Neuroscience

Researchers from the Allen Institute for Brain Science have published the first comprehensive, large-scale data set on how the brain of a mammal is wired, providing a groundbreaking data resource and fresh insights into how the nervous system processes information. Their landmark paper in this week’s issue of the journal Nature both describes the publicly available Allen Mouse Brain Connectivity Atlas, and demonstrates the exciting knowledge that can be gleaned from this valuable resource.

(Image: Connectivity Dot-o-Gram)

“Understanding how the brain is wired is among the most crucial steps to understanding how the brain encodes information,” explains Hongkui Zeng, Senior Director of Research Science at the Allen Institute for Brain Science. “The Allen Mouse Brain Connectivity Atlas is a standardized, quantitative, and comprehensive resource that will stimulate exciting investigations around the entire neuroscience community, and from which we have already gleaned unprecedented details into how structures are connected inside the brain.”

Using the data, Allen Institute scientists were able to demonstrate that there are highly specific patterns in the connections among different brain regions, and that the strengths of these connections vary with greater than five orders of magnitudes, balancing a small number of strong connections with a large number of weak connections. This publication comes just as the research team wraps up more than four years of work to collect and make publicly available the data behind the Allen Mouse Brain Connectivity Atlas project, with the completion of the Atlas announced in March 2014.

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First major report using data from the BrainSpan Atlas of the Developing Human Brain shines a light on where genes are turned on in the brain during mid-pregnancy, what goes wrong in developmental disorders like autism, and what makes human brains unique.

Researchers at the Allen Institute for Brain Science have generated a high-resolution blueprint for how to build a human brain, with a detailed map of where different genes are turned on and off during mid-pregnancy at unprecedented anatomical resolution. This first major report using data from the BrainSpan Atlas of the Developing Human Brain is published in the journal Nature this week. The data provide exceptional insight into diseases like autism that are linked to early brain development, and to the origins of human uniqueness. The rich data set is publicly available to everyone via the Allen Brain Atlas data portal.

“Knowing where a gene is expressed in the brain can provide powerful clues about what its role is,” says Ed Lein, Investigator at the Allen Institute for Brain Science. “This atlas gives a comprehensive view of which genes are on and off in which specific nuclei and cell types while the brain is developing during pregnancy. This means that we have a blueprint for human development: an understanding of the crucial pieces necessary for the brain to form in a normal, healthy way, and a powerful way to investigate what goes wrong in disease.”

This paper represents the first major report to make use of data collected for the BrainSpan Atlas of the Developing Human Brain, a big science consortium initiative which seeks to create a map of the transcriptome across the entire course of human development. “Coming on the first anniversary of the BRAIN Initiative, this is a terrific example of the potential for public-private partnerships to accelerate progress in neuroscience,” says Lein.

Thomas R. Insel, Director of the National Institute of Mental Health, praises the BrainSpan Atlas as an already invaluable tool to researchers. “While we have had previous reports of molecular and cellular changes during human brain growth, the BrainSpan Atlas is the first comprehensive map of the dramatic trajectory of gene expression across prenatal and postnatal development,” he says. “This atlas is already transforming the way scientists approach human brain development and neurodevelopmental disorders like autism and schizophrenia. Although the many genes associated with autism and schizophrenia don’t show a clear relationship to each other in the adult brain, the BrainSpan Atlas reveals how these diverse genes are connected in the prenatal brain.”

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A new University of Illinois study finds that obese children are slower than healthy-weight children to recognize when they have made an error and correct it. The research is the first to show that weight status not only affects how quickly children react to stimuli but also impacts the level of activity that occurs in the cerebral cortex during action monitoring.

“I like to explain action monitoring this way: when you’re typing, you don’t have to be looking at your keyboard or your screen to realize that you’ve made a keystroke error. That’s because action monitoring is occurring in your brain’s prefrontal cortex,” said Charles Hillman, a U of I professor of kinesiology and faculty member in the U of I’s Division of Nutritional Sciences.

As an executive control task that requires organizing, planning, and inhibiting, action monitoring requires people to be computational and conscious at all times as they process their behavior. Because these higher-order cognitive processes are needed for success in mathematics and reading, they are linked with success in school and positive life outcomes, he said.

“Imagine a child in a math class constantly checking to make sure she’s carrying the digit over when she’s adding. That’s an example,” he added.

In the study, the scientists measured the behavioral and neuroelectric responses of 74 preadolescent children, half of them obese, half at a healthy weight. Children were fitted with caps that recorded electroencephalographic activity and asked to participate in a task that presented left- or right-facing fish, predictably facing in either the same or the opposite direction. Children were asked to press a button based on the direction of the middle (that is, target) fish. The flanking fish either pointed in the same direction (facilitating) or in the opposite direction (hindering) their ability to respond successfully.

“We found that obese children were considerably slower to respond to stimuli when they were involved in this activity,” Hillman said.

The researchers also found that healthy-weight children were better at evaluating their need to change their behavior in order to avoid future errors.

“The healthy-weight kids were more accurate following an error than the obese children were, and when the task required greater amounts of executive control, the difference was even greater,” he reported.

A second evaluation measured electrical activity in the brain “that occurs at the intersection of thought and action,” Hillman said. “We can measure what we call error-related negativity (ERN) in the electrical pattern that the brain generates following errors. When children made an error, we could see a larger negative response. And we found that healthy-weight children are better able to upregulate the neuroelectric processes that underlie error evaluation.”

Scientists in the Hillman lab and elsewhere have seen a connection between healthy weight and academic achievement, “but a study like this helps us understand what’s happening. There are certainly physiological differences in the brain activity of obese and healthy-weight children. It’s exciting to be able to use functional brain imaging to see the way children’s weight affects the aspects of cognition that influence and underlie achievement,” said postdoctoral researcher and co-author Naiman Khan.

Networked nerve cells are the control center of organisms. In a nematode, 300 nerve cells are sufficient to initiate complex behavior. To understand the properties of the networks, researchers switch cells on and off with light and observe the resulting behavior of the organism. In the Science journal, scientists now present a protein that facilitates the control of nerve cells by light. It might be used as a basis of studies of diseases of the nervous system.

(Image caption: Nerve cells form networks that can process signals. Photo: J. Wietek/HU Berlin).

To switch a nerve cell with light, certain proteins forming ion channels in the cell membrane are used. These proteins are called channelrhodopsins. If light strikes the channels, they open and ions enter and render the cell specifically active or inactive. In this way, a very fine tool is obtained to study functions in the network of nerve cells. So far, however, large amounts of light have been required and only closely limited areas in the network could be switched. The ChlocC channelrhodopsin presented now reacts about 10,000 times more sensitively to light than other proteins used so far for switching off nerve cells.

“For the modification of the protein, we analyzed its structure on the computer,” Marcus Elstner, KIT, explains. The theoretical chemist and his team modeled the proteins that consist of about 5000 atoms. For this purpose, they used the highest-performance computers of KIT’s computing center, the Steinbuch Centre for Computing, SCC. Together with the protein environment, i.e. the cell membrane and cell water, about 100,000 atoms had to be considered for the computations that took several weeks. “It was found that ion conductivity of the channel is essentially based on three amino acids in the central region, i.e. on about 50 atoms in the channel only.” By exchanging the amino acids, scientists have now succeeded in increasing the sensitivity of the ion channel.

Light-activated ion channels, the so-called channelrhodopsins, from microalgae have been used since 2005. In neural sections or living transgenic model organisms, such as flies, zebrafish, or mice, they allow for the specific activation of selected cells with light. Thus, understanding of their role in the cell structure can be improved. This technology is known as optogenetics and applied widely. In the past years, it contributed to the better understanding of the biology of signal processing. So far inaccessible neural pathways were mapped and many relationships were discovered among proteins, cells, tissues, and functions of the nervous system.

Within the framework of the study reported in the latest Science issue, researchers from Karlsruhe, Hamburg, and Berlin developed the ion channels further. Jonas Wietek and Nona Adeishvili working in the team of Peter Hegemann at the Humboldt-Universität Berlin have succeeded in identifying the selectivity filter of the channelrhodopsins and in modifying it such that negatively charged chloride ions are conducted. These chloride-conducting channels have been called ChlocC by the scientists. Hiroshi Watanabe from the team of Marcus Elstner, Karlsruhe Institute of Technology (KIT), computed ion distribution in the protein and visualized the increased chloride distribution. Simon Wiegert from the team of Thomas Oertner of the Center for Molecular Neurobiology, Hamburg, demonstrated that ChlocC can be introduced into selected neurons for the inactivation of the latter with very small light intensities similar to the processes taking place in the living organism. With ChloC a novel optogenetic tool is now available that can be used in neurosciences to study the switching of neural networks together with the already known light-activated cation channels that mainly conduct sodium ions and protons. This fundamental knowledge might help better understand the mechanisms of diseases like epilepsy and Parkinson’s. In some years from now, this may give rise to therapy concepts, which might be much more specific than the medical drugs used today.

Researchers at Lancaster University have invented a new imaging tool inspired by the humble sewing machine which is providing fresh insight into the origins of Alzheimer’s and Parkinson’s disease.

These diseases are caused by tiny toxic proteins too small to be studied with traditional optical microscopy.

Previously it was thought that Alzheimer’s was caused by the accumulation of long ‘amyloid’ fibres at the centre of senile plaques in the brain, due to improper folding of a protein called amyloid-β.

But new research suggests that these fibres and plaques are actually the body’s protective response to the presence of even smaller, more toxic structures made from amyloid-β called ‘oligomers’.

Existing techniques are not sufficient to get a good look at these proteins; optical microscopy does not provide enough resolution at this scale, and electron microscopy gives the resolution but not the contrast.

To solve the problem, Physicist Dr Oleg Kolosov and his team at Lancaster have developed a new imaging technique - Ultrasonic Force Microscopy (UFM) - inspired by the motion of a sewing machine. Their work has been published in Scientific Reports.

Dr Kolosov said: “By using a vibrating scanner, which moves quickly up and down like the foot of a sewing machine needle, the friction between the sample and the scanner was reduced – resulting in a better quality, and high contrast nanometre scale resolution image.”

It is one of a new generation of tools being developed worldwide to bring the oligomers into focus, enabling medical researchers to understand how they behave.

At Lancaster, Claire Tinker used UFM to image these oligomers. To help see them more clearly she needed to increase the contrast of the image and used poly-L-lysine (PLL) which kept the proteins stuck to the slides as the vibrating scanner was passed over them.

Lancaster University Biomedical Scientist Professor David Allsop said: “These high quality images are vitally important if we are to understand the pathways involved in formation of these oligomers, and this new technique will now be used to test the effects of inhibitors of oligomer formation that we are developing as a possible new treatment for Alzheimer’s disease.”

The technique worked so well that the team now hopes to develop it so that oligomer formation can be monitored as they are made in real time.

This would give researchers a clearer understanding of the early phases of Alzheimer’s and Parkinson’s and could potentially be one way of developing a future test for these diseases.

A study in The Journal of General Physiology provides new evidence that the ubiquitous sodium pump is more complex—and more versatile—than we thought.

(Image caption: Structure of the sodium pump, which researchers reveal to be more versatile than previously thought)

The sodium pump is present in the surface membrane of all animal cells, using energy derived from ATP to transport sodium and potassium ions in opposite directions across the cell boundary. By setting up transmembrane gradients of these two ions, the pump plays a vital role in many important processes, including nerve impulses, heartbeats, and muscular contraction.

Now, Rockefeller University researchers Natascia Vedovato and David Gadsby demonstrate that, in addition to its role as a sodium and potassium ion transporter, the pump can simultaneously import protons into the cell. Their study not only provides evidence of “hybrid” function by the pump, it also raises important questions about whether the inflow of protons through sodium pumps might play a role in certain pathologies.

The sodium pump exports three sodium ions out of the cell and imports two potassium ions into the cell during each transport cycle. Vedovato and Gadsby show that, during this normal cycle, the pump develops a passageway that enables protons to cross the membrane. When the pump releases the first of the three sodium ions to the cell exterior, a newly emptied binding site becomes available for use by an external proton, allowing it to then make its way into the cytoplasm. The protons travel a distinct route, and proton inflow is not required for successful transport of sodium and potassium.

Import of protons is high when their extracellular concentration is high (pH is low) and membrane potential is negative. The authors therefore speculate that proton inflow might have important implications under conditions in which extracellular pH is lowered, such as in muscle during heavy exercise, in the heart during a heart attack, or in the brain during a stroke.

Researchers at the Centre for Addiction and Mental Health have discovered two new genes linked to intellectual disability, according to two research studies published concurrently in early March in the journals Human Genetics and Human Molecular Genetics.

“Both studies give clues to the different pathways involved in normal neurodevelopment,” says CAMH Senior Scientist Dr. John Vincent, who heads the MiND (Molecular Neuropsychiatry and Development) Laboratory in the Campbell Family Mental Health Research Institute at CAMH. “We are building up a body of knowledge that is informing us which kinds of genes are important to, and involved in, intellectual disabilities.”

In the first study, Dr. Vincent and his team used microarray genotyping to map the genes of a large consanguineous (intermarriage within the extended family) Pakistani family, in which five members of the youngest generation were affected with mild to moderate intellectual disability. Dr. Vincent identified a truncation in the FBXO31 gene, which plays a role in the way that proteins are processed during neuronal development, particularly in the cerebellar cortex.

In the second study, using the same techniques, Dr. Vincent and his team analyzed the genes of two consanguineous families, one Austrian and one Pakistani, and identified a disruption in the METTL23 gene linked to mild recessive intellectual disability. The METTL23 gene is involved in methylation—a process important to brain development and function.

About one per cent of children worldwide are affected by non-syndromic (i.e., the absence of any other clinical features) intellectual disability, a condition characterized by an impaired capacity to learn and process new or complex information, leading to decreased cognitive functioning and social adjustment. Although trauma, infection and external damage to the unborn fetus can lead to an intellectual disability, genetic defects are a principal cause.

These studies were part of an ongoing study of affected families in Pakistan, where the cultural tradition of large families and consanguineous marriages among first cousins increases the likelihood of inherited intellectual disability in offspring.

“Although it is easier to find and track genes in consanguineous families, these genes are certainly not limited to them,” Dr. Vincent points out. A recent study estimated that 13–24 per cent of intellectual disability cases among individuals of European descent have autosomal recessive causes, meaning that results of this study are very relevant to populations such as Canada.

Autosomal recessive gene mutations have traditionally been more difficult to trace, resulting in a paucity of research in this area. Parents of affected children show no symptoms, and the child must inherit one defective copy of the gene from each parent, so that only one in four offspring are likely to be affected. Smaller families, therefore, show a decreased incidence and are less amenable to this kind of study.

Dr. Vincent is currently engaged in a study that will screen Canadian populations with autism and intellectual disability for autosomal recessive gene mutations. Results will be available later this year.

A total of 42 genes linked to non-syndromic autosomal recessive forms of intellectual disability have now been identified; estimates suggest that up to 2,500 autosomal genes might be linked with intellectual disability, the majority being recessive.

Common psychiatric disorders, such as anxiety and addiction, likely result from changes in brain circuitry. Understanding structural and functional brain connections – and how they change in psychiatric disorders – could lead to novel preventive and therapeutic strategies.

The bed nucleus of the stria terminalis (BNST) has been linked to both anxiety and addiction, but its circuitry in humans has not been described. Jennifer Blackford, Ph.D., assistant professor of Psychiatry, and colleagues used two neuroimaging methods – diffusion tensor imaging and functional MRI – to identify patterns of connectivity between the BNST and other brain regions in healthy individuals. The BNST showed connections to multiple subcortical brain regions, including limbic, thalamic and basal ganglia structures, which matched reported connections in rodents. The researchers also identified two novel BNST connections: to the temporal pole and to the paracingulate gyrus.

The findings, reported in NeuroImage, provide a map of BNST neurocircuitry and lay the foundation for future studies of the circuits that mediate anxiety and addiction.

Memories are difficult to produce, often fragile, and dependent on any number of factors—including changes to various types of nerves. In the common fruit fly—a scientific doppelganger used to study human memory formation—these changes take place in multiple parts of the insect brain.

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have been able to pinpoint a handful of neurons where certain types of memory formation occur, a mapping feat that one day could help scientists predict disease-damaged neurons in humans with the same specificity.

“What we found is that while a lot of the neurons will respond to sensory stimuli, only a certain subclass of neurons actually encodes the memory,” said Seth Tomchik, a TSRI biologist who led the study, which was published March 27, 2014, online ahead of print by the journal Current Biology.

The researchers examined a type of neuron called dopaminergic neurons—which respond to dopamine, a well-known neurotransmitter—and are involved in shaping diverse behaviors, including learning, motivation, addiction and obesity.

In the study, the scientists followed the stimulation of a large number of these neurons when an odor was paired with an aversive event such as a mild electric shock. The scientists then used imaging technology to follow changes in the brains of live flies, mapping the activation patterns of signaling molecules within the neurons and observing learning-related plasticity—in which neurons change and develop memory traces.

The scientists found that the neurons that did encode memories responded to a cellular signaling messenger known as cAMP (cyclic adenosine monophosphate) that is vital for many biological processes. cAMP is involved in a number of psychological disorders such as bipolar disorder and schizophrenia, and its dysregulation may underlie some cognitive symptoms of Alzheimer’s disease and Neurofibramatosis I.

In fact, the study pointed to a specific location in the brain—a particular lobe with a region known as the mushroom body—where the neurons appear to be particularly sensitive to elevated amounts of cAMP.

According to Tomchik, that’s an important finding in terms of human memory because olfactory memory formation in the fruit fly is very similar to human memory formation. 

“We have a good model in these two classes of neurons, one that encodes and one that doesn’t,” he said. “Now we know exactly where the memory formation should be and where to look to see how disease may disrupt it.”

Tamara Boto, the first author of the study and a member of Tomchik’s laboratory, added, “We know where, but we don’t yet know the mechanism of why only these subsets are affected. That’s our next job—to figure that out.”