FASD impacts brain development throughout childhood and adolescence not just at birth

Medical researchers at the University of Alberta recently published findings showing that brain development is delayed throughout childhood and adolescence for people born with Fetal Alcohol Spectrum Disorder (FASD).

Christian Beaulieu and Carmen Rasmussen, the two primary investigators in the research study, recently published the results of their work in the peer-reviewed journal, The Journal of Neuroscience. Their team scanned 17 people with FASD, and 27 people without the disorder, who were between 5 and 15 years old. Each participant underwent two to three scans, with each scan taking place two to four years apart. This is the first research study involving multiple scans of the same FASD study participants.

Researchers used an advanced MRI method that examines white matter in the brain. White matter forms connections between various regions of the brain and usually develops significantly during childhood and adolescence. Those who took part in the study were imaged multiple times, to see what kinds of changes occurred in brain development as the participants aged. Those without the disorder had marked increases in brain volume and white matter – growth that was lacking in those with FASD. However, the advanced MRI method revealed greater changes in the brain wiring of white matter in the FASD group, which the authors suggest may reflect compensation for delays in development earlier in childhood.

“These findings may suggest that significant brain changes happened earlier in the study participants who didn’t have FASD,” says the study’s first author, Sarah Treit, who is a student in the Centre for Neuroscience at the U of A. “This study suggests alcohol-induced injury with FASD isn’t static – those with FASD have altered brain development, they aren’t developing at the same rate as those without the disorder. And our research showed those with FASD consistently scored lower on all cognitive measures in the study.”

Treit said the research team also made other important observations. Children with FASD who demonstrated the greatest changes in white matter development also made the greatest gains in reading ability – “so the connection seems relevant.” And those with the most severe FASD showed the greatest changes in white matter brain wiring. Scans also confirmed those with FASD have less overall brain volume – this issue neither rectified itself nor worsened throughout the course of the study.

Beaulieu is a researcher in the Department of Biomedical Engineering, while Rasmussen works in the Department of Pediatrics. Their research was funded by the Canadian Institutes of Health Research.

The team is continuing their research in this area, in hopes of finding a biomarker for FASD, and to examine how the brain changes from adolescence into adulthood in those with the disorder. The advanced MRI imaging the team used can pinpoint brain damage present in those with FASD, and could one day guide medical interventions for those with the disorder, which affects one in every 100 Canadians.

Robots Strike Fear in the Hearts of Fish

Anxious Zebrafish Help NYU-Poly Researchers Understand How Alcohol Affects Fear

The latest in a series of experiments testing the ability of robots to influence live animals shows that bio-inspired robots can not only elicit fear in zebrafish, but that this reaction can be modulated by alcohol. These findings may pave the way for new methodologies for understanding anxiety and other emotions, as well as substances that alter them.

Maurizio Porfiri, associate professor of mechanical and aerospace engineering at the Polytechnic Institute of New York University (NYU-Poly) and Simone Macrì, a collaborator at the Istituto Superiore di Sanità in Rome, Italy, published their findings in PLOS ONE, an international, peer-reviewed, open-access, online publication.

This latest study expands Porfiri and Macrì’s efforts to determine how bio-inspired robots can be employed as reliable stimuli to elicit reactions from live zebrafish. Previous studies have established that zebrafish show a strong affinity for robotic members designed to swim and appear as one of their own and that this preference can be abolished by exposing the fish to ethanol.

Porfiri and Macri, along with students Valentina Cianca and Tiziana Bartolini, hypothesized that robots could be used to induce fear as well as affinity and designed a robot mimicking the morphology and locomotion pattern of the Indian leaf fish, a natural predator of the zebrafish. In the lab, they simulated a harmless predatory scenario, placing the zebrafish and the robotic Indian leaf fish in separate compartments of a three-section tank. The other compartment was left empty. The control group uniformly avoided the robotic predator, showing a preference for the empty section.

To determine whether alcohol would affect fear responses, the researchers exposed separate groups of fish to different doses of ethanol in water. Ethanol has been shown to influence anxiety-related responses in humans, rodents and some species of fish. The zebrafish exposed to the highest concentrations of ethanol showed remarkable changes in behavior, failing to avoid the predatory robot. Acute administration of ethanol causes no harm and has no lasting effect on zebrafish.

“These results are further evidence that robots may represent an exciting new approach in evaluating and understanding emotional responses and behavior,” said Porfiri. “Robots are ideal replacements as independent variables in tests involving social stimuli—they are fully controllable, stimuli can be reproduced precisely each time, and robots can never be influenced by the behavior of the test subjects.”

To validate their findings and ensure that the zebrafish behavior being modulated was, in fact, a fear-based response, Porfiri and his collaborators conducted two traditional anxiety tests and evaluated whether the results obtained therein were sensitive to ethanol administration.

They placed test subjects in a two-chamber tank with one well-lit side and one darkened side, to establish which conditions were preferable. In a separate tank, they simulated a heron attack from the water’s surface—herons also prey on zebrafish—and measured how quickly and how many fish took shelter from the attack. As expected, the fish strongly avoided the dark compartment, and most sought shelter very quickly from the heron attack. Ethanol exposure significantly modulated these fear responses as well, abolishing the preference for the light compartment and significantly slowing the fishes’ retreat to shelter during the simulated attack.

“We hoped to see a correlation between the robotic Indian leaf fish test results and the results of the other anxiety tests, and the data support that,” Porfiri explained. “The majority of control group fish avoided the robotic predator, preferred the light compartment and sought shelter quickly after the heron attack. Among ethanol-exposed fish, there were many more who were unaffected by the robotic predator, preferred the dark compartment and were slow to swim to shelter when attacked.”

Porfiri and his colleagues believe zebrafish may be a suitable replacement for higher-order animals in tests to evaluate emotional responses. This novel robotic approach would also reduce the number of live test subjects needed for experiments and may inform other areas of inquiry, from collective behavior to animal protection.

Scientists decode mechanisms of cell orientation in the brain

Transmembrane protein NG2 controls orientation of cell migration toward the wound / Publication in the prestigious Journal of Neuroscience

When the central nervous system is injured, oligodendrocyte precursor cells (OPC) migrate to the lesion and synthesize new myelin sheaths on demyelinated axons. Scientists at the Institute of Molecular Cell Biology at Johannes Gutenberg University Mainz (JGU) have now discovered that a distinct protein regulates the direction and movement of OPC toward the wound. The transmembrane protein NG2, which is expressed at the surface of OPCs and down-regulated as they mature to myelinating oligodendrocytes, plays an important role in the reaction of OPC to wounding. The results of this study have recently been published in the renowned Journal of Neuroscience.

The myelin sheath functions to electrically isolate axons of many nerve fibers and is synthesized by oligodendrocytes which mature from the OPC. In the case of injury, neural cells send out signaling molecules which attract the OPC. The NG2 protein helps OPCs to react to some of these and move in a directed and orientated fashion. “We were able to prove in cell biological experiments that NG2 orientates OPC toward the lesion and ensures targeted OPC migration toward the wound through the regulation of cell polarity”, explained Dr. Fabien Binamé, lead author of the study. Supported by funding of the German Research Foundation (DFG), Dr. Fabien Binamé is currently carrying out his research at the Institute of Molecular Cell Biology headed by Professor Jacqueline Trotter.

"The function and mode of operation of NG2 is not yet fully understood", added co-author Dominik Sakry, who was also involved in the study. "But it looks as if the NG2-associated regulatory mechanism becomes apparent only in cases of injury of the nervous system."

Diseases such as Multiple Sclerosis or brain tumors go hand in hand with damage of nerve tissue. “The results of our study on NG2-mediated basic mechanisms of cell orientation and migration could aid in understanding the repair of damaged demyelinated tissue, or be important for treatment of highly active migratory brain tumors which often express high levels of NG2”, said Professor Jacqueline Trotter, head of the JGU Institute of Molecular Cell Biology.

The flexible tail of the prion protein poisons brain cells

For decades, there has been no answer to the question of why the altered prion protein is poisonous to brain cells. Neuropathologists from the University of Zurich and University Hospital Zurich have now shown that it is the flexible tail of the prion protein that triggers cell death. These findings have far-reaching consequences: only those antibodies that target the tail of the prion protein are suitable as potential drugs for combating prion diseases.

Prion proteins are the infectious pathogens that cause Mad Cow Disease and Creutzfeldt-Jakob disease. They occur when a normal prion protein becomes deformed and clumped. The naturally occurring prion protein is harmless and can be found in most organisms. In humans, it is found in our brain cell membrane. By contrast, the abnormally deformed prion protein is poisonous for the brain cells. Adriano Aguzzi, Professor of Neuropathology at the University of Zurich and University Hospital Zurich, has spent many years exploring why this deformation is poisonous. Aguzzi’s team has now discovered that the prion protein has a kind of «switch» that controls its toxicity. This switch covers a tiny area on the surface of the protein. If another molecule, for example an antibody, touches this switch, a lethal mechanism is triggered that can lead to very fast cell death.

Flexible tail induces cell death

In the current edition of «Nature», the scientists demonstrate that the prion protein molecule comprises two functionally distinct parts: a globular domain, which is tethered to the cell membrane, and a long and unstructured tail. Under normal conditions, this tail is very important in order to maintain the functioning of nerve cells. By contrast, in the case of a prion infection the pathogenic prion protein interacts with the globular part and the tail causes cell death – this is the hypothesis put forward by the researchers.

Aguzzi and his team tested this by generating mimetic antibodies in tissue sections from the cerebellum of mice which have a similar toxicity to that of a prion infection. The researchers found that these antibodies tripped the switch of the prion protein. «Prion proteins with a trimmed version of the flexible tail can, however, no longer damage the brain cells, even if their switch has been recognized by antibodies», explains Adriano Aguzzi. «This flexible tail is responsible for causing cell death.» If the tail is bound and made inaccessible using a further antibody, activation of the switch can likewise no longer trigger cell death.

«Our discovery has far-reaching consequences for understanding prion diseases», says Aguzzi. The findings reveal that only those antibodies that target the prion protein tail are suitable for use as potential drugs. By contrast, antibodies that trip the switch of the prion are very harmful and dangerous.

By tracking maggots’ food choices, scientists open significant new window into human learning

The squirming larva of the humble fruit fly, which shares a surprising amount of genetic material with the human being, is helping scientists to understand the way we learn information from one another.

Fruit flies have long served as models for studying behaviour because their cognitive mechanisms are parallel to humans’, but much simpler to study.

Fruit flies exhibit many of the same basic behaviours as humans and share 87 per cent of the material that is responsible for genetically based neurological disorders, making them a potent model for study.

While adult fruit flies have been studied for decades, the new paper reveals that their larvae, which are even simpler organisms, may be more valuable models for behavioral research. A fruit fly larva has only 3,000 neurons, for example, while a human has about 10 billion.

The McMaster researchers were able to prove that the larvae, or maggots, are capable of social learning, which opens the door to many other experiments that could provide valuable insights into human behaviour, end even lead to treatments for human disorders, the scientists say.

“People have been studying adult flies for decades now,” explains the study’s lead author, Zachary Durisko. “The larval stage is much simpler in terms of the brain, but behaviour at the larval stage has been less well studied. Here we have a complex behaviour in this even simpler model.”

Durisko and Reuven Dukas, both of McMaster’s Department of Psychology, Neuroscience and Behaviour, have shown that fruit fly larvae are able to distinguish which food sources have been used by other larvae and utilize the information to benefit themselves by choosing to eat from those same established sources instead of available alternatives.

The maggots’ attraction to food that others have been eating is based on smell, and is roughly equivalent to a person arriving in a new city, seeing two restaurants and choosing a busy one over an empty one, the researchers explain.

“They prefer the social over the non-social like we would do, and they learn to prefer the social over the non-social,” Dukas says.

In fact, the motivations may be similar in each case, and could include accepting the judgment of others as an indication of quality and seeking the company of others for protection from harm.

Durisko, the lead author, recently completed his PhD at McMaster, and Dukas, his co-author, is a professor at the university. Their work is published in the prestigious Proceedings of the Royal Society B, one of the society’s biological journals.

The researchers used several combinations of foods, both completely fresh and previously used, and of varying degrees of nutritional value, to compare the maggots’ preferences.

Cockatoos know what is going on behind barriers

For investigating spatial memory and tracking in animals and human infants a number of setups have been habitually used. These can roughly be subdivided depending on what is being moved: a desired object (food reward), the hiding places for this object or the test animal itself: In the original invisible displacement tasks, designed by French psychologist Jean Piaget in the 50s, the reward is moved underneath a small cup behind one or more bigger screens and its contents is shown in between visits: if the cup is empty we know that the reward must be behind the last screen visited. Humans solve this task after about two years of age, whereas in primates only the great apes show convincing results.

Likely to be even more challenging in terms of attention, are “Transposition” tasks: the reward is hidden underneath one of several equal cups, which are interchanged one or more times. Human children struggle with this task type more than with the previous and do not solve it reliably before the age of three to four years whereas adult apes solve it but have more trouble with double than single swaps.

In “Rotation” tasks several equal cups, one bearing a reward are aligned in parallel on a rotatable platform, which is rotated at different angles. “Translocation” tasks are similar except that the cups are not rotated but the test animal is carried around the arrangement and released at different angles to the cup alignment. Children find Translocation tasks easier than Rotation tasks and solve them at two to three years of age.

A team of international Scientists tested eight Goffin cockatoos (Cacatua goffini), a conspicuously inquisitive and playful species on visible as well as invisible Piagetian object displacements and derivations of spatial transposition, rotation and translocation tasks.  Birgit Szabo, one of the experimenters from the University of Vienna, says: “The majority of our eight birds readily and spontaneously solved Transposition, Rotation and Translocation tasks whereas only two out of eight choose immediately and reliably the correct location in the original Piagetian invisible displacement task in which a smaller cup is visiting two of three bigger screens”. Alice Auersperg, the manager of the Goffin Lab who was also one of the experimenters, explains: “Interestingly and just opposite to human toddlers our cockatoos had more problems solving the Piagetian invisible displacements than the transposition task with which children struggle until the age of four. Transpositions are highly demanding in terms of attention since two occluding objects are moved simultaneously. Nevertheless, in contrast to apes, which find single swaps easier than double the cockatoos perform equally in both conditions”.

Similarly, Goffins had little complications with Rotations and Translocation tasks and some of them solved them at four different angles. Again, in contrast to children, which find Translocations easier than Rotations, the cockatoos showed no significant differences between the two tasks. Auguste von Bayern from the University of Oxford adds: ” We assume that the ability to fly and prey upon or being preyed upon from the air is likely to require pronounced spatial rotation abilities and may be a candidate trait influencing the animals’ performance in rotation and translocation tasks”.

Thomas Bugnayer from the University of Vienna concludes: “Finding that Goffins solve transposition, rotation and translocation tasks, which are likely to pose a large cognitive load on working memory, was surprising and calls for more comparative data in order to better understand the relevance of such accurate tracking abilities in terms of ecology and sociality”.