead to a better understanding of diabetes.

And the ability to spy on ion channel activity could prove invaluable for cancer researchers. “You could use this technique to measure how chemotherapy affects cell death or to figure out why cancer cells don’t die,” Burke says.

Another important potential use is in drug screening. Fifteen percent of all pharmaceuticals act on ion channels; knowing how they do it could greatly improve the reliability of testing to ensure a drug’s safety and effectiveness.

“This wire, a few atoms across, is sensitive enough to measure with unprecedented resolution the way neurons work,” Burke says.

The study’s lead author is Weiwei Zhou, and co-authors are Yung Yu Wang, Tae-Sun Lim, Ted Pham and Dheeraj Jain.

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Deep brain stimulation tested as treatment for cognitive changes in Parkinson’s

UC Davis first to test low-frequency strategy for cognitive processing.

Kia Shahlaie, UC Davis

By Karen Finney, UC Davis

Surgeons at UC Davis Health System are testing an innovative method of limiting cognitive decline in patients with Parkinson’s disease. The treatment — deep brain stimulation, or DBS — involves delivering low levels of electrical stimulation to a part of the brain that controls the abilities to think, plan and remember.

Parkinson’s affects more than a million U.S. adults, with as many as 60,000 new diagnoses each year. It occurs when brain cells die that release dopamine — a chemical necessary for effective cell signaling — leading to the disease’s hallmark symptoms of movement slowness, rigidity and tremors. But it also alters cognition, said Kia Shahlaie, assistant professor of neurological surgery and principal investigator of the study.

“Parkinson’s disease profoundly affects learning and memory as it progresses, and we currently have no good treatments for these aspects of the disease,” said Shahlaie.

DBS reduces the motor symptoms of Parkinson’s but hasn’t been shown to improve cognition. Based on promising recent research, including studies in his own lab, Shahlaie’s new study will involve low-frequency stimulation.

“Other studies used high-frequency stimulation that works for reducing motor symptoms,” said Shahlaie. “This is the first to test a low-frequency strategy for cognitive processing.”

Participants in the clinical study have advanced Parkinson’s disease and are scheduled to begin DBS of the subthalamic nucleus (STN), a structure located deep in the brain that controls motor symptoms. They will first receive low-frequency (or theta) stimulation targeting an isolated portion of the STN involved in cognition. Detailed before-and-after tests of memory, learning and rule use will determine if the approach improves cognitive processing.

“We are part of a new frontier of DBS investigation to find out if it can help correct both motor and non-motor symptoms and preserve quality of life for our patients,” said Shahlaie.

The study is funded in part by a donation from the Chevo Foundation, a Sacramento-based philanthropy focused on raising awareness and research funding for Parkinson’s disease.

For additional details about the study, call (916) 734-3660.

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Drug perks up old muscles, aging brains

UC Berkeley finding could lead to drug interventions for humans.

A small-molecule drug may hold the key to fitter muscle and brain as we age. (Credit: iStock)

By Robert Sanders, UC Berkeley

Whether you’re brainy, brawny or both, you may someday benefit from a drug found to rejuvenate aging brain and muscle tissue.

Researchers at the University of California, Berkeley, have discovered that a small-molecule drug simultaneously perks up old stem cells in the brains and muscles of mice, a finding that could lead to drug interventions for humans that would make aging tissues throughout the body act young again.

“We established that you can use a single small molecule to rescue essential function in not only aged brain tissue but aged muscle,” said co-author David Schaffer, director of the Berkeley Stem Cell Center and a professor of chemical and biomolecular engineering. “That is good news, because if every tissue had a different molecular mechanism for aging, we wouldn’t be able to have a single intervention that rescues the function of multiple tissues.”

The drug interferes with the activity of a growth factor, transforming growth factor beta 1 (TGF-beta1), that Schaffer’s UC Berkeley colleague Irina Conboy showed over the past 10 years depresses the ability of various types of stem cells to renew tissue.

“Based on our earlier papers, the TGF-beta1 pathway seemed to be one of the main culprits in multi-tissue aging,” said Conboy, an associate professor of bioengineering. “That one protein, when upregulated, ages multiple stem cells in distinct organs, such as the brain, pancreas, heart and muscle. This is really the first demonstration that we can find a drug that makes the key TGF-beta1 pathway, which is elevated by aging, behave younger, thereby rejuvenating multiple organ systems.”

The UC Berkeley team reported its results in the current issue of the journal Oncotarget. Conboy and Schaffer are members of a consortium of faculty who study aging within the California Institute for Quantitative Biosciences (QB3).

Depressed stem cells lead to aging

Aging is ascribed, in part, to the failure of adult stem cells to generate replacements for damaged cells and thus repair the body’s tissues. Researchers have shown that this decreased stem cell activity is largely a result of inhibitory chemicals in the environment around the stem cell, some of them dumped there by the immune system as a result of chronic, low-level inflammation that is also a hallmark of aging.

In 2005, Conboy and her colleagues infused old mice with blood from young mice – a process called parabiosis – reinvigorating stem cells in the muscle, liver and brain/hippocampus and showing that the chemicals in young blood can actually rejuvenate the chemical environment of aging stem cells. Last year, doctors began a small trial to determine whether blood plasma from young people can help reverse brain damage in elderly Alzheimer’s patients.

Such therapies are impractical if not dangerous, however, so Conboy, Schaffer and others are trying to track down the specific chemicals that can be used safely and sustainably for maintaining the youthful environment for stem cells in many organs. One key chemical target for the multi-tissue rejuvenation is TGF-beta1, which tends to increase with age in all tissues of the body and which Conboy showed depresses stem cell activity when present at high levels.

Five years ago, Schaffer, who studies neural stem cells in the brain, teamed up with Conboy to look at TGF-beta1 activity in the hippocampus, an area of the brain important in memory and learning. Among the hallmarks of aging are a decline in learning, cognition and memory. In the new study, they showed that in old mice, the hippocampus has increased levels of TGF-beta1 similar to the levels in the bloodstream and other old tissue.

Using a viral vector that Schaffer developed for gene therapy, the team inserted genetic blockers into the brains of old mice to knock down TGF-beta1 activity, and found that hippocampal stem cells began to act more youthful, generating new nerve cells.

Drug makes old tissue cleverer

The team then injected into the blood a chemical known to block the TGF-beta1 receptor and thus reduce the effect of TGF-beta1. This small molecule, an Alk5 kinase inhibitor already undergoing trials as an anticancer agent, successfully renewed stem cell function in both brain and muscle tissue of the same old animal, potentially making it stronger and more clever, Conboy said.

“The key TGF-beta1 regulatory pathway became reset to its young signaling levels, which also reduced tissue inflammation, hence promoting a more favorable environment for stem cell signaling,” she said. “You can simultaneously improve tissue repair and maintenance repair in completely different organs, muscle and brain.”

The researchers noted that this is only a first step toward a therapy, since other biochemical cues also regulate adult stem cell activity. Schaffer and Conboy’s research groups are now collaborating on a multi-pronged approach in which modulation of two key biochemical regulators might lead to safe restoration of stem cell responses in multiple aged and pathological tissues.

“The challenge ahead is to carefully retune the various signaling pathways in the stem cell environment, using a small number of chemicals, so that we end up recalibrating the environment to be youth-like,” Conboy said. “Dosage is going to be the key to rejuvenating the stem cell environment.”

Other co-authors of the paper are former graduate student Hanadie Yousef, now at Stanford University; and Michael Conboy, Adam Morgenthaler, Christina Schlesinger, Lukasz Bugaj, Preeti Paliwal and Christopher Greer of UC Berkeley’s bioengineering department and QB3.

The work was supported by grants from the National Institutes of Health, California Institute for Regenerative Medicine and a Rogers Family Foundation Bridging-the-Gap Award.

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Research finds differences in brains, behavior of girls and boys with autism

UC Davis study uses imaging technique to neuroanatomically subdivide corpus callosum.

New research by the MIND Institute finds that the brains and behavior of girls with autism differs from that of boys with autism and typically developing girls.

By Phyllis Brown, UC Davis

New research conducted by the UC Davis MIND Institute on a large cohort of preschoolers with autism spectrum disorder has found differences in the underlying biology of their brains, and in their behavior, that may help explain how the condition affects a little-studied and poorly understood population of children: girls.

Autism spectrum disorder is diagnosed much more frequently in boys than girls, at a ratio of 4 to 1. Despite recent efforts, little research has been done on girls — there are fewer of them, so fewer are represented in autism research. An estimated 1 in 42 boys has autism; in girls the statistic is 1 in 189.

The U.S. Centers for Disease Control and Prevention currently estimates the overall incidence of autism at 1 in 68 children born today.

In a brain study, the researchers found differences in the corpus callosum, the region of the brain that connects the left and right hemispheres.

That study is published online today (May 12) in the journal Molecular Autism, as part of a special issue devoted to gender differences. It adds to the growing body of evidence that suggests that in autism, there are underlying biological differences between boys and girls.

In separate research presented at the International Meeting for Autism Research (IMFAR) in Salt Lake City May 13-16, the researchers find that the behavioral differences between girls who have autism and typically developing same-age girls are much greater than the differences between boys with autism and typically developing same-age males. The finding suggests that girls with autism have greater social impairments than do boys.

The research was led by Christine Wu Nordahl, assistant professor in the UC Davis Department of Psychiatry and Behavioral Sciences and principal investigator of the Girls with Autism Imaging of Neurodevelopment (GAIN) study.

“It’s important to identify differences in underlying biology in boys and girls, because this could help us determine whether there are different etiologies of autism, and that potentially could lead us to different treatments and interventions,” Nordahl said.

Brain study

The magnetic resonance imaging (MRI) study of brain structure was conducted in a large sample of 3- to 5-year-old children, 112 boys and 27 girls — a large number for girls with autism — and 53 boys and 29 girls who were developing typically and served as control subjects.

“Previous studies have found alterations in the corpus callosum in children and adults with autism, but most were focused on males only, or had very small female sample sizes,” Nordahl said.

The study used a technique called diffusion tensor imaging (DTI), a type of magnetic resonance imaging that allowed the researchers to neuroanatomically subdivide the corpus callosum, based on where in the cerebral cortex the fibers projected.

“We found that the organization of callosal fibers was different in boys and girls with autism, particularly those projecting into the frontal lobes,” she said. “The frontal lobes are involved in many aspects of functioning, including social behavior, goal-directed behavior and executive functioning. Differences in the patterns of callosal fibers projecting to these areas may lead to differences in how autism manifests in boys and girls.”

Behavioral study

For the preliminary research presented at IMFAR, Nordahl explored behavioral differences in boys and girls with autism. Research in the area previously has been inconsistent.

“Most behavioral studies of gender differences directly compare males and females with autism. Our approach was to evaluate social impairments in a large group of children that included girls and boys with both autism and typical development,” Nordahl said. “We were interested not only in directly comparing boys and girls with autism, but also in assessing how boys and girls with autism compare in relation to their typically developing peers.”

“We found that the behavioral differences between girls with autism and typically developing girls are much larger than differences between boys with autism and typically developing boys,” she said. “In other words, girls with autism deviate further from typically developing girls than boys with autism relative to typically developing males, suggesting that girls with autism have more severe social impairments than boys.”

Nordahl said that much more works needs to be done to understand the sex differences between male and female children with autism, and particularly, increasing the numbers of female children who participate in autism research.

Future studies in Nordahl’s laboratory will include targeted recruitment of girls with autism, in order to carry out a comprehensive evaluation of behavioral and neurobiological differences in boys and girls with autism in relation to each other, as well as to their typically developing peers.

“There definitely is a need to evaluate more girls with autism, to fully understand the differences between boys and girls,” she said.

Nordahl said that the GAIN Study hopes to evaluate an additional 100 preschool-aged girls with autism during the next three years.

For further information regarding enrollment in the study contact Study Coordinator Michelle Huynh, (916) 703-0410, mmhuynh@ucdavis.edu.

The study was funded by the National Institute of Mental Health R01 MH089626, U24 MH081810, R00 MH085099 and the UC Davis MIND Institute. Statistical support was provided by the MIND Institute Intellectual and Developmental Disabilities Research Center U54 HD079125.

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Study sheds new light on low-light vision

Brain handles day- and nighttime optical signals the same, reacts quickly to loss of input.

Alyssa Brewer, UC Irvine

By Heather Ashbach, UC Irvine

Driving down a dimly lit road at midnight can tax even those with 20/20 vision, but according to a recent UC Irvine study, the brain processes the experience no differently than if it were noon. The same study also reveals how quickly the brain adapts to vision loss, contradicting earlier research and opening the door to novel treatments.

The findings, which appear in the April 21 edition of Proceedings of the National Academy of Sciences, are significant for those who have suffered retinal damage or disease, said cognitive scientist Alyssa Brewer, the lead author.

“Previous research suggested that the two areas of the brain responsible for color processing received input only from cone photoreceptors – the parts of the retina used in central, normal daylight vision for things like reading and seeing details and colors in a scene,” she said.

However, Brewer and co-author Brian Barton, a postdoctoral researcher in cognitive sciences, employed functional MRI to determine that rod photoreceptors, which are only active under very low light, also play a role in the color experience and use the same neural pathways that cones do.

“This is surprising because there are no rods in the central part of the retina, the part we use to see fine details,” Brewer said. “We are functionally blind in the center of our vision under low light, something we call a ‘rod scotoma.’”

To compensate for this vision loss, people look at objects under low light at an angle that accesses the rod receptors.

This adaptation gives researchers an opportunity to track how the brain responds to what the eye sees without using central vision – similar to the way individuals with retinal damage interpret what they see.

Brewer and Barton had test subjects sit in a completely dark room for 30 minutes and then view checkerboard stimuli under very low light while their brain activity was measured with fMRI. In addition to the neural pathway finding, they discovered that the brain adapts immediately to required shifts in vision – a process previous work had said could take months.

“The amount and timing of the brain’s ability to reorganize to compensate for a loss of visual input is very important for us to understand what types of rehabilitation can help recovery,” Brewer said. “The temporary and reversible rod scotoma from low-light conditions provides an excellent way for us to study how the brain reacts and recovers from vision loss, something we found to be immediate rather than long-term.”

“By being able to accurately track how the brain responds to retinal damage, we can begin to create new rehabilitation techniques that could help restore vision,” she added.

The study is available online at www.pnas.org/content/early/2015/04/01/1423673112.full.pdf.

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New combination treatment strategy to ‘checkmate’ brain tumors

Three different classes of anti-cancer drugs work synergistically against brain tumors.

Normal cell dividing (left) and stressed cancer cell dividing (right). PLK1 inhibitors stress cancer cells, making them easier to kill.

By Heather Buschman, UC San Diego

Therapies that specifically target mutations in a person’s cancer have been much-heralded in recent years, yet cancer cells often find a way around them. To address this, researchers at the UC San Diego School of Medicine and Moores Cancer Center identified a promising combinatorial approach to treating glioblastomas, the most common form of primary brain cancer.

The study, published May 5 by Oncotarget, demonstrates that a mouse model of glioblastoma and human glioblastoma tissue removed from patients and cultured in the lab can be effectively treated by combining three classes of anti-cancer drugs: a drug that targets a cancer mutation in the Epidermal Growth Factor Receptor (EGFR) gene, a drug that increases stress in cancer cells and a drug that damages cancer cell DNA.

“Developing therapies against glioblastoma is like a chess game. For each therapy administered, or move, by the physician, the cancer makes a counter-move,” said senior author Clark Chen, M.D., Ph.D., associate professor of neurosurgery and vice chair of research and academic development at UC San Diego.

In up to 50 percent of glioblastomas, mutations in the EGFR gene render cancer cells insensitive to growth regulation by environmental cues, allowing them to grow uncontrollably. Yet highly specific EGFR inhibitors are not particularly effective against glioblastomas with EGFR mutations.

“When glioblastoma cells are treated with EGFR inhibitors, they turn on another receptor to bypass the need for EGFR,” said Chen. “Any hope of an effective treatment requires a combination of moves strategically designed for a checkmate.”

To develop such a strategy, Chen and his group turned to PLK1, a protein that regulates stress levels within glioblastoma cells and is essential for their survival. Chen and his group found that glioblastoma cells that developed resistance to EGFR inhibitors remain universally dependent on this protein.

In mouse models of glioblastoma and in explants of human glioblastoma, singular treatment with an EGFR inhibitor, a PLK1 inhibitor or the current standard of care drug (a DNA-damaging agent), each temporarily halted glioblastoma growth. But, like the human disease, the tumor eventually grew back. However, no detectable tumor recurrence was observed when a combination of all three classes of drugs was administered. The treated mice tolerated this combination regimen without showing significant side effects.

“It is often assumed that if we find the cancer-causing mutation and inhibit the function of that mutation, we will be able to cure cancer,” said study co-author Bob S. Carter, M.D., Ph.D., chief of neurosurgery at UC San Diego. “Our study demonstrates that the reality is far more complex. Our results provide a blueprint for how to leverage fundamental biologic concepts to tackle this challenging complexity.”

The three drugs administered to mice in this study were: BI2536, a PLK1 inhibitor; Gefitnib, an EGFR inhibitor; and TMZ, the standard-of-care chemotherapy for glioblastoma. The study authors note that while the safety or side effects of treating human patients will all three drugs is unknown, all are individually well-tolerated in humans. The clinical safety profiles of Gefitinib and TMZ are well-established for glioblastoma patients and PLK1 inhibitors have so far been well-tolerated in clinical trials (one has advanced to phase three clinical trials for acute myeloid leukemia).

Co-authors of this study include Ying Shen, UC San Diego and Shanghai Jiao Tong University; Jie Li, Diahnn Futalan, Tyler Steed, Jeffrey M Treiber, and Zack Taich, UC San Diego; Masayuki Nitta, Dana-Farber Cancer Institute; Deanna Stevens, Jill Wykosky, Frank B. Furnari, Webster K. Cavenee, and Arshad Desai, UC San Diego and Ludwig Cancer Research; Hong-Zhuan Chen, Shanghai Jiao Tong University; Oren J. Becher, Duke University Medical Center; Richard Kennedy, Queen’s University of Belfast; Fumiko Esashi, University of Oxford; and Jann N. Sarkaria, Mayo Clinic.

This research was funded, in part, by the Sontag Foundation, Burroughs Wellcome Foundation, Kimmel Foundation, Doris Duke Foundation and Forbeck Foundation.

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UC teams receive $3.5M for neuroscience research

UCLA, UCSF teams among Allen Distinguished Investigator recipients.

Six groups of researchers from leading academic institutions, including three from the University of California, have been awarded funding from the Paul G. Allen Family Foundation in the field of neuroscience.

The Allen Distinguished Investigator (ADI) grants fund a total of $7.5 million over three years to solve one of the most challenging roadblocks in neuroscience: growing mature human brain cells in the laboratory.

The recipients include two teams from UCLA and one from UC San Francisco.

UCLA honorees William Lowry and Kathrin Plath will receive $1.3 million, while the other UCLA team, Daniel Geschwind and Steve Horvath, will receive $1.2 million.

UCSF honorees Erik Ullian and David Rowitch will receive $1 million in funding.

“I was happily surprised by the announcement,” Ullian said. “The great thing about this funding is that it will allow us to try to move our research forward in a new and high risk/high reward direction.”

The six projects chosen to receive ADI grants in the field of neuronal maturation all tackle one or more of these challenges in bold new ways, including using innovative technologies and novel points of view.

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Seeing through Alzheimer’s disease

UC Berkeley’s William Jagust uses imaging to help find insights into Alzheimer’s.

William Jagust’s Alzheimer’s research has found evidence of neuron networks breaking down. (Photo by Peg Skorpinski, UC Berkeley)

By Wallace Ravven

A jury would have to acquit. Two tough guys are caught at the scene of a brutal beating, but no one witnessed the crime. No video cameras or cell phone captured the assault. Maybe both men arrived after the attack. Or one might have acted alone. They’re suspicious, but not guilty beyond a reasonable doubt.

The same might be said about our current understanding of how Alzheimer’s disease develops. Two proteins — called beta-amyloid and tau — definitely muck up neurons in Alzheimer’s victims.  Amyloid clumps into plaques that interfere with cell-to-cell communication. Tau proteins contort into tangled fibers inside the cells.

But until recently, neuroscientists have not been able to track the course of Alzheimer’s in the brain. Amyloid and tau might not destroy neurons directly, or perhaps amyloid works alone, wrecking the delicate integrity of neural networks and degrading memory.

Researchers have been limited to a single snapshot of the brain — one view of the battlefield provided by an autopsy. The course and chronology of the damage that steals memory are still up for grabs.

“We’ve been scratching our heads about how these two proteins are related to each other and to the cause of Alzheimer’s for literally 100 years,” says Berkeley neuroscientist William Jagust. “We don’t know the difference between ‘normal’ memory loss and the likely pathology associated with tau. We don’t know whether amyloid or tau is most important in Alzheimers, or if amyloid plaques between neurons affect the tau tangles inside cells.”

But there’s a sense of anticipation in the air, buoyed by researchers’ increasing ability to peer into the brains of people struggling with Alzheimer’s as well as  seniors free of its grip. In the past decade, PET scans and other powerful new imaging tools have begun to fill in the story of how healthy and damaged brains change throughout life.

“We still have many questions and few answers,” Jagust says. “But brain PET scanning in both diseased and healthy people is sort of blowing that wide open. We now have the tools to study the progression of plaque formation from its earliest stages and to determine how amyloid and tau affect cognitive decline over time.

Before PET scanning, Jagust says, researchers already knew from autopsies that about a third of older people with amyloid plaques had no symptoms of cognitive decline.

“This created the argument: ‘If they have no symptoms, how can it be that amyloid causes Alzheimer’s?’ You can’t answer that with an autopsy.” But if periodic PET scans show increasing plaque deposition over time as cognitive loss becomes severe, then the plaque argument becomes much stronger.

Research in his lab supports the hypotheses that plaques interfere with the formation or maintenance of synaptic connections. Using the metabolic imaging technique of functional MRI, he focused on plaque-ridden brains of healthy older people, and found indirect, but strong evidence that connections within networks of neurons were breaking down.

“Parts of the brain that should be connected strongly are becoming weakly connected, and parts that are normally not strongly connected become so. It’s almost like the brain is becoming rewired.”

But the rewiring evidence cuts both ways. In another study, Jagust found that some people with amyloid plaques performed as well on memory tests as those who were plaque-free. In some of them, novel connections appeared between neurons in their brains, suggesting new networks were in play.

“There is evidence of ‘rewiring’ that appears to be detrimental, but also evidence of ‘rewiring’ that may serve a compensatory role  — providing a cognitive reserve,” he says. “The balance between these in individuals may explain why some decline and others do not.” The research was published in 2013 in the Journal of Neuroscience and in 2014 in Nature Neuroscience.

Several large clinical trials have shown that experimental immunotherapeutic drugs can at least moderately slow Alzheimer’s amyloid plaque deposition. So far, the decline in plaque buildup has not slowed memory loss. But Jagust is confident that the tremendous boost in brain imaging will lead to effective therapies.

One ambitious study, just launched at Harvard and UC San Diego neuroscientists, combines refined imaging and drug trial, focusing on 1,000 people in their 70s and 80s. Study participants do not have Alzheimer’s, though some have amyloid plaques. Researchers hope that by intervening early enough with drugs to slow plaque accumulation, they can prevent or at least delay severe cognitive loss. If early intervention is key, then so is the ability to detect even the slightest sign of neurological damage. The Jagust Lab is using statistical and computational approaches to refine PET scan sensitivity.

In images of people’s brains with significant amyloid deposits, the protein shows up clearly as fiery orange bands across the cerebral cortex, or gray matter areas of the brain. Jagust suspects that improved scanning will allow researchers to spot mere traces that hint at possible trouble to come. The lab is also beginning studies that will image accumulations of tau, allowing the researchers to understand the relationships between tau and amyloid, and provide another target for drug development.

“If the images can tease apart the different roles of beta-amyloid and tau, and if we can detect damage in its very earliest stages, we would have strong reason to hope that new drugs can spare or significantly slow cognitive damage. I don’t think this is being overly optimistic.”

In recognition of his research on brain aging and dementia, Jagust received the 2013 Potamkin Prize for Research in Pick’s, Alzheimer’s and Related Diseases by the American Academy of Neurology and the American Brain Foundation.

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National Eye Institute awards $3.2M for visionary retina research

Project an effort to better understand how visual data processed before sent to brain.

Human retinal cells taken with adaptive optics scanning laser ophthalmoscopy. Real-time eye tracking allows researchers to optically stimulate individual photoreceptors, as illustrated by the green focused beam in the main figure and in the inset, which shows a magnified mosaic of cones, the cells in the retina responsible for color vision. The dark branched structures are shadows of blood vessels. (Image courtesy of Lawrence Sincich and Kady Bruce, University of Alabama Birmingham.)

By Sarah Yang, UC Berkeley

The National Eye Institute (NEI) has awarded a five-year, $3.2 million grant for a UC Berkeley-led project to map the interaction of retinal cells in an effort to better understand how visual data is processed before it is sent to the brain.

The project is among five awards announced today (May 1) by the NEI as part of its Audacious Goals Initiative, an ambitious program to catalyze research into treatments for blindness. The focus of the initiative is on restoring sight by regenerating neurons and neural connections in the visual system, particularly in the retina.

The NEI is committing up to $17.9 million over five years for this effort.

Austin Roorda, a UC Berkeley professor of optometry and vision science, is the principal investigator of the retinal mapping project. He will be working with E.J. Chichilnisky and Daniel Palanker, both professors of ophthalmology at Stanford University, and B. Hyle Park, an assistant professor of bioengineering at UC Riverside.

The research team will design a system that can not only map cellular interaction in the retina, but can also help monitor the function in regenerated cells. The system will incorporate eye tracking components and adaptive optics.

“We have entered the research phase of the Audacious Goals Initiative. Projects in this first round of AGI funding will bridge gaps in current technology, enabling later phases of the initiative,” said Dr. Paul Sieving, NEI director, in a press statement. Sieving is scheduled to detail the research grants today at the 2015 Association for Research in Vision and Ophthalmology annual meeting.

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Cal-BRAIN selects 16 California research projects for seed grants

Projects will speed development of new brain technologies.

By Jeff Gattas and Inga Kiderra, UC San Diego

Cal-BRAIN, a California research grants program that aims to revolutionize our understanding of the brain, has selected 16 projects to receive inaugural seed grants of $120,000 each. The projects represent efforts around the state to create new technologies capable of measuring brain activity in greater depth, breadth and detail than is currently possible.

An initiative led jointly by UC San Diego and the Lawrence Berkeley National Laboratory, Cal-BRAIN is short for California Blueprint for Research to Advance Innovations in Neuroscience. The program was signed into law in June 2014 and is the California complement to the federal BRAIN Initiative announced by President Barack Obama in 2013.

“State investment is critical to the advancement of important research in California,” said UC San Diego Chancellor Pradeep K. Khosla. “This funding will enable some of our nation’s most talented and innovative researchers to make discoveries that will transform lives and benefit society for years to come.”

Scientists from all California nonprofit research institutions were eligible to apply for Cal-BRAIN grants. And 126 interdisciplinary teams submitted their proposals.

The 16 funded projects will be carried out at 10 UC campuses as well as Caltech, Stanford and the University of Southern California.

“Interdisciplinary, and multi-institutional, research brings many insights and skills to this vital and urgent area of inquiry,” said Sandra A. Brown, vice chancellor for research at UC San Diego. “Support for our work in neurotechnologies will pay dividends in understanding, and healing, the brain.”

The projects will seek to measure four different aspects of the brain’s activity: electrical activity, neurochemical activity, metabolic activity and gene activity. The technological strategies include advances in microscopy, brain imaging, sensors based on nanotechnology and neural prosthetics, explained UC San Diego’s Ralph Greenspan, who co-directs Cal-BRAIN with Paul Alivisatos of the Lawrence Berkeley National Laboratory.

All of the projects aim at innovations that will be applicable to the full spectrum of brain disorders, Greenspan said, and several are specifically keyed to traumatic brain injury, paralysis, epilepsy and Alzheimer’s.

“We are tremendously excited by the quality and originality of the proposals. Getting these innovative projects launched is an essential step in realizing Cal-BRAIN’s goals,” said Greenspan, who, in addition to co-directing Cal-BRAIN, is also director of the Center for Brain Activity Mapping of the Kavli Institute for Brain and Mind at UC San Diego.

The proposals were reviewed by experts outside of California, to reduce the possibility of conflicts of interest. They were first assessed by Cal-BRAIN’s out-of-state scientific advisory board which then made recommendations on relevant subject experts, also out-of-state, to conduct detailed reviews. The review criteria included scientific quality, significance, innovation and scalability. The Cal-BRAIN directors made the final selections based on the reviews and also on relevance to the Cal-BRAIN mission.

Cal-BRAIN has an initial budget allocation of $2 million. The seed grants account for 96 percent, or $1.92 million, of the monies. The remaining $80,000 is going to administrative costs and for conferences with researchers and various California stakeholder groups.

California Assembly Speaker Toni Atkins (D-San Diego), State Sen. Marty Block (D-San Diego), Gov. Jerry Brown and former California Senate President Pro Tem Darrell Steinberg (D-Sacramento) were strong champions of Cal-BRAIN.

“This inter-institutional initiative would not have been possible without the support of the governor and our state legislative leaders who saw the value of Cal-BRAIN’s ability to focus research teams throughout California on the next medical frontier – the brain,” Khosla said. “We are grateful for their resolve to keep California at the forefront of brain research.”

For a full list of the funded projects, including principal investigators and abstracts, see the Cal-BRAIN website.

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The art of mantaining cognitive health as our brains age

Most people can take steps to improve their health, UCSF professor says.

By Laura Kurtzman, UC San Francisco

Brains age, just like the rest of the body, even for those don’t get neurological disease, according to an Institute of Medicine report released on April 14.

“Some of the changes that one observes doesn’t mean that it’s all over, gloom and doom,” the committee’s vice chair, Kristine Yaffe, M.D., told the Washington Post.

While aging does more damage to some than others, most people can take steps to improve their health, according to Yaffe, the Roy and Marie Scola Endowed Chair and professor of psychiatry, neurology and epidemiology at UCSF and chief of geriatric psychiatry and director of the Memory Disorders Clinic at the San Francisco VA Medical Center.

The committee proposed three actions to help maintain cognitive function with age: staying physically active; managing blood pressure and diabetes; and stopping smoking. Aging adults should also pay careful attention to health conditions and medications that could influence their cognitive health.

Having an active social and intellectual life can also promote cognitive health, as can getting good sleep. Aging individuals should treat any sleep disorders that develop and be aware of the delirium that can be caused by medications and hospitalization.

The committee advised caution when evaluating claims that brain training and nutritional supplements can improve cognition.

The scientific literature has shown that older adults can get better at trained abilities, although often more slowly than younger adults, and that they can maintain these skills. But it’s less clear whether these benefits transfer to real-world activities like driving or remembering an appointment.

As for nutritional supplements, the report says the medical literature does not offer convincing support that any of them can prevent cognitive decline.

The committee urged more protections for older adults, who lose an estimated $2.9 billion a year, directly and indirectly, because of financial fraud. The report said government and the financial services industry should take steps to protect older adults from exploitation and help preserve their independence.

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Washington Post: Everything ages, even your brain. Don’t worry so much. It’s probably not Alzheimer’s.

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