Study shows how brain tumor cells move and damage tissue, points to possible therapy

Researchers at the University of Alabama at Birmingham have shed new light on how cells called gliomas migrate in the brain and cause devastating tumors. The findings, published June 19, 2014 in Nature Communications, show that gliomas — malignant glial cells — disrupt normal neural connections and hijack control of blood vessels.

The study provides insight into the mechanisms of how glioma cells spread throughout the brain as a devastating form of brain cancer, and potentially offers a tantalizing opportunity for therapy.

A hallmark of gliomas is that the cells can migrate away from a central tumor, invading healthy brain tissue. Even if a tumor mass is surgically removed, malignant cells that have migrated are left behind, and can grow into a new tumor.

To grow, glioma cells need access to nutrients in the blood supply, and it is known that gliomas travel along blood vessels within the brain. Now, researchers in the lab of neuroscientist Harald Sontheimer, Ph.D., professor in the UAB Department of Neurobiology, have discovered that, as they move, gliomas dislodge astrocytic endfeet, which play a critical role in regulating blood flow in the brain.

Astrocytes are star-shaped cells in the brain that surround blood vessels and connect to them through projections called endfeet, which extend from the astrocyte and latch onto the vessel wall. The surface of nearly every blood vessel in the brain is covered by endfeet, which regulate the smooth muscle cells on the walls of blood vessels. Through that connection, instructions can be given to the muscle cells to constrict the blood vessel and limit blood flow, or dilate the vessel and increase blood flow.

Sontheimer, director of the UAB Center for Glial Biology in Medicine, says that, as a person performs different neurological functions, blood flow needs to be increased to the areas responsible for that function and correspondingly decreased in other areas to maintain balance.

The arrival of a glioma cell changes all that.

“Glioma cells traveling along blood vessels literally cut the connection of astrocytic endfeet with the vessels and push them out of the way,” said Sontheimer. “By disrupting this important neural connection, adverse cognitive effects could be expected. Additionally, our study showed that gliomas then take control of the blood vessels for their own ends. And those ends are primarily to obtain nutrients from blood so that they can continue to grow and spread.”

Sontheimer’s team says the glioma cells tend to congregate at blood vessel junctions, almost as if camping alongside a stream where it joins a river. The ready supply of nutrients would allow the cell to grow into a larger tumor mass.

By traveling on the outside of a blood vessel, glioma cells are able to access nutrients from the blood stream. As a side effect to that process, they damage the blood brain barrier. The barrier, a layer of endothelial cells, protects the brain by restricting passage of harmful substances from the blood stream into brain tissue.

“We found that, when gliomas push away the astrocytic endfeet, damage occurs to the integrity of the endothelial cells that make up the blood brain barrier,” said Stefanie Robel, Ph.D., a postdoctoral researcher in Sontheimer’s lab and co-first author of the study. “The barrier becomes weakened, and begins to leak. A leak across the barrier can cause severe damage to brain tissue.”

“That leakage appears to be a consequence of glioma cells’ migrating along the blood vessels in their search for nutrients,” said Stacey Watkins, an M.D./Ph.D. student in Sontheimer’s lab and co-first author. “When glioma cells contact the vessels, they have direct access to nutrients.”

But amid the deleterious effects that Sontheimer’s team observed — shearing away the endfeet from their blood vessels, disrupting normal brain activity, hijacking control of blood vessels and causing leaks in the blood brain barrier — he says there may be a silver lining. The idea that gliomas cause the blood brain barrier to become porous and leak might open up a new avenue to kill the malignant cells as they migrate.

Chemotherapy, usually delivered intravenously, is not considered an effective strategy for killing gliomas. Chemotherapeutic agents are very effective in killing cancer cells elsewhere in the body, but the predominant belief is that such drugs will not pass the blood brain barrier and thus will not reach their target.

“Chemotherapy is typically not tried in cases of glioma until after other therapies such as surgery and radiation have been employed,” Sontheimer said. “Our findings, which suggest that gliomas actually weaken the blood brain barrier and cause leakage, might indicate that high-dose, intravenous chemotherapy used early on following a diagnosis of brain cancer would be beneficial.”

The study, funded by the National Institutes of Health and the American Brain Tumor Association, was conducted on a clinically relevant mouse model of human malignant glioma.

Sontheimer says logical next steps would be to further examine the cognitive impact of severing the astrocytic endfeet connection to blood vessels.

Those with episodic amnesia are not ‘stuck in time,’ says philosopher Carl Craver

In 1981, a motorcycle accident left Toronto native Kent Cochrane with severe brain damage and dramatically impaired episodic memory. Following the accident, Cochrane could no longer remember events from his past. Nor could he predict specific events that might happen in the future.

When neuroscientist Endel Tulving, PhD, asked him to describe what he would do tomorrow, Cochrane could not answer and described his state of mind as “blank.”

Psychologists and neuroscientists came to know Cochrane, who passed away earlier this year, simply as “KC.” Many scientists have described KC as “stuck in time,” or trapped in a permanent present.

It has generally been assumed that people with episodic amnesia experience time much differently than those with more typical memory function. 

However, a recent paper in Neuropsychologia co-authored by Carl F. Craver, PhD, professor of philosophy and of philosophy-neuroscience-psychology, both in Arts & Sciences at Washington University in St. Louis, disputes this type of claim.

“It’s our whole way of thinking about these people that we wanted to bring under pressure,” Craver said. “There are sets of claims that sound empirical, like ‘These people are stuck in time.’ But if you ask, ‘Have you actually tested what they know about time?’ the answer is no.”

Time and consciousness

A series of experiments convinced Craver and his co-authors that although KC could not remember specific past experiences, he did in fact have an understanding of time and an appreciation of its significance to his life.

Interviews with KC by Craver and his colleagues revealed that KC retained much of what psychologists refer to as “temporal consciousness.” KC could order significant events from his life on a timeline, and he seemed to have complete mastery of central temporal concepts.

For example, KC understood that events in the past have already happened, that they influence the future, and that once they happen, they cannot be changed. 

He also knew that events in the future don’t remain in the future, but eventually become present. Even more interestingly, KC’s understanding of time influenced his decision-making.

If KC truly had no understanding of time, Craver argues, then he and others with his type of amnesia would act as if only the present mattered. Without understanding that present actions have future consequences or rewards, KC would have based his actions only upon immediate outcomes. However, this was not the case.

On a personality test, KC scored as low as possible on measures of hedonism, or the tendency to be a self-indulgent pleasure-seeker.

In systematic tests of his decision-making, carried out with WUSTL’s Len Green, PhD, professor of psychology, and Joel Myerson, PhD, research professor of psychology, and researchers at York University in Toronto, KC also showed that he was willing to trade a smaller, sooner reward for a larger, later reward.

In other words, KC’s inability to remember past events did not affect his ability to appreciate the value of future rewards. 

‘Questions are now wide open’

KC’s case reveals how much is left to discover about memory and how it relates to human understanding of time.

“If you think about memory long enough it starts to sound magical,” Craver said. “How is it that we can replay these events from our lives? And what’s going on in our brains that allows us to re-experience these events from our past?”

Craver hopes that this article — the last to be published about KC during his lifetime — brings these types of questions to the forefront. 

“These findings open up a whole new set of questions about people with amnesia,” Craver said. “Things that we previously thought were closed questions are now wide open.”

(Image credit)

Hormones affect voting behavior

Researchers from the University of Nebraska at Omaha (UNO), the University of Nebraska-Lincoln (UNL) and Rice University have released a study that shows hormone levels can affect voter turnout.

As witnessed by recent voter turnout in primary elections, participation in U.S. national elections is low, relative to other western democracies. In fact, voter turnout in biennial national elections ranges includes only 40 to 60 percent of eligible voters.

The study, published June 22 in Physiology and Behavior, reports that while participation in electoral politics is affected by a host of social and demographic variables, there are also biological factors that may play a role, as well. Specifically, the paper points to low levels of the stress hormone cortisol as a strong predictor of actual voting behavior, determined via voting records maintained by the Secretary of State.

"Politics and political participation is an inherently stressful activity," explained the paper’s lead author, Jeff French, Varner Professor of Psychology and Biology and director of UNO’s neuroscience program. "It would logically follow that those individuals with low thresholds for stress might avoid engaging in that activity and our study confirmed that hypothesis."

Additional authors on the paper are Adam Guck and Andrew K. Birnie from UNO’s Department of Psychology; Kevin B. Smith and John R. Hibbing from UNL’s Department of Political Science; and John R. Alford from the Department of Political Science at Rice University.

The study is part of a larger body of research exploring connections between biology and political orientation, led by Smith and Hibbing. Previous studies have involved twins, eye-tracking equipment and skin conductance in their efforts to identify physical and genetic links to political beliefs.

"It’s one more piece of solid evidence that there are biological markers for political attitudes and behavior," said Smith. "It’s long been known that cortisol levels are associated with your willingness to interact socially – that’s something fairly well established in the research literature. The big contribution here is that nobody really looked at politics and voting behaviors before."

"This research shows that cortisol is related to a willingness to participate in politics," he said.

To reach their conclusion, researchers collected the saliva of over 100 participants who identified themselves as highly conservative, highly liberal or disinterested in politics altogether and analyzed the levels of cortisol found.

Cortisol was measured in saliva collected from the participants before and during activities designed to raise and lower stress. These data were then compared against the participants’ earlier responses regarding involvement in political activities (voting and nonvoting) and religious participation.

"Not only did the study show, expectedly, that high-stress activities led to higher levels of cortisol production, but that political participation was significantly correlated with low baseline levels of cortisol," French explained. "Participation in another group-oriented activity, specifically religious participation, was not as strongly associated with cortisol levels. Involvement in nonvoting political activities, such as volunteering for a campaign, financial political contributions, or correspondence with elected officials, was not predicted by levels of stress hormones."

According to the study, the only other factor that was predictive of voting behavior was age; older adults were likely to have voted more often than younger adults. Research from other groups has also pointed to education, income, and race as important predictors of voting behavior.

In explaining why elevated cortisol could be linked with lower rates of participation in elections, French cited previous experiments in which high levels of afternoon cortisol are linked to major depressive disorder, social withdrawal, separation anxiety and enhanced memory for fearful stimuli.

"High afternoon cortisol is reflective of a variety of social, cognitive, and emotional processes, and may also influence a trait as complex as voting behavior," French suggested.

"The key takeaway from this research, I believe, is that while social scientists have spent decades trying to predict voting behavior based on demographic information, there is much to be learned from looking at biological differences as well," he said. "Many factors influence the decision to participate in the most important political activity in our democracy, and our study demonstrates that stress physiology is an important biological factor in this decision. Our experiment helps to more fully explain why some people engage in electoral politics and others do not."

Study shows moving together builds bonds from the time we learn to walk

Whether they march in unison, row in the same boat or dance to the same song, people who move in time with one another are more likely to bond and work together afterward.

It’s a principle established by previous studies, but now researchers at McMaster have shown that moving in time with others even affects the social behaviour of babies who have barely learned to walk.

“Moving in sync with others is an important part of musical activities,” says Laura Cirelli, lead author of a paper now posted online and scheduled to appear in an upcoming issue of the journal Developmental Science. “These effects show that movement is a fundamental part of music that affects social behavior from a very young age.”

Cirelli and her colleagues in the Department of Psychology, Neuroscience & Behaviour showed that 14-month-old babies were much more likely to help another person after the experience of bouncing up and down in time to music with that person.

Cirelli and fellow doctoral student Kate Einarson worked under the supervision of Professor Laurel Trainor, a specialist in child development research.

They tested 68 babies in all, to see if bouncing to music with another person makes a baby more likely to assist that person by handing back “accidentally” dropped objects.

Working in pairs, one researcher held a baby in a forward-facing carrier and stood facing the second researcher. When the music started to play, both researchers would gently bounce up and down, one bouncing the baby with them. Some babies were bounced in sync with the researcher across from them, and others were bounced at a different tempo.

When the song was over, the researcher who had been facing the baby then performed several simple tasks, including drawing a picture with a marker. While drawing the picture, she would pretend to drop the marker to see whether the infant would pick it up and hand it back to her – a classic test of altruism in babies.

The babies who had been bounced in time with the researcher were much more likely to toddle over, pick up the object and pass it back to the researcher, compared to infants who had been bounced at a different tempo than the experimenter.

While babies who had been bounced out of sync with the researcher only picked up and handed back 30 per cent of the dropped objects, in-sync babies came to the researcher’s aid 50 per cent of the time. The in-sync babies also responded more quickly.

The findings suggest that when we sing, clap, bounce or dance in time to music with our babies, these shared experiences of synchronous movement help form social bonds between us and our babies.

It’s a significant finding, Cirelli believes, because it shows that moving together to music with others encourages the development of altruistic helping behaviour among those in a social group. It suggests that music is an important part of day care and kindergarten curriculums because it helps to build a co-operative social climate.

Cirelli is now researching whether the experience of synchronous movement with one person leads babies to extend their increased helpfulness to other people or whether infants reserve their altruistic behaviour for their dancing partners.

How Aging Can Intensify Damage of Spinal Cord Injury

In the complex environment of a spinal cord injury, researchers have found that immune cells in the central nervous system of elderly mice fail to activate an important signaling pathway, dramatically lowering chances for repair after injury.

These studies were the first to show that spinal cord injuries are more severe in elderly mice than in young adults, corroborating previous anecdotal findings from clinical settings. They also revealed a previously unknown player in the repair of spinal cord injuries in young adults.

A key messenger in that pathway is a receptor on the surface of microglia, immune system cells in the central nervous system that are called into action by the trauma of the spinal cord injury.

In young adult mice, this receptor is activated by microglia to recognize and make use of an inflammation-related signaling chemical that is found in the central nervous system after a spinal cord injury. The microglia in the elderly mice, however, do not activate the receptor at all.

The study showed that the difference in receptor activation has consequences later in the recovery process. The kinds of cells recruited to the injury site in young adult mice appear to have more value in the repair process than do the cells that show up in elderly mice. A host of experiments traced those differing effects back to whether or not microglia activated the receptor.

“The microglia are regulated by several different cell types and different signals, and it appears a lot of those systems change with age,” said Jonathan Godbout, associate professor of neuroscience at The Ohio State University and senior author of the study.

“We’ve shown evidence that this more severe injury occurs in an aging animal, and that the difference in recovery is related to the ability to express the receptor. The consequence is we have a different profile of cells at the injury site, and in aging mice, that environment is less reparative.”

These differences at the cellular level were associated with vast differences in the characteristics of injury and recovery. The lesions on the injured spinal cord were 38 percent longer, on average, in elderly mice than in young adult mice. In addition, the older mice were unable to gain movement of their hind limbs by the time most younger mice had regained that mobility.

The research is published in the Journal of Neuroscience.

The receptor in question is called the IL-4 alpha receptor, and its job is to “see” the infusion of interleukin-4, or IL-4, in the central nervous system after the spinal injury. IL-4 is a cytokine, a type of protein connected to immune system function. Many cytokines promote inflammation, but IL-4 is associated with curbing inflammation.

Godbout and colleagues observed that IL-4 in the central nervous systems in both young adult and aging mice sent signals to recruit additional repair cells to the injury site – cells called macrophages and monocytes. These are types of white blood cells that originate in the bone marrow and circulate in what is known as the “periphery,” via blood and outside the central nervous system. But only in young adult mice were these types of cells contributors to wound healing and clearing of debris, necessary inflammatory functions that help rather than harm.

“This was surprising to us because aging is typically associated with increased inflammation so we’d expect to see higher levels of inflammatory cytokines in the aged mice,” said first author Ashley Fenn, who just received her Ph.D. in neuroscience from Ohio State. “But in the aged mice with a spinal cord injury, we saw reduced levels of some inflammatory signals associated with a failure to reprogram the microglia with IL-4 toward a reparative profile. That’s how we figured out the IL-4 is unique in the spinal cord injury paradigm, that it induces an inflammatory response that appears to be beneficial.”

The IL-4 in the young adult mice also led to production of arginase, a protein that serves as a biomarker of the injury repair response. Significantly less arginase was detected in the injured elderly mice, another signal that the disabled receptor interfered with IL-4’s assistance in injury repair.

The communication among systems has long been a focus of Godbout’s research. He is an investigator in Ohio State’s Institute for Behavioral Medicine Research (IBMR) and Center for Brain and Spinal Cord Repair.

“There is some level of communication going on between the central nervous system microglia and the peripheral immune system’s macrophages. In our model, differences in that communication affected the ability to bring in cells to the site of the injury. Maybe the aging microenvironment brings in cells that are less beneficial,” he said.

About 200,000 people are currently living with a spinal cord injury in the United States, and an estimated 12,000 to 20,000 new injuries occur each year, according to the Centers for Disease Control and Prevention.

Though any therapy based on this research would take many years to develop, Godbout and Fenn said that finding a drug that could stimulate expression of the IL-4 alpha receptor in elderly spinal cord injury patients might have potential to improve their outcomes.

Study finds that learning by repetition impairs recall of details

When learning, practice doesn’t always make perfect.

UC Irvine neurobiologists Zachariah Reagh and Michael Yassa have found that while repetition enhances the factual content of memories, it can reduce the amount of detail stored with those memories. This means that with repeated recall, nuanced aspects may fade away.

In the study, which appears this month in Learning & Memory, student participants were asked to look at pictures either once or three times. They were then tested on their memories of those images. The researchers found that multiple views increased factual recall but actually hindered subjects’ ability to reject similar “imposter” pictures. This suggests that the details of those memories may have been shaken loose by repetition.

This discovery supports Reagh’s and Yassa’s Competitive Trace Theory – published last year in Frontiers in Behavioral Neuroscience – which posits that the details of a memory become more subjective the more they’re recalled and can compete with bits of other similar memories. The scientists hypothesize that this may even lead to false memories, akin to a brain version of the telephone game.

Yassa, an assistant professor of neurobiology & behavior, said that these findings do not discredit the practice of repetitive learning. However, he noted, pure repetition alone has limitations. For a more enriching and lasting learning experience through which nuance and detail are readily recalled, other memory techniques should be used to complement repetition.

Anxiety in invertebrates opens research avenues

For the first time, CNRS researchers and the Université de Bordeaux have produced and observed anxiety-like behavior in crayfish, which disappears when a dose of anxiolytic is injected. This work, published in Science on June 13, 2014, shows that the neuronal mechanisms related to anxiety have been preserved throughout evolution. This analysis of ancestral behavior in a simple animal model opens up new avenues for studying the neuronal bases for this emotion.

Anxiety can be defined as a behavioral response to stress, consisting in lasting apprehension of future events. It prepares individuals to detect threats and anticipate them appropriately so as to increase their chances of survival. However, when stress is chronic, anxiety becomes pathological and may lead to depression.

Until now, non-pathological anxiety had only been described in humans and a few vertebrates. For the first time, it has been observed in an invertebrate. To achieve this, researchers at the Institut de Neurosciences Cognitives et Intégratives d’Aquitaine (CNRS/Université de Bordeaux) and the Institut des Maladies Neurodégénératives (CNRS/Université de Bordeaux) repeatedly exposed crayfish to an electric field for thirty minutes. They then placed the crayfish in an aquatic cross-shaped maze. Two arms of the maze were lit up (which repels the crustaceans) and two were dark—which they find reassuring.

The researchers analyzed the exploratory behavior of the crayfish. Those made anxious tended to remain in the dark areas of the maze, by contrast to control crayfish, which explored the entire maze. This behavior is an adaptive response to a felt stress: the animal aims to minimize the risk of meeting an attacker. This emotional state wore itself out after about one hour.

Anxiety in crayfish is correlated to increased serotonin concentration in their brains. Neurotransmitter serotonin is involved in regulating many physiological processes in both invertebrates and humans. It is released when stress is experienced and regulates several responses related to anxiety, such as increasing blood glucose levels. The researchers have also highlighted that injecting an anxiolytic commonly used in humans (benzodiazepine) stops the prevention behavior in crayfish. This shows how early neural mechanisms that trigger or inhibit anxiety-like behavior appeared in the evolutionary process and that they have been well preserved over time.

This work provides researchers specializing in stress and anxiety with a unique animal model. Crayfish have a simple nervous system whose neurons are easy to record, so they may shed light on the neuronal mechanisms at work when stress is experienced, as well as on the role of neurotransmitters such as serotonin or GABA. The team now plans to study anxiety in crayfish subject to social stress and the neuronal changes that occur when the anxiety is prolonged for several days.