(Image caption: The presence of p45 (green staining) and p75 (red staining) indicates that motor neurons increase both p45 and p75 expression after sciatic nerve injury in an animal. Image credit: Courtesy of the Salk Institute for Biological Studies)

Scientists uncover new clues to repairing an injured spinal cord

Frogs, dogs, whales, snails can all do it, but humans and primates can’t. Regrow nerves after an injury, that is—while many animals have this ability, humans don’t. But new research from the Salk Institute suggests that a small molecule may be able to convince damaged nerves to grow and effectively rewire circuits. Such a feat could eventually lead to therapies for the thousands of Americans with severe spinal cord injuries and paralysis.

"This research implies that we might be able to mimic neuronal repair processes that occur naturally in lower animals, which would be very exciting," says the study’s senior author and Salk professor Kuo-Fen Lee. The results were published today in PLOS Biology.

For a damaged nerve to regain function, its long, signal-transmitting extensions known as axons need to grow and establish new connections to other cells.

In a study published last summer in PLOS ONE, Lee and his colleagues found that the protein p45 promotes nerve regeneration by preventing the axon sheath (known as myelin) from inhibiting regrowth. However, humans, primates and some other more advanced vertebrates don’t have p45. Instead, the researchers discovered a different protein, p75, that binds to the axon’s myelin when nerve damage occurs in these animals. Instead of promoting nerve regeneration, p75 actually halts growth in damaged nerves.

"We don’t know why this nerve regeneration doesn’t occur in humans. We can speculate that the brain has so many neural connections that this regeneration is not absolutely necessary," Lee says.

In the study published today, the scientists looked at how two p75 proteins bind together and form a pair that latches onto the inhibitors released from damaged myelin.

By studying the configurations of the proteins in solutions using nuclear magnetic resonance (NMR) technology, the researchers found that the growth-promoting p45 could disrupt the p75 pairing.

"For reasons that are not understood, when p45 comes in, it breaks the pair apart," says Lee, holder of the Helen McLoraine Chair in Molecular Neurobiology.

What’s more, the p45 protein was able to bind to the specific region in the p75 protein that is critical for the formation of the p75 pair, thus decreasing the amount of p75 pairs that bond to inhibitors release from myelin. With less p75 pairs available to bond to inhibitor signals, axons were able to regrow.

The findings suggest that an agent—either p45 or another disrupting molecule—that can effectively break the p75 pair could offer a possible therapy for spinal cord damage.

One method of therapy could be to introduce more p45 protein to injured neurons, but a smarter tactic might be to introduce a small molecule that jams the link between the two p75 proteins, Lee says. “Such an agent could possibly get through the blood-brain barrier and to the site of spinal cord injuries,” he says.

The next step will be to see if introducing p45 helps regenerate damaged human nerves. “That is what we hope to do in the future,” Lee says.

Researchers boost insect aggression by altering brain metabolism

Scientists report they can crank up insect aggression simply by interfering with a basic metabolic pathway in the insect brain. Their study, of fruit flies and honey bees, shows a direct, causal link between brain metabolism (how the brain generates the energy it needs to function) and aggression.

The team reports its findings in the Proceedings of the National Academy of Sciences.

The new research follows up on previous work from the laboratory of University of Illinois entomology professor and Institute for Genomic Biology director Gene Robinson, who also led the new analysis. When he and his colleagues looked at brain gene activity in honey bees after they had faced down an intruder, the team found that some metabolic genes were suppressed. These genes play a key role in the most efficient type of energy generation in cells, a process called oxidative phosphorylation.

“It was a counterintuitive finding because these genes were down-regulated,” Robinson said. “You tend to think of aggression as requiring more energy, not less.”

In the new study, postdoctoral researcher Clare Rittschof used drugs to suppress key steps in oxidative phosphorylation in the bee brains. She saw that aggression increased in the drugged bees in a dose-responsive manner, Robinson said. But the drugs had no effect on chronically stressed bees – they were not able to increase their aggression in response to an intruder.

“Something about chronic stress changed their response to the drug, which is a fascinating finding in and of itself,” Robinson said. “We want to know just how this experience gets under their skin to affect their brain.”

In separate experiments, postdoctoral researcher Hongmei Li-Byarlay and undergraduate student Jonathan Massey found that reduced oxidative phosphorylation in fruit flies also increased aggression. Using advanced fly genetics, the team found this effect only when oxidative phosphorylation was reduced in neurons, but not in neighboring cells known as glia. This finding, too, was surprising, since “glia are metabolically very active, and are the energy storehouses of the brain,” Robinson said.

The findings offer insight into the immediate and longer-term changes that occur in response to threats, Robinson said.

“When an animal faces a threat, it has an immediate aggressive response, within seconds,” Robinson said. But changes in brain metabolism take much longer and cannot account for this immediate response, he said. Such changes likely make individuals more vigilant to subsequent threats.

“This makes good sense in an ecological sense,” Robinson said, “because threats often come in bunches.”

The fact that the researchers observed these effects in two species that diverged 300 million years ago makes the findings even more compelling, Robinson said.

“Because fruit flies and honey bees are separated by 300 million years of evolution, this is a very robust and well-conserved mechanism.”

Our brains judge a face’s trustworthiness - Even when we can’t see it

Our brains are able to judge the trustworthiness of a face even when we cannot consciously see it, a team of scientists has found. Their findings, which appear in the Journal of Neuroscience, shed new light on how we form snap judgments of others.

“Our findings suggest that the brain automatically responds to a face’s trustworthiness before it is even consciously perceived,” explains Jonathan Freeman, an assistant professor in New York University’s Department of Psychology and the study’s senior author.

“The results are consistent with an extensive body of research suggesting that we form spontaneous judgments of other people that can be largely outside awareness,” adds Freeman, who conducted the study as a faculty member at Dartmouth College.

The study’s other authors included Ryan Stolier, an NYU doctoral candidate, Zachary Ingbretsen, a research scientist who previously worked with Freeman and is now at Harvard University, and Eric Hehman, a post-doctoral researcher at NYU.

The researchers focused on the workings of the brain’s amygdala, a structure that is important for humans’ social and emotional behavior. Previous studies have shown this structure to be active in judging the trustworthiness of faces. However, it had not been known if the amygdala is capable of responding to a complex social signal like a face’s trustworthiness without that signal reaching perceptual awareness.

To gauge this part of the brain’s role in making such assessments, the study’s authors conducted a pair of experiments in which they monitored the activity of subjects’ amygdala while the subjects were exposed to a series of facial images.

These images included both standardized photographs of actual strangers’ faces as well as artificially generated faces whose trustworthiness cues could be manipulated while all other facial cues were controlled. The artificially generated faces were computer synthesized based on previous research showing that cues such as higher inner eyebrows and pronounced cheekbones are seen as trustworthy and lower inner eyebrows and shallower cheekbones are seen as untrustworthy.

Prior to the start of these experiments, a separate group of subjects examined all the real and computer-generated faces and rated how trustworthy or untrustworthy they appeared. As previous studies have shown, subjects strongly agreed on the level of trustworthiness conveyed by each given face.

In the experiments, a new set of subjects viewed these same faces inside a brain scanner, but were exposed to the faces very briefly—for only a matter of milliseconds. This rapid exposure, together with another feature known as “backward masking,” prevented subjects from consciously seeing the faces. Backward masking works by presenting subjects with an irrelevant “mask” image that immediately follows an extremely brief exposure to a face, which is thought to terminate the brain’s ability to further process the face and prevent it from reaching awareness. In the first experiment, the researchers examined amygdala activity in response to three levels of a face’s trustworthiness: low, medium, and high. In the second experiment, they assessed amygdala activity in response to a fully continuous spectrum of trustworthiness.

Across the two experiments, the researchers found that specific regions inside the amygdala exhibited activity tracking how untrustworthy a face appeared, and other regions inside the amygdala exhibited activity tracking the overall strength of the trustworthiness signal (whether untrustworthy or trustworthy)—even though subjects could not consciously see any of the faces.

“These findings provide evidence that the amygdala’s processing of social cues in the absence of awareness may be more extensive than previously understood,” observes Freeman. “The amygdala is able to assess how trustworthy another person’s face appears without it being consciously perceived.”

Eating Baked or Broiled Fish Weekly Boosts Brain Health

Eating baked or broiled fish once a week is good for the brain, regardless of how much omega-3 fatty acid it contains, according to researchers at the University of Pittsburgh School of Medicine. The findings, published online recently in the American Journal of Preventive Medicine, add to growing evidence that lifestyle factors contribute to brain health later in life.

Scientists estimate that more than 80 million people will have dementia by 2040, which could become a substantial burden to families and drive up health care costs, noted senior investigator James T. Becker, Ph.D., professor of psychiatry, Pitt School of Medicine. Some studies have predicted that lifestyle changes such as a reduction in rates of physical inactivity, smoking and obesity could lead to fewer cases of Alzheimer’s disease and other conditions of cognitive impairment in the elderly. The anti-oxidant effect of omega-3 fatty acids, which are found in high amounts in fish, seeds and nuts, and certain oils, also have been associated with improved health, particularly brain health.

“Our study shows that people who ate a diet that included baked or broiled, but not fried, fish have larger brain volumes in regions associated with memory and cognition,” Dr. Becker said. “We did not find a relationship between omega-3 levels and these brain changes, which surprised us a little. It led us to conclude that we were tapping into a more general set of lifestyle factors that were affecting brain health of which diet is just one part.”

Lead investigator Cyrus Raji, M.D., Ph.D., who now is in radiology residency training at UCLA, and the research team analyzed data from 260 people who provided information on their dietary intake, had high-resolution brain MRI scans, and were cognitively normal at two time points during their participation in the Cardiovascular Health Study (CHS), a 10-year multicenter effort that began in 1989 to identify risk factors for heart disease in people over 65.

“The subset of CHS participants answered questionnaires about their eating habits, such as how much fish did they eat and how was it prepared,” Dr. Raji said. “Baked or broiled fish contains higher levels of omega-3s than fried fish because the fatty acids are destroyed in the high heat of frying, so we took that into consideration when we examined their brain scans.”

People who ate baked or broiled fish at least once a week had greater grey matter brain volumes in areas of the brain responsible for memory (4.3 percent) and cognition (14 percent) and were more likely to have a college education than those who didn’t eat fish regularly, the researchers found. But no association was found between the brain differences and blood levels of omega-3s.

“This suggests that lifestyle factors, in this case eating fish, rather than biological factors contribute to structural changes in the brain,” Dr. Becker noted. “A confluence of lifestyle factors likely are responsible for better brain health, and this reserve might prevent or delay cognitive problems that can develop later in life.”

(Image caption: LB1 in three different views to illustrate facial asymmetry. A is the actual specimen, B is the Right side doubled at the midline and mirrored, and C is the left side doubled and mirrored. Differences in left and right side facial architectures are apparent, and illustrate growth abnormalities of LB1. Credit: A, E. Indriati, B and C, D.W. Frayer)

Flores bones show features of Down syndrome, not a new “hobbit” human

In October 2004, excavation of fragmentary skeletal remains from the island of Flores in Indonesia yielded what was called “the most important find in human evolution for 100 years.” Its discoverers dubbed the find Homo floresiensis, a name suggesting a previously unknown species of human.

Now detailed reanalysis by an international team of researchers including Robert B. Eckhardt, professor of developmental genetics and evolution at Penn State, Maciej Henneberg, professor of anatomy and pathology at the University of Adelaide, and Kenneth Hsü, a Chinese geologist and paleoclimatologist, suggests that the single specimen on which the new designation depends, known as LB1, does not represent a new species. Instead, it is the skeleton of a developmentally abnormal human and, according to the researchers, contains important features most consistent with a diagnosis of Down syndrome.

"The skeletal sample from Liang Bua cave contains fragmentary remains of several individuals," Eckhardt said. "LB1 has the only skull and thighbones in the entire sample."

No substantial new bone discoveries have been made in the cave since the finding of LB1.

Initial descriptions of Homo floresiensis focused on LB1’s unusual anatomical characteristics: a cranial volume reported as only 380 milliliters (23.2 cubic inches), suggesting a brain less than one third the size of an average modern human’s and short thighbones, which were used to reconstruct a creature standing 1.06 meters (about 3.5 feet tall). Although LB1 lived only 15,000 years ago, comparisons were made to earlier hominins, including Homo erectus and Australopithecus. Other traits were characterized as unique and therefore indicative of a new species.

A thorough reexamination of the available evidence in the context of clinical studies, the researchers said, suggests a different explanation.

The researchers report their findings in two papers published today (Aug. 4) in the Proceedings of the National Academy of Sciences (1, 2).

In the first place, they write, the original figures for cranial volume and stature are underestimates, “markedly lower than any later attempts to confirm them.” Eckhardt, Henneberg, and other researchers have consistently found a cranial volume of about 430 milliliters (26.2 cubic inches).

"The difference is significant, and the revised figure falls in the range predicted for a modern human with Down syndrome from the same geographic region," Eckhardt said.

The original estimate of 3.5 feet for the creature’s height was based on extrapolation combining the short thighbone with a formula derived from an African pygmy population. But humans with Down syndrome also have diagnostically short thighbones, Eckhardt said.

Though these and other features are unusual, he acknowledged, “unusual does not equal unique. The originally reported traits are not so rare as to have required the invention of a new hominin species.”

Instead, the researchers build the case for an alternative diagnosis: that of Down syndrome, one of the most commonly occurring developmental disorders in modern humans.

"When we first saw these bones, several of us immediately spotted a developmental disturbance," said Eckhardt, "but we did not assign a specific diagnosis because the bones were so fragmentary. Over the years, several lines of evidence have converged on Down syndrome."

The first indicator is craniofacial asymmetry, a left-right mismatch of the skull that is characteristic of this and other disorders. Eckhardt and colleagues noted this asymmetry in LB1 as early as 2006, but it had not been reported by the excavating team and was later dismissed as a result of the skull’s being long buried, he said.

A previously unpublished measurement of LB1’s occipital-frontal circumference — the circumference of the skull taken roughly above the tops of the ears — allowed the researchers to compare LB1 to clinical data routinely collected on patients with developmental disorders. Here too, the brain size they estimate is within the range expected for an Australomelanesian human with Down syndrome.

LB1’s short thighbones not only match the height reduction seen in Down syndrome, Eckhardt said, but when corrected statistically for normal growth, they would yield a stature of about 1.26 meters, or just over four feet, a figure matched by some humans now living on Flores and in surrounding regions.

These and other Down-like characteristics, the researchers state, are present only in LB1, and not in the other Liang Bua skeletal remains, further evidence of LB1’s abnormality.

"This work is not presented in the form of a fanciful story, but to test a hypothesis: Are the skeletons from Liang Bua cave sufficiently unusual to require invention of a new human species?" Eckhardt said.

"Our reanalysis shows that they are not. The less strained explanation is a developmental disorder. Here the signs point rather clearly to Down syndrome, which occurs in more than one per thousand human births around the world."

Prenatal Alcohol Exposure Alters Development of Brain Function

In the first study of its kind, Prapti Gautam, PhD, and colleagues from The Saban Research Institute of Children’s Hospital Los Angeles found that children with fetal alcohol spectrum disorders (FASD) showed weaker brain activation during specific cognitive tasks than their unaffected counterparts. These novel findings suggest a possible neural mechanism for the persistent attention problems seen in individuals with FASD. The results of this study will be published in Cerebral Cortex on August 4.

“Functional magnetic resonance imaging (fMRI) has been used to observe brain activity during mental tasks in children with FASD, but we are the first to utilize these techniques to look at brain activation over time,” says Gautam. “We wanted to see if the differences in brain activation between children with FASD and their healthy peers were static, or if they changed as children got older.”

FASD encompasses the broad spectrum of symptoms that are linked to in utero alcohol exposure, including cognitive impairment, deficits in intelligence and attention and central nervous system abnormalities. These symptoms can lead to attention problems and higher societal and economic burdens common in individuals with FASD.

During the period of childhood and adolescence, brain function, working memory and attention performance all rapidly improve, suggesting that this is a crucial time for developing brain networks. To study how prenatal alcohol exposure may alter this development, researchers observed a group of unaffected children and a group of children with FASD over two years. They used fMRI to observe brain activation through mental tasks such as visuo-spatial attention—how we visually perceive the spatial relationships among objects in our environment —and working memory.

“We found that there were significant differences in development brain activation over time between the two groups, even though they did not differ in task performance,” notes Elizabeth Sowell, PhD, director of the Developmental Cognitive Neuroimaging Laboratory at The Saban Research Institute and senior author on the manuscript. “While the healthy control group showed an increase in signal intensity over time, the children with FASD showed a decrease in brain activation during visuo-spatial attention, especially in the frontal, temporal and parietal brain regions.”

These results demonstrate that prenatal alcohol exposure can change how brain signaling develops during childhood and adolescence, long after the damaging effects of alcohol exposure in utero. The atypical development of brain activation observed in children with FASD could explain the persistent problems in cognitive and behavioral function seen in this population as they mature.

(Image caption: Part of a brain slice in which a transplanted induced neural stem cell is fully integrated in the neuronal network of the brain (blue) to develop into a complex and functional neuron.)

Implanted Neurons become Part of the Brain

Scientists at the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg have grafted neurons reprogrammed from skin cells into the brains of mice for the first time with long-term stability. Six months after implantation, the neurons had become fully functionally integrated into the brain. This successful, because lastingly stable, implantation of neurons raises hope for future therapies that will replace sick neurons with healthy ones in the brains of Parkinson’s disease patients, for example. The Luxembourg researchers published their results in the current issue of ‘Stem Cell Reports’.

The LCSB research group around Prof. Dr. Jens Schwamborn and Kathrin Hemmer is working continuously to bring cell replacement therapy to maturity as a treatment for neurodegenerative diseases. Sick and dead neurons in the brain can be replaced with new cells. This could one day cure disorders such as Parkinson’s disease. The path towards successful therapy in humans, however, is long. “Successes in human therapy are still a long way off, but I am sure successful cell replacement therapies will exist in future. Our research results have taken us a step further in this direction,” declares stem cell researcher Prof. Schwamborn, who heads a group of 15 scientists at LCSB.

In their latest tests, the research group and colleagues from the Max Planck Institute and the University Hospital Münster and the University of Bielefeld succeeded in creating stable nerve tissue in the brain from neurons that had been reprogrammed from skin cells. The stem cell researchers’ technique of producing neurons, or more specifically induced neuronal stem cells (iNSC), in a petri dish from the host’s own skin cells considerably improves the compatibility of the implanted cells. The treated mice showed no adverse side effects even six months after implantation into the hippocampus and cortex regions of the brain. In fact it was quite the opposite – the implanted neurons were fully integrated into the complex network of the brain. The neurons exhibited normal activity and were connected to the original brain cells via newly formed synapses, the contact points between nerve cells.

The tests demonstrate that the scientists are continually gaining a better understanding of how to treat such cells in order to successfully replace damaged or dead tissue. “Building upon the current insights, we will now be looking specifically at the type of neurons that die off in the brain of Parkinson’s patients – namely the dopamine-producing neurons,” Schwamborn reports. In future, implanted neurons could produce the lacking dopamine directly in the patient’s brain and transport it to the appropriate sites. This could result in an actual cure, as has so far been impossible. The first trials in mice are in progress at the LCSB laboratories on the university campus Belval.