Researchers observe brain development in utero

New investigation methods using functional magnetic resonance tomography (fMRT) offer insights into fetal brain development. These “in vivo” observations will uncover different stages of the brain’s development. A research group at the Computational Imaging Research Lab from the MedUni Vienna has observed that parts of the brain that are later responsible for sight are already active at this stage.

To obtain insights into the development of the human brain in utero, the study group observed 32 fetuses from the 21st to 38th week of pregnancy (an average pregnancy lasts 40 weeks). The architecture of the brain is developed particularly during the middle trimester of pregnancy. Using functional magnetic resonance tomography, it was possible to measure activity and thereby gain information about the most important cortical and sub-cortical structures of the developing brain. During the period of the 26th to 29th week of pregnancy in particular, short-range neuronal connections developed especially actively, while in contrast to this, long-range nerve connections exhibited more linear growth during pregnancy. “It became apparent that the areas responsible for sensory perception are developed first and only then, around four weeks later, do the areas responsible for more complex, cognitive skills come along,” says first author Andras Jakab from the Computational Imaging Research Lab at the MedUni Vienna, explaining the results.

In another study, the study group led by Veronika Schöpf and Georg Langs was able to demonstrate for a correlation of eye movement and areas of the brain which are later responsible to process vision as early as the 30th to the 36th weeks of pregnancy. The fact that newborn babies first have to learn to “process” visual stimuli after birth is already known. It has now been possible to demonstrate that this important development starts even before birth. The research group investigated the relationship between eye movements and brain activity. Even at this stage of development, motor visual movement is linked to the areas in the visual cortex of the brain responsible for processing optical signals. “The relationship between eye movement and the responsible areas of the brain has therefore been demonstrated for the first time in utero”, explains first author Veronika Schöpf.

(Image caption: Three-dimensional reconstruction of a synapse in the mouse brain. Readily releasable fusionable synaptic vesicles (blue, around 45 millionths of a millimetre in diameter) are docked at the cell membrane. Credit: © MPI f. Experimental Medicine/ Benjamin H. Cooper)

Synapses always on the starting blocks

While neurons rapidly propagate information in their interior via electrical signals, they communicate with each other at special contact points known as the synapses. Chemical messenger substances, the neurotransmitters, are stored in vesicles at the synapses. When a synapse becomes active, some of these vesicles fuse with the cell membrane and release their contents. To ensure that valuable time is not lost, synapses always have some readily releasable vesicles on standby. With the help of high-resolution, three-dimensional electron microscopy, scientists at the Max Planck Institute of Experimental Medicine in Göttingen succeeded in demonstrating that these fusionable vesicles have a very special characteristic: they already have close contact with the cell membrane long before the actual fusion occurs. In addition, the research team also decoded the molecular machinery that facilitates the operation of this docking mechanism.

The fusion of the neurotransmitter vesicles with the cell membrane involves close cooperation between numerous protein components, which monitor each other and ensure that every single ‘participant’ is always in the right place. This is referred to as the fusion machinery and the comparison is an apt one: if a cogwheel in a clock mechanism is broken, the hands do not move. In a similar way, faulty or missing molecules impair synaptic operations.

In research studies carried out some years ago, Nils Brose and his colleague JeongSeop Rhee from the Max Planck Institute of Experimental Medicine in Göttingen already demonstrated that the transmission of information at the synapses in genetically modified mice, in which all known genes of the Munc13 or CAPS proteins had been switched off, is severely defective. Although the neurons of the genetically modified mice do not differ from those of healthy mice when examined under an optical microscope, if Munc13 is missing, the release of neurotransmitters actually grinds to a halt completely. Brose and Rhee’s findings showed that to be able to react immediately to signals at all times, each synapse must keep a small number of ‘readily releasable’ fusionable vesicles on standby.

But how do Munc13 and CAPS convert the vesicles to this kind of fusionable state? To answer this question, the Göttingen-based scientists studied the synaptic contacts in the minutest possible detail. To do this, neurobiologists Cordelia Imig and Ben Cooper, who have been working with Brose and Rhee for many years, used a high-pressure freezing process. This involves the rapid freezing of neurons in the brain tissue under high pressure so that no disruptive ice crystals are formed and the fine structure of the cells is particularly well conserved. The samples obtained in this way were then analysed using electron tomography. Using this method, electron microscope images of a structure are recorded from many different angles, in a similar way to the process used in medical computed tomography. The individual images can then be combined on the computer to give a high-resolution three-dimensional image – of a synapse in this case (see image).

“Our results showed that readily releasable vesicles in healthy synapses touch the cell membrane,” explains Cooper. “However, if Munc13 and CAPS proteins are missing, the vesicles do not reach the active zone and accumulate a few nanometres away from it.” To their astonishment, the researchers also observed that SNARE proteins, which collaborate with Munc13 and CAPS in the nerve endings, are also involved in this docking process. SNARE proteins are found in the cell and vesicle membranes of healthy synapses and control the fusion of the two membranes during neurotransmitter release. When a vesicle approaches the cell membrane, the individual SNARE molecules line up opposite each other like the sides of a zip and pull the membranes close to each other in this way. The vesicles await the starting gun for their fusion in this state – in the starting blocks, so to speak.

The findings of the neurobiologists in Göttingen prove that Munc13, CAPS and SNARE proteins closely align the vesicle and cell membrane in the synapse, long before the signal for fusion is given. This is the only way that the fast and controlled transmission of information at the synapse can be guaranteed, thanks to which we can react specifically to information from our environment. “It had long been clear that synapses have to be extremely fast to carry out all of the many complex brain functions. Our study shows for the first time how this is managed at the molecular level and on the level of the synaptic vesicles,” says Brose. Because almost all of the protein components involved in this process also play a role in neurological and psychiatric diseases, the Göttingen-based scientists believe that their discovery will soon benefit medical research.

(Image caption: In the top image, cells from a mouse model of amyotrophic lateral sclerosis caused normal healthy brain cells (green) to die. But when scientists blocked an enzyme in the cells from the mouse model, more of the normal cells and their branches survived (bottom))

Heart drug may help treat ALS

Digoxin, a medication used in the treatment of heart failure, may be adaptable for the treatment of amyotrophic lateral sclerosis (ALS), a progressive, paralyzing disease, suggests new research at Washington University School of Medicine in St. Louis.

ALS, also known as Lou Gehrig’s disease, destroys the nerve cells that control muscles. This leads to loss of mobility, difficulty breathing and swallowing and eventually death. Riluzole, the sole medication approved to treat the disease, has only marginal benefits in patients.

But in a new study conducted in cell cultures and in mice, scientists showed that when they reduced the activity of an enzyme or limited cells’ ability to make copies of the enzyme, the disease’s destruction of nerve cells stopped. The enzyme maintains the proper balance of sodium and potassium in cells.

“We blocked the enzyme with digoxin,” said senior author Azad Bonni, MD, PhD. “This had a very strong effect, preventing the death of nerve cells that are normally killed in a cell culture model of ALS.”

The findings appear online Oct. 26 in Nature Neuroscience.

The results stemmed from Bonni’s studies of brain cells’ stress responses in a mouse model of ALS. The mice have a mutated version of a gene that causes an inherited form of the disease and develop many of the same symptoms seen in humans with ALS, including paralysis and death.

Efforts to monitor the activity of a stress response protein in the mice unexpectedly led the scientists to another protein: sodium-potassium ATPase. This enzyme ejects charged sodium particles from cells and takes in charged potassium particles, allowing cells to maintain an electrical charge across their outer membranes.

Maintenance of this charge is essential for the normal function of cells. The particular sodium-potassium ATPase highlighted by Bonni’s studies is found in nervous system cells called astrocytes. In the ALS mice, levels of the enzyme are higher than normal in astrocytes.

Bonni’s group found that the increase in sodium-potassium ATPase led the astrocytes to release harmful factors called inflammatory cytokines, which may kill motor neurons.

Recent studies have suggested that astrocytes may be crucial contributors to neurodegenerative disorders such as ALS, and Alzheimer’s, Huntington’s and Parkinson’s diseases. For example, placing astrocytes from ALS mice in culture dishes with healthy motor neurons causes the neurons to degenerate and die.

“Even though the neurons are normal, there’s something going on in the astrocytes that is harming the neurons,” said Bonni, the Edison Professor of Neurobiology and head of the Department of Anatomy and Neurobiology.

How this happens isn’t clear, but Bonni’s results suggest the sodium-potassium ATPase plays a key role. When he conducted the same experiment but blocked the enzyme in ALS astrocytes using digoxin, the normal motor nerve cells survived. Digoxin blocks the ability of sodium-potassium ATPase to eject sodium and bring in potassium.

In mice with the mutation for inherited ALS, those with only one copy of the gene for sodium-potassium ATPase survived an average of 20 days longer than those with two copies of the gene. When one copy of the gene is gone, cells make less of the enzyme.

“The mice with only one copy of the sodium-potassium ATPase gene live longer and are more mobile,” Bonni said. “They’re not normal, but they can walk around and have more motor neurons in their spinal cords.”

Many important questions remain about whether and how inhibitors of the sodium-potassium ATPase enzyme might be used to slow progressive paralysis in ALS, but Bonni said the findings offer an exciting starting point for further studies.

Ultra-high-field MRI reveals language centres in the brain in much more detail

In a new investigation by the University Department of Neurology, it has been possible for the first time to demonstrate that the areas of the brain that are important for understanding language can be pinpointed much more accurately using ultra-high-field MRI (7 Tesla) than with conventional clinical MRI scanners. This helps to protect these areas more effectively during brain surgery and avoid accidentally damaging it.

Before brain surgery, it is important to precisely understand the areas of the brain required for language in order to avoid injuring them during the procedure. Their position can shift considerably, especially in patients with tumours or brain injuries. The brain’s flexibility also means that language centres can shift to other regions. If the areas responsible for language control and processing are injured during a brain operation, the patient can be left unable to communicate. In order to create a “map” of the language control centres prior to the operation, functional magnetic resonance imaging (fMRI) is used these days.

A multi-centre study from 2013 demonstrated the advantages of fMRI-assisted localisation of the motor centres in the brain. In a new investigation by the working group led by Roland Beisteiner (University Department of Neurology), it has been possible for the first time to demonstrate that the areas of the brain that are important for understanding language can be pinpointed even more accurately using ultra-high-field MRI (7 Tesla) than with conventional clinical MRI scanners. The focus lies on the two most important language centres in the brain known as Wernicke’s area (which controls the understanding of language) and Broca’s area (which controls the motor functions involved with speech).

The brain is scanned for activity while the patient is carrying out speech exercises. This allows the areas required for speech to be localised much more accurately than previously. “Ultra-high-field MR offers much greater sensitivity than classic MRI scanners”, explains Roland Beisteiner, “allowing even very weak signals to be recorded in areas that would otherwise have been missed.”

Activity in dendrites is critical in memory formation

Why do we remember some things and not others? In a unique imaging study, two Northwestern University researchers have discovered how neurons in the brain might allow some experiences to be remembered while others are forgotten. It turns out, if you want to remember something about your environment, you better involve your dendrites.

Using a high-resolution, one-of-a-kind microscope, Daniel A. Dombeck and Mark E. J. Sheffield peered into the brain of a living animal and saw exactly what was happening in individual neurons called place cells as the animal navigated a virtual reality maze.

The scientists found that, contrary to current thought, the activity of a neuron’s cell body and its dendrites can be different. They observed that when cell bodies were activated but the dendrites were not activated during an animal’s experience, a lasting memory of that experience was not formed by the neurons. This suggests that the cell body seems to represent ongoing experience, while dendrites, the treelike branches of a neuron, help to store that experience as a memory.

"There are a lot of theories on memory but very little data as to how individual neurons actually store information in a behaving animal," said Dombeck, assistant professor of neurobiology in the Weinberg College of Arts and Sciences and the study’s senior author. "Now we have uncovered signals in dendrites that we think are very important for learning and memory. Our findings could explain why some experiences are remembered and others are forgotten."

In the brain’s hippocampus, there are hundreds of thousands of place cells — neurons essential to the brain’s GPS system. Dombeck and Sheffield are the first to image the activity of individual dendrites in place cells.

Their findings contribute to our understanding of how the brain represents the world around it and also point to dendrites as a new potential target for therapeutics to combat memory deficits and debilitating diseases, such as Alzheimer’s disease (AD). Disruption to the brain’s GPS system is one of the first symptoms of AD, with many patients unable to find their way home. Understanding how place cells and their dendrites store these types of memories could help us find new ways to treat the disease.

The Northwestern study will be published Oct. 26 by the journal Nature.

Neuroscientist John O’Keefe discovered place cells in 1971 (and received this year’s Nobel Prize in physiology and medicine), but it is only in the last few years that scientists, such as Dombeck and Sheffield, have been able to image these neurons that represent a map of where we are in our environment.

In their study, Dombeck and Sheffield found dendrite signals that could explain how an animal can experience something without storing the experience as a memory.

They saw that dendrites are not always activated when the cell body is activated in a neuron. Signals produced in the dendrites (used to store information) and signals within the neuron cell body (used to compute and transmit information) can be either highly synchronized or desynchronized depending on how well the neurons remember different features of the maze.

Scientists have long believed that the neuronal tasks of computing and storing information are connected — when neurons compute information, they are also storing it, and vice versa. The Northwestern study provides evidence against this classic view of neuronal function.

"We experience events all the time, which must be represented in the brain by the activity of neurons, but not all these events can be recalled later," said Mark E. J. Sheffield, a postdoctoral fellow in Dombeck’s lab and first author of the study.

"A daily commute to work, for example, requires the activity of millions of neurons, but you would be hard pressed to remember what was happening halfway through your commute last Tuesday," Sheffield said. "How is it then that the neurons could be activated during the commute without storing that information in the brain? Now we may have an explanation for how this occurs."

Dombeck and Sheffield built their own laser scanning microscope that can image neurons on multiple planes. They then studied individual animals navigating (on a trackball) a virtual reality maze constructed using the video game Quake II.

Each lit-up structure seen in the images they took indicate a neuron firing action potentials. The activity of these neurons represents an animal’s experience of where it is in the environment, the researchers said. Whether the neurons store this experience or not appears to depend on the activity of the neurons’ dendrites.

(Image credit)

Just 30 minutes of exercise has benefits for the brain

University of Adelaide neuroscientists have discovered that just one session of aerobic exercise is enough to spark positive changes in the brain that could lead to improved memory and coordination of motor skills.

A study conducted by researchers in the University’s Robinson Research Institute has found changes in the brain that were likely to make it more “plastic” after only 30 minutes of vigorous exercise.

The study involved a small group of healthy people aged in their late 20s to early 30s who rode exercise bikes. They were monitored for changes in the brain immediately after the exercise and again 15 minutes later.

"We saw positive changes in the brain straight away, and these improvements were sustained 15 minutes after the exercise had ended," says research leader Associate Professor Michael Ridding.

"Plasticity in the brain is important for learning, memory and motor skill coordination. The more ‘plastic’ the brain becomes, the more it’s able to reorganise itself, modifying the number and strength of connections between nerve cells and different brain areas."

Associate Professor Ridding says past research has shown that regular physical activity can have positive effects on brain function and plasticity, but it was unknown whether a stand-alone session of exercise would also have similar positive effects.

"We now have evidence suggesting that it does," he says. "This exercise-related change in the brain may, in part, explain why physical activity has a positive effect on memory and higher-level functions."

Associate Professor Ridding says there is now mounting evidence that engaging in aerobic exercise positively influences brain function in many ways - at cellular and molecular levels, as well as in the brain’s architecture.

"Although this was a small sample group, it helps us to better understand the overall picture of how exercise influences the brain," he says.

"We know that plasticity is also important for recovery from brain damage, so this opens up potential therapeutic avenues for patients.

"Further research will be required to see what the possible long-term benefits could be for patients as well as healthy people."

The pleasure of learning new words

From our very first years, we are intrinsically motivated to learn new words and their meanings. First language acquisition occurs within a permanent emotional interaction between parents and children. However, the exact mechanism behind the human drive to acquire communicative linguistic skills is yet to be established.

In a study published in the journal Current Biology, researchers from the University of Barcelona (UB), the Bellvitge Biomedical Research Institute (IDIBELL) and the Otto von Guericke University Magdeburg (Germany) have experimentally proved that human adult word learning exhibit activation not only of cortical language regions but also of the ventral striatum, a core region of reward processing. Results confirm that the motivation to learn is preserved throughout the lifespan, helping adults to acquire a second language.

Researchers determined that the reward region that is activated is the same that answers to a wide range of stimuli, including food, sex, drugs or game. “The main objective of the study was to know to what extent language learning activates subcortical reward and motivational systems”, explains Pablo Ripollés, PhD student at UB-IDIBELL and first author of the article. “Moreover, the fact that language could be favoured by this type of circuitries is an interesting hypothesis from an evolutionary point of view”, points out the expert.

According to Antoni Rodríguez Fornells, UB lecturer and ICREA researcher at IDIBELL, “the language region has been traditionally located at an apparently encapsulated cortical structure which has never been related to reward circuitries, which are considered much older from an evolutionary perspective”. “The study —he adds— questions whether language only comes from cortical evolution or structured mechanisms and suggests that emotions may influence language acquisition processes”.

By using diffusion tensor imaging, UB-IDIBELL researchers reconstructed the white matter pathways that link brain regions in each participant. Experts were able to correlate the number of new words learnt by each person during the experiment with a low myelin index, a measure of structure integrity. Results proved that subjects who presented higher myelin concentrations in the structures that carry information to the ventral striatum —in other words, those that are best connected to the reward area— were able to learn more words.

“Results provide a neural substrate of the influence that reward and motivation circuitries may have in learning words from context”, affirms Josep Marco Pallarès, UB-IDIBELL researcher. The activation of these circuitries during word learning suggests future research lines aimed at stimulating reward regions to improve language learning in patients with linguistic problems. 

The fact that non-linguistic subcortical mechanisms, which are much older from an evolutionary perspective, work together with language cortical regions —which appeared latter— suggests new language theories trying to explain how reward mechanisms have influenced and supported one of our primal urges: the desire to acquire language and to communicate.

Experiment with words and gambling

Researchers carried out an experiment with thirty-six adults who participated in two magnetic resonance sessions. On the first one, functional magnetic resonance was used to measure participants’ brain activity while they perform two different tasks. This technique enables to detect accurately what brain regions are active while a person is performing a certain activity. In the first task, participants must learn the meaning of some new words from context in two different sentences. For instance, subjects saw on a screen the sentences: “Every Sunday the grandmother went to the jedin” and “The man was buried in the jedin”. Considering both sentences, participants could learn that the word jedin means “graveyard”. Then, participants completed two runs of a standard-event-related money gambling task.

The experiment revealed that when subjects inferred and memorized the meaning of a new word, brain activity in the ventral striatum was increased. Indeed, the same ventral striatum activation was observed when earning money in gambling. Therefore, to learn the meaning of a new word activates reward and motivational circuitries like in gambling activities. Moreover, it was observed that word learning produce an increase of brain activity synchronization between the ventral striatum and cortical language regions.