TAG: "Neuroscience"

Researchers hone in on Alzheimer’s disease


Gordon supercomputer helps guide new drug designs.

Researchers studying peptides using the Gordon supercomputer at the San Diego Supercomputer Center (SDSC) at UC San Diego have found new ways to elucidate the creation of the toxic oligomers associated with Alzheimer’s disease.

Igor Tsigelny, a research scientist with SDSC, the UCSD Moores Cancer Center and the Department of Neurosciences, focused on the small peptide called amyloid-beta, which pairs up with itself to form dimers and oligomers.

The scientists surveyed all the possible ways to look at the dynamics of conformational changes of these peptides and the possibility that they might organize into the oligomers theorized to be responsible for the degenerative brain disease. In the Feb. 14 issue of the Journal of Alzheimer’s Disease, the researchers suggest their results may generate new targets for drug development.

“Our research has identified amino acids for point mutations that either enhanced or suppressed the formation and toxicity of oligomer rings,” said Tsigelny, the study’s lead author. “Aggregation of misfolded neuronal proteins and peptides may play a primary role in neurodegenerative disorders, including Alzheimer’s disease.”

Tsigelny also noted that recent improvements in computational processing speed have allowed him and other researchers to use a variety of tools, including computer simulations, to take new approaches to examining amyloid-beta, which has proven too unstable for traditional approaches such as X-ray crystallography.

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Brain-training research benefits batters


Study with UC Riverside baseball players significantly improves vision, reduces strikeouts.

Four words no baseball player wants to hear: Strike three. You’re out.

The UC Riverside’s baseball team heard those words less frequently in the 2013 season after participating in novel brain-training research that significantly improved the vision of individual players and may have added up to four or five games to the win column.

The results of that study appear in a paper, “Improved vision and on-field performance in baseball through perceptual learning,” published in today’s (Feb. 17) issue of the peer-reviewed Current Biology.

Most studies of visual abilities focus on mechanisms that might be used to improve sight, such as exercising the ocular muscles. Improvements in vision resulting from those experiments typically do not transfer to real-world tasks, however.

A team of UCR psychologists — professors Aaron Seitz and Daniel Ozer and recent Ph.D. graduate Jenni Deveau —  combined multiple perceptual-learning approaches to determine if improvements gained from an integrated, perceptual learning-based training program would transfer to real-world tasks.

They did.

Before the start of the 2013 NCAA Division 1 baseball season the UCR researchers assigned 19 baseball players to complete 30 25-minute sessions of a vision-training video game Seitz developed. Another 18 team members received no training. Players who participated in the training saw a 31 percent improvement in visual acuity — some gaining as much as two lines on the Snellen eye chart — and greater sensitivity to contrasts in light.

“The vision tests demonstrate that training-based benefits transfer outside the context of the computerized training program to standard eye charts,” Seitz said. “Players reported seeing the ball better, greater peripheral vision and an ability to distinguish lower-contrast objects.”

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Renowned neuroscientist joins UC Irvine


Bruce McNaughton named Distinguished Professor of neurobiology & behavior.

Bruce McNaughton, UC Irvine

Bruce McNaughton, one of the foremost experts on the brain mechanisms underlying memory storage and cognition, has joined the UC Irvine School of Biological Sciences as a Distinguished Professor of neurobiology & behavior. He joins three other bio sci faculty members with the Distinguished Professor title — one of the campus’s highest academic ranks — and is one of only 28 campuswide to receive this designation.

“It’s a great honor … to recruit such a prominent scholar as Dr. McNaughton,” said Frank LaFerla, the Hana & Francisco J. Ayala Dean of the School of Biological Sciences. “His recruitment adds to the rich and strong tradition of neuroscience research at UC Irvine, and many investigators on campus are looking forward to collaborating with his laboratory.”

McNaughton’s work integrates theory, computational modeling and technological development to decode the neural mechanisms of learning and memory, and his research contributions have significantly advanced the understanding of memory. Much of his research program is founded on the idea that to truly fathom cognition, one needs to study neural “population codes” that can only be understood by recording the activity of many neurons simultaneously. McNaughton has been a pioneer in the development of technologies to enable the study of these neural codes for memory. Prior to his breakthrough work, it was impossible to take readings simultaneously from large numbers of neighboring neurons.

McNaughton comes to UC Irvine from the University of Lethbridge in Alberta, Canada, where he was a professor of neuroscience. He was the first recipient of the Alberta Heritage Foundation for Medical Research’s Polaris Award, the largest biomedical sciences research grant in Canada ($20 million over 10 years). Before his appointment at Lethbridge, he was on the faculty at the University of Arizona from 1990 to 2008. McNaughton has also been awarded other high-profile prizes during his career, including a Jacob Javits Neuroscience Investigator Award from the National Institute of Neurological Disorders & Stroke and a MERIT Award from the National Institute of Mental Health.

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How the brain recognizes speech sounds


Shaping of sound by our mouths leaves acoustic trail the brain can follow, say researchers.

Edward Chang, UC San Francisco

Edward Chang, UC San Francisco

UC San Francisco researchers are reporting a detailed account of how speech sounds are identified by the human brain, offering an unprecedented insight into the basis of human language.

The finding, they said, may add to our understanding of language disorders, including dyslexia.

Scientists have known for some time the location in the brain where speech sounds are interpreted, but little has been discovered about how this process works.

Now, in today’s (Jan. 30) edition of Science Express, the fast-tracked online version of the journal Science, the UCSF team reports that the brain does not respond to the individual sound segments known as phonemes – such as the b sound in “boy” – but is instead exquisitely tuned to detect simpler elements, which are known to linguists as “features.”

This organization may give listeners an important advantage in interpreting speech, the researchers said, since the articulation of phonemes varies considerably across speakers, and even in individual speakers over time.

The work may add to our understanding of reading disorders, in which printed words are imperfectly mapped onto speech sounds. But because speech and language are a defining human behavior, the findings are significant in their own right, said UCSF neurosurgeon and neuroscientist Edward F. Chang, M.D., senior author of the new study.

“This is a very an intriguing glimpse into speech processing,” said Chang, associate professor of neurological surgery and physiology. “The brain regions where speech is processed in the brain had been identified, but no one has really known how that processing happens.”

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Scientists discover new genetic forms of neurodegeneration


Several promising targets identified for development of new treatments.

Joseph Gleeson, UC San Diego

Joseph Gleeson, UC San Diego

In a study published in the Jan. 31issue of Science, an international team led by scientists at the UC San Diego School of Medicine report doubling the number of known causes for the neurodegenerative disorder known as hereditary spastic paraplegia. HSP is characterized by progressive stiffness and contraction of the lower limbs and is associated with epilepsy, cognitive impairment, blindness and other neurological features.

Over several years, working with scientific colleagues in parts of the world with relatively high rates of consanguinity or common ancestry, UC San Diego researchers recruited a cohort of more than 50 families displaying autosomal recessive HSP – the  largest such cohort assembled to date. The scientists analyzed roughly 100 patients from this cohort using a technique called whole exome sequencing, which focuses on mapping key portions of the genome. They identified a genetic mutation in almost 75 percent of the cases, half of which were in genes never before linked with human disease.

“After uncovering so many novel genetic bases of HSP, we were in the unique position to investigate how these causes link together. We were able to generate an ‘HSP-ome,’ a map that included all of the new and previously described causes,” said senior author Joseph G. Gleeson, M.D., Howard Hughes Medical Institute investigator, professor in the UC San Diego departments of neurosciences and pediatrics and at Rady Children’s Hospital-San Diego, a research affiliate of UC San Diego.

The HSP-ome helped researchers locate and validate even more genetic mutations in their patients, and indicated key biological pathways underlying HSP. The researchers also were interested in understanding how HSP relates to other groups of disorders. They found that the HSP-ome links HSP to other more common neurodegenerative disorders, such as Alzheimer’s disease and amyotrophic lateral sclerosis.

“Knowing the biological processes underlying neurodegenerative disorders is seminal to driving future scientific studies that aim to uncover the exact mechanisms implicated in common neurodegenerative diseases, and to indicate the path toward development of effective treatments,” said Gleeson.

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Modeling H.M.’s brain


3-D model of famous amnesiac’s brain helps illuminate human memory.

Jacopo Annese examines final brain tissue slides, which were also digitized for study by researchers worldwide.

Jacopo Annese examines final brain tissue slides, which were also digitized for study by researchers worldwide.

During his lifetime, Henry G. Molaison (H.M.) was the best-known and possibly the most-studied patient of modern neuroscience.  Now, thanks to the postmortem study of his brain, based on histological sectioning and digital three-dimensional construction led by Jacopo Annese, Ph.D., at the University of California, San Diego, scientists around the globe will finally have insight into the neurological basis of the case that defined modern studies of human memory.

The microscopic anatomical model of the whole brain and detailed 3-D measurements of the medial temporal lobe (MTL) region are described in a paper to be published online in Nature Communications today (Jan. 28).

H.M. was an epileptic patient whose severe and almost total amnesia was the unexpected result of a bilateral surgical ablation of the MTL, including the hippocampus, in 1953. Until his death in 2008, the purity and severity of H.M.’s memory impairment, along with his willingness to participate in continual testing, made his case uniquely influential.

While his intellectual abilities, personality, language and perceptual skills remained intact, he was unable to store information in long-term memory.  After his brain operation, H.M. was profoundly impaired in forming new declarative memories. This unfortunate outcome became the catalyst for over 50 years of scientific discoveries (and thousands of publications) that have radically changed scientists’ basic understanding of memory function. His case was significant because it provided the first conclusive evidence for the involvement of the hippocampus in forming new memories.

In December 2009, Annese and his team dissected H.M.’s brain into 2,401 thin tissue slices that were then preserved cryogenically in serial order. While the brain was being sliced, the researchers collected an unabridged series of digital images of the surface of the block, corresponding to each tissue section. These images were archived and used to create a three-dimensional microscopic model of the whole brain.  The model of H.M.’s brain contains clues to help understand the surgery performed in 1953, and the level of sampling and image quality afforded by this study represents a significant advance over the MRI scans performed with H.M.  when he was alive.

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UC receives two grants in NFL, GE Head Health Challenge


$20M initiative seeks to improve safety of athletes, soldiers who sustain traumatic brain injury.

When the Broncos and the Seahawks meet on the gridiron for Super Bowl XLVIII, player and team statistics — passer ratings, rushing yards, sacks and fumbles — will be tossed around like, well, a football.

One statistic not likely to be mentioned: the number of players on each team who have sustained concussions over the course of the 2013-14 season — five and six, respectively, according to the National Football League (NFL) Injury Report. And some players have suffered more than one.

To address health issues related to head injuries — which may not appear until long after a player has retired — the NFL has teamed with GE to create the Head Health Challenge, a $20 million research initiative. Among the 16 round-one winners is Scott Grafton, a professor in UC Santa Barbara’s Department of Psychological and Brain Sciences and director of the campus’s Brain Imaging Center, and UC San Francisco, which is teaming with startup Ayasdi.

The goal of the Head Health Challenge is to improve the safety of athletes as well as that of members of the military and anyone else who has experienced mild traumatic brain injury. The winners, each of whom will receive a $300,000 award to advance his or her research, were selected from more than 400 entries from 27 countries.

“Our effort is in developing imaging methods that serve as biomarkers for mild brain injury,” said Grafton. “Once you have a biomarker, you have a whole new toolbox for identifying appropriate therapies.”

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Protein interaction may drive most common genetic cause of Parkinson’s


Findings challenge conventional wisdom, point to new therapeutic strategies.

Steve Finkbeiner and Gaia Skibinski

Steve Finkbeiner and Gaia Skibinski

The most devastating aspect of Parkinson’s disease may not be its debilitating symptoms, which rob its victims of their ability to control their own movement. It may not be the millions around the world and their families who suffer each day from the disease’s harmful effects. Instead, it may in fact be that its root causes remain largely a mystery. But now, scientists at the Gladstone Institutes have discovered how the interplay between two proteins in the brain fuels the degradation and death of the class of brain cells, or neurons, that leads to Parkinson’s. These findings, which stand in stark contrast to conventional wisdom, lay much-needed groundwork for developing treatments that target the disease’s elusive underlying mechanisms.

In the latest issue of the Journal of Neuroscience, researchers in the laboratory of Gladstone Investigator Steve Finkbeiner, M.D., Ph.D., harnessed the power of their one-of-a-kind robotic microscope to track the lifespan of individual neurons over time. The microscope has been used to study a variety of neurodegenerative diseases, and in this study, they focus their attention on LRRK2 — the most common genetic cause of Parkinson’s.

Scientists have long known that mutations in LRRK2 cause misfolded versions of the LRRK2 protein to accumulate in neurons. The prevailing hypothesis has been that misfolded LRRK2 boosts the activity of a type of enzyme called kinase, and that this heightened kinase activity is what drives cell death. Scientists have also looked to the fact that mutant LRRK2 tends to clump together into so-called inclusion bodies (IBs) as another contributor to the disease’s progression.

“As a result, researchers have used the presence of IBs and heightened kinase activity as a proxy for measuring LRRK2’s harmful effects, rather than measuring LRRK2 levels directly,” explained Finkbeiner, who is the associate director of neurological research at Gladstone as well as a professor at the University of California, San Francisco, with which Gladstone is affiliated. “But we were unconvinced that these were the main drivers of cell death — so we decided to take a closer look at what was happening inside the cell.”

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UC San Diego launches unprecedented Down syndrome study


Goal: gain better understanding of adults with the disease, discover indicators of Alzheimer’s.

William Mobley, UC San Diego

William Mobley, UC San Diego

To many, Down syndrome (DS) is a childhood condition. But improved health care means that individuals with DS now routinely reach age 50 or 60 years of age, sometimes beyond.  However, if they live long enough, people with Down syndrome are almost certain to develop Alzheimer’s disease (AD).

Risk estimates vary, but the National Down Syndrome Society says that nearly 25 percent of individuals with DS over the age of 35 show signs of Alzheimer’s-type dementia, a percentage that dramatically increases with age. Almost all develop dementia by the age of 60.

“The more we learn about Down syndrome and Alzheimer’s disease, the more we realize these conditions – one seen at birth, the other quite late in life – are two sides of the same coin,” said William C. Mobley, M.D., Ph.D., professor and chair of the Department of Neurosciences at UC San Diego School of Medicine. “Autopsies of DS and AD brains reveal virtually identical pathologies – the same telltale amyloid plaques and neurofibrillary tangles.”

Under the auspices of the Alzheimer’s Disease Cooperative Study (ADCS), based at the UC San Diego School of Medicine, a new clinical study called the Down Syndrome Biomarker Initiative (DSBI) was launched in March. According to the study’s director, Michael Rafii, M.D., Ph.D. – medical director of the ADCS – its aim is to discover indicators of Alzheimer’s and study progression of the disease, with the ultimate goal of better understanding brain aging and AD in adults with Down syndrome.

The three-year pilot study has enrolled 12 participants, aged 30 to 60 years of age. Study participants will be screened for various biomarkers of AD, using tests that include three types of brain scans, retinal amyloid imaging and blood tests, among others.

“Findings to date using MRI and amyloid PET scans indicate that individuals with Down syndrome show the same brain patterns as those in the general population with the earliest stages of the memory-robbing disease, called prodromal AD,” said Rafii. He added that indications of increased brain amyloid deposition – the insoluble protein aggregates found in the brains of patients with AD that are thought to be an underlying cause of the disease – is similar in individuals with DS and those in the general population with AD.

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Brain trauma raises risk of later PTSD in active-duty Marines


Deployment-related injuries are biggest predictor, but not the only factor.

Dewleen Baker

Dewleen Baker

In a novel study of U.S. Marines investigating the association between traumatic brain injury (TBI) and the risk of post-traumatic stress disorder (PTSD) over time, a team of scientists led by researchers from the Veterans Affairs San Diego Healthcare System and UC San Diego School of Medicine report that TBIs suffered during active-duty deployment to Iraq and Afghanistan were the greatest predictor for subsequent PTSD, but found pre-deployment PTSD symptoms and high combat intensity were also significant factors.

The findings are published in the Dec. 11 online issue of JAMA Psychiatry.

The team, headed by principal investigator Dewleen G. Baker, M.D., research director at the VA Center of Excellence for Stress and Mental Health, professor in the Department of Psychiatry at UC San Diego and a practicing psychiatrist in the VA San Diego Healthcare System, analyzed 1,648 active-duty Marines and Navy servicemen from four infantry battalions of the First Marine Division based at Camp Pendleton in north San Diego County. The servicemen were evaluated approximately one month before a scheduled 7-month deployment to Iraq or Afghanistan, one week after deployment had concluded, and again three and six months later.

PTSD is a psychiatric condition in which stress reactions become abnormal, chronic and may worsen over time. The condition is linked to depression, suicidal tendencies, substance abuse, memory and cognition dysfunction and other health problems.

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Brain cancer cells hide while drugs seek


Tumor cells temporarily lose mutation to evade drugs targeting mutation.

Human brain specimen with glioblastoma multiforme

Human brain specimen with glioblastoma multiforme

A team of scientists, led by principal investigator Paul S. Mischel, M.D., a member of the Ludwig Institute for Cancer Research and professor in the Department of Pathology at the UC San Diego School of Medicine, has found that brain cancer cells resist therapy by dialing down the gene mutation targeted by drugs, then re-amplify that growth-promoting mutation after therapy has stopped.

The findings are published in today’s (Dec. 5) online issue of Science.

“This discovery has considerable clinical implications because if cancer cells can evade therapy by a ‘hide-and-seek’ mechanism, then the current focus (of drug therapies) is unlikely to translate into better outcomes for patients,” said Mischel.

In recent years, new cancer therapies have emerged that target tell-tale gene mutations to identify specific cancer cells for destruction. Unfortunately, a variety of “resistance mechanisms” have also emerged, among them incomplete target suppression, second-site mutations and activation of alternative kinases or enzymes that maintain growth-promoting signals to the cancer itself.

“Most research is aimed at developing better drugs or better drug combinations to suppress these downstream signals,” Mischel said. “However, one thing that has not been carefully considered is whether cancer cells can modulate the levels of – and thus their dependence on – the target of the drug, evade therapy, and then re-acquire the oncogene to promote tumor growth when the drug is withdrawn.”

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Kids whose bond with mother was disrupted early in life show changes in brain


UCLA researchers examine impact on amygdala.

Nim Tottenham, UCLA

Nim Tottenham, UCLA

Children who experience profound neglect have been found to be more prone to a behavior known as “indiscriminate friendliness,” characterized by an inappropriate willingness to approach adults, including strangers.

UCLA researchers are now reporting some of the first evidence from human studies suggesting that this behavior is rooted in brain adaptations associated with early-life experiences. The findings appear in the Dec. 1 issue of the peer-reviewed journal Biological Psychiatry.

The UCLA group used functional magnetic resonance imaging (fMRI) to demonstrate that youths who experienced early maternal deprivation — specifically, time in an institution such as an orphanage prior to being adopted — show similar responses to their adoptive mother and to strangers in a brain structure called the amygdala; for children never raised in an institutional setting, the amygdala is far more active in response to the adoptive mother.

This reduced amygdala discrimination in the brain correlated with parental reports of indiscriminate friendliness. The longer the child spent in an institution before being adopted, the greater the effects.

“The early relationship between children and their parents or primary caregivers has implications for their social interaction later in life, and we believe the amygdala is involved in this process,” said Aviva Olsavsky, a resident physician in psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA and the study’s first author. “Our findings suggest that even for children who have formed attachments to their adoptive parents, this early period of deprivation has led to changes in the brain that were likely adaptations and that may persist over time.”

Indiscriminate friendliness is in some sense a misnomer. The behavior is not characterized by a deep friendliness but simply by a lack of reticence that most young children show toward strangers.

“This can be a very frightening behavior for parents,” said Nim Tottenham, an associate professor of psychology at UCLA and the study’s senior author. “The stranger anxiety or wariness that young children typically show is a sign that they understand their parents are very special people who are their source of security. That early emotional attachment serves as a bedrock for many of the developmental processes that follow.”

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