Posts tagged cerebral cortex
Articles and news from the latest research reports.
Common links between neurodegenerative diseases identified
Diseases of the central nervous system are a big burden to society. According to estimates, they cost €800 billion per year in Europe. And for most of them, there is no definitive cure. This is true, for example, for Parkinson disease. Although good treatments exist to manage its symptoms, they become more and more ineffective as the disease progresses. Now, the EU-funded REPLACES project, completed in 2013, which associated scientists with clinicians, has shed light on the abnormal working of a particular brain circuitry related to Parkinson’s disease. The results of the project suggest that these same circuits are implicated in different forms of pathologies. And this gives important insights into the possible common links between neurodegenerative diseases such as Parkinson and intellective disabilities or autism.
Existing treatments for Parkinson are very effective at the beginning. When the disease progresses, however, drugs, such as levodopa and so-called dopamine agonists, produce side effects that are sometimes even worse than the initial symptoms of the condition. In particular, they cause a complication called dyskinesia, characterised by abnormal involuntary movements. Therapies are therefore sought that allow better management of symptoms.
The project focused on the study of a highly plastic brain circuitry, which connects regions of the cerebral cortex with the basal ganglia. It is involved in very important functions such as learning and memory. “This system, based onglutamate as a mean of signalling between neurons, has also been discovered to be damaged in Parkinson disease,” says Monica Di Luca, professor of neuropharmacology at the University of Milan, Italy, and the project coordinator. She adds: “Parkinson’s more well-known and characteristic trait is the selective loss of cells producers of neurotransmitter dopamine.”
Researchers involved into the project studied the function and plasticity of this circuit in different animal models of Parkinson disease, from mice to non-human primates. They found that exactly the same alterations were present and conserved. This makes it an interesting and alternative target for trying to re-establish the correct functioning and reverse the symptoms of the disease.
One expert agrees with the need to target alternative target systems. “What researchers are trying to do is to intervene to modulate other systems that do not involve dopamine and obtain a better symptoms management,” explains Erwan Bezard, a researcher at the Neurodenerative Diseases Institute at the University of Bordeaux, in France. He also works on alternative targets in Parkinson disease. In monkeys, compounds that target glutamate receptors, used in combination with traditional drugs, have previously shown to improve some deficits in voluntary motor control.
But the research has also shed some light into apparently unrelated diseases. It is becoming more and more obvious that the same alterations in the working of the communication systems among neurons are shared among different diseases. “This is why we speak about ‘synaptopathies’: there are common players among Parkinson disease, autism and other forms of intellectual disabilities and even schizophrenia. Several of the mutated genes are the same, and affect the signalling systems through common molecules,” says Claudia Bagni, who works on synaptic plasticity in the context of intellectual disabilities at the University of Leuven, in Belgium and University of Rome Tor Vergata, in Italy. “For example, the glutamatergic system is also affected in the X-fragile syndrome, the most common form of inherited intellectual disability.”
Progress is in sight thanks to a much better understanding of the working of the abnormal synapses in Parkinson disease, and experiments performed in monkeys showing encouraging results. Indeed, “the team studied human primates, the model system closest to humans, and therefore their findings are relevant to human health.” says Bagni. Project researchers hope the door is now opened for the first clinical trials in humans. “We have identified a potential new target for treatment, and tested a couple of molecules in animals,” says Di Luca, the “next step would be to find a partnership with pharmaceutical industries interested in pursuing this research.”
Transplanting interneurons: Getting the right mix
Despite early optimistic studies, the promise of curing neurological conditions using transplants remains unfulfilled. While researchers have exhaustively cataloged different types of cells in the brain, and also the largely biochemical issues underlying common diseases, neural repair shops are still a ways off. Fortunately, significant progress is being made towards identifying the broader operant principles that might bear on any one disease work-around. A review just published in Science focuses on recent work on transplanting interneurons—a diverse family of cells united by their mutual love of inhibition and their local loyalty. The UCLA-based authors, reach the conclusion that the fate of transplanted neurons ultimately depends less on the influences of the new host environment, and more on the early upbringing of the cells within the donor embryo.
A Critical Window into the Developing Human Brain Profiled in Nature
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.”
(Source: alleninstitute.org)
Silicon-based probe microstructure could underpin safer neural implants
Neural probe arrays are expected to significantly benefit the lives of amputees and people affected by spinal cord injuries or severe neuromotor diseases. By providing a direct route of communication between the brain and artificial limbs, these arrays record and stimulate neurons in the cerebral cortex.
(Image caption: The compact neural probe array consists of a three-dimensional probe array, a custom 100-channel neural recording chip and a flexible polyimide polymer cable. Credit: A*STAR Institute of Microelectronics)
The need for neural probe arrays that are compact, reliable and deliver high performance has prompted researchers to use microfabrication techniques to manufacture probe arrays. Now, a team led by Ming-Yuan Cheng from the A*STAR Institute of Microelectronics, Singapore, has developed a three-dimensional probe array for chronic and long-term implantation in the brain. This array is compact enough to freely float along with the brain when implanted on the cortex.
The neural probe array needs to be implanted in the subarachnoid space of the brain, a narrow region of 1–2.5 millimeters in depth that lies between the pia mater and dura mater brain meninges. “A high-profile array may touch the skull and damage the tissue when relative micromotions occur between the brain and the probes,” explains Cheng. To avoid this problem, the array should be as thin as possible.
Study first to offer detailed map of mouse’s cerebral cortex
The mammalian cerebral cortex, long thought to be a dense single interrelated tangle of neural networks, actually has a “logical” underlying organizational principle, according to a study appearing in the journal Cell.
Researchers have identified eight distinct neural subnetworks that together form the connectivity infrastructure of the mammalian cortex — the part of the brain involved in higher-order functions such as cognition, emotion and consciousness.
“This study is the first comprehensive mapping of the most developed region of the mammalian brain: the cerebral cortex. The cortex is highly complex and made up of many densely interconnected structures, but when you strip it down, is organized into a small number of subnetworks,” said senior author Hongwei Dong of the USC Institute for Neuroimaging and Informatics (INI).
The cerebral cortex is the outermost layer of neural tissue in the brain and is one of the most extensively studied brain structures in the field of neuroscience. However, before this study, its underlying organizational principle was still largely unclear.
“Think about it: The brain is built for logic, so it’s organization must be logical. The brain’s architectural organization is arranged such that all of its substructures most efficiently work in conjunction to produce appropriate behaviors,” said Dong, associate professor of neurology at the Keck School of Medicine of USC. “We want to find the code to how the brain is structurally organized.”
The study is also a reminder that while there is more data than ever, the quality and reliability of information still matters. In contrast to past patchwork attempts, Dong and his team undertook an effort to directly develop a whole-brain mouse atlas of brain pathways. Across the cortex, they injected fluorescent molecules. These molecules were then transported along the brain’s “cellular highways” — the neuronal pathways — and meticulously tracked using a high-resolution microscope.
The uniformity and completeness of the scientists’ effort across the entire cortex provided for a searchable image database of cortical connections, which the researchers are making open-access and publicly available.
It also allowed them to reliably see patterns: the seemingly inscrutable mass of connections in the cerebral cortex is highly organized, consisting of eight distinct subnetworks that are relatively segregated.
“The systematic and comprehensive manner in which the data were collected lent itself to a detailed analysis through which these subnetworks emerged,” explained co-lead author Houri Hintiryan of the USC Laboratory of Neuro Imaging.
So that scientists around the world may continue to look for fundamental structural insights, the full, interactive imaging dataset is viewable at Mouse Connectome Project, providing a resource for researchers interested in studying the anatomy and function of cortical networks throughout the brain.
“It really is quite tedious,” Dong said of collecting the data, “and labor-intensive, and it requires highly specialized skills and technology. But think of the Human Genome Project and how much it accelerated the process of discovery and the whole field when infrastructures existed for people to share and compare. That was our motivation.”
How these subnetworks interact will provide a crucial baseline from which to better understand diseases of “disconnection” such as autism and Alzheimer’s disease, in which the manifestations of symptoms are potentially a result of disordered or damaged connections.
The researchers’ map of the mouse cerebral cortex can be compared to data on disease-affected brains, brains in development and genetic information. It will also offer necessary context for humans, who behaved just like other mammals only a few thousand years ago and who still share most underlying basic behavioral characteristics such as hunger and pain.
“The fundamental logic of mammalian brains is the same, particularly when it comes to basic behaviors such as eating, sleeping and social behaviors” said Dong, who noted that similar studies in humans have thus far not gotten to the cellular level. “There are lots of organizing principles to brain structures that we are just beginning to understand.”
The researchers identified the brain subnetworks based on their high degree of interconnectivity — though relatively independent, several structures provide communication routes through which the subnetworks interact. Combined with behavioral data from past research and information about subcortical targets, these interconnections imply remarkable functional significance for the subnetworks.
Four of the eight identified subnetworks in the mouse cortex relate to sensation and movement of the body — what the researchers dub somatic sensorimotor. In particular, the researchers identified separate subnetworks for movements in the face, upper limbs, lower limbs and trunk, and whiskers. Together, these networks facilitate motor behaviors such as eating and drinking, reaching and grabbing, locomotion and exploration of the environment.
Two other subnetworks are comprised of structures located along the midline of the cerebral cortex. These medial subnetworks seem devoted to the integration of visual, auditory and somatic sensory information, according to the study. Several other structures located along the side of the brain form two lateral subnetworks, one of which potentially serves to regulate the internal status of the body (i.e., taste, hunger, visceral information) and the other as a “mega-integration” subnetwork that allows the interaction of information from nearly the entire cortex.
Scientists identify gene linking brain structure to intelligence
For the first time, scientists at King’s College London have identified a gene linking the thickness of the grey matter in the brain to intelligence. The study is published today in Molecular Psychiatry and may help scientists understand biological mechanisms behind some forms of intellectual impairment.
The researchers looked at the cerebral cortex, the outermost layer of the human brain. It is known as ‘grey matter’ and plays a key role in memory, attention, perceptual awareness, thought, language and consciousness. Previous studies have shown that the thickness of the cerebral cortex, or ‘cortical thickness’, closely correlates with intellectual ability, however no genes had yet been identified.
An international team of scientists, led by King’s, analysed DNA samples and MRI scans from 1,583 healthy 14 year old teenagers, part of the IMAGEN cohort. The teenagers also underwent a series of tests to determine their verbal and non-verbal intelligence.
Dr Sylvane Desrivières, from the MRC Social, Genetic and Developmental Psychiatry Centre at King’s College London’s Institute of Psychiatry and lead author of the study, said: “We wanted to find out how structural differences in the brain relate to differences in intellectual ability. The genetic variation we identified is linked to synaptic plasticity – how neurons communicate. This may help us understand what happens at a neuronal level in certain forms of intellectual impairments, where the ability of the neurons to communicate effectively is somehow compromised.”
She adds: “It’s important to point out that intelligence is influenced by many genetic and environmental factors. The gene we identified only explains a tiny proportion of the differences in intellectual ability, so it’s by no means a ‘gene for intelligence’.”
The researchers looked at over 54,000 genetic variants possibly involved in brain development. They found that, on average, teenagers carrying a particular gene variant had a thinner cortex in the left cerebral hemisphere, particularly in the frontal and temporal lobes, and performed less well on tests for intellectual ability. The genetic variation affects the expression of the NPTN gene, which encodes a protein acting at neuronal synapses and therefore affects how brain cells communicate.
To confirm their findings, the researchers studied the NPTN gene in mouse and human brain cells. The researchers found that the NPTN gene had a different activity in the left and right hemispheres of the brain, which may cause the left hemisphere to be more sensitive to the effects of NPTN mutations. Their findings suggest that some differences in intellectual abilities can result from the decreased function of the NPTN gene in particular regions of the left brain hemisphere.
The genetic variation identified in this study only accounts for an estimated 0.5% of the total variation in intelligence. However, the findings may have important implications for the understanding of biological mechanisms underlying several psychiatric disorders, such as schizophrenia, autism, where impaired cognitive ability is a key feature of the disorder.
(Source: kcl.ac.uk)
A Load Off Your Mind
Engineering professors are devising a brain scanner that will sense when you’re going into information overload
Picture an air-traffic controller tracking 10 planes approaching an airport. Now imagine he’s having trouble focusing on all 10 aircraft, perhaps because he’s been up all night or just has a lot on his mind. What would happen if his computer sensed his mental fatigue, removed one plane from his oversight and reassigned it to a controller who just started her shift?
The scenario might seem like science fiction, but with new technology being developed by Tufts researchers Robert Jacob and Sergio Fantini, it could be quite real someday. Jacob and Fantini have developed a brain-scanning device that allows a computer to sense the level of mental exertion of its user and adjust tasks accordingly to achieve the correct balance between boredom and overload.
“Humans and computers are two powerful information processors connected by this miserably narrow bandwidth—a mouse and a keyboard,” says Jacob, a professor of computer science in the School of Engineering. Jacob’s challenge is to find ways to create a more direct connection between machine and human brain to make both more efficient.
Image caption: Stem cells in the cortex of a mouse embryo (cell nuclei: blue). © MPI f. Molecular Cell Biology and Genetics/ D. Stenzel
Brain development - the pivotal role of the stem cell environment
Higher mammals, such as humans, have markedly larger brains than other mammals. Scientists from the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden recently discovered a new mechanism governing brain stem cell proliferation. It serves to boost the production of neurons during development, thus causing the enlargement of the cerebral cortex – the part of the brain that enables us humans to speak, think and dream. The surprising discovery made by the Dresden-based researchers: two components in the stem cell environment – the extracellular matrix and thyroid hormones – work together with a protein molecule found on the stem cell surface, a so-called integrin. This likely explains why iodine deficiency in pregnant women has disastrous consequences for the unborn child, affecting its brain development adversely – without iodine, no thyroid hormones are produced. “Our study highlights this relationship and provides a potential explanation for the condition neurologists refer to as cretinism”, says Wieland Huttner, Director at the Max Planck Institute in Dresden. This neurological disorder severely impairs the mental abilities of a person.
In the course of evolution, certain mammals, notably humans, have developed larger brains than others, and therefore more advanced cognitive abilities. Mice, for example, have brains that are around a thousand times smaller than the human one. In their study, which was conducted in cooperation with the Fritz Lipmann Institute in Jena, the researchers in Dresden wanted to identify factors that determine brain development, and understand how larger brains have evolved.
A cosy bed for brain stem cells
Brain neurons are generated from stem cells called basal progenitors that are able to proliferate in humans, but not in mice. In humans, basal progenitors are surrounded by a special environment, a so-called extracellular matrix (ECM), which is produced by the progenitors themselves. Like a cosy bed, it accommodates the proliferating cells. Mice lack such ECM, which means that they generate fewer neurons and have a smaller brain.
The scientists therefore conducted tests to see whether in mice, basal progenitors start to proliferate if a comparable cell environment is simulated. The result: “We simulated an extracellular matrix for the brain stem cells using a stimulating antibody. This antibody activates an integrin on the cell surface of basal progenitors and thus stimulates their proliferation”, explains Denise Stenzel, who headed the experiments.
Because a requirement of thyroid hormones for proper brain development was previously known, the researchers blocked the production of these hormones in pregnant rats to see if their absence would inhibit basal progenitor proliferation in the embryos. Indeed, fewer progenitors and, consequently, neurons were produced, likely explaining the abnormal brain development in the absence of thyroid hormones. When the action of these hormones on the integrin was blocked, the ECM-simulating antibody alone was no longer able to induce basal progenitor proliferation.
A combination of ECM and thyroid hormones thus appears necessary for basal progenitors to proliferate and produce enough neurons for brain development. Human brain stem cells produce the suitable environment naturally. “That is probably how, in the course of evolution, we humans developed larger brains”, says Wieland Huttner, summing up the study. The research produced another important finding: “We were able to explain the role of iodine in embryonic brain development at the cellular level”, says Denise Stenzel. Iodine is essential for the production of thyroid hormones, and an iodine deficiency in pregnant women is known to have adverse effects on the brain development of the unborn child.
Switching brain development on, and off
The possibility of nerve cell regeneration is a step closer after neuroscientists identified the genetic signals that play a crucial role in normal development - driving stem cells to produce neurons that are correctly positioned and connected neurons within the brain.
Published in Cerebral Cortex, a study led by Dr Julian Heng of the Australian Regenerative Medicine Institute (ARMI) at Monash University, has identified a transcription factor, RP58, which is an important “off switch” for the process of nerve cell formation.
“Known as RP58, this gene switches off Rnd2 expression to control the proper positioning of neurons within the fetal brain - a crucial process,” Dr Heng said.
Absence of RP58 has been linked to a rare brain developmental disorder known as Terminal 1q deletion syndrome, where patients suffer reduced brain growth, experience epileptic seizures and are intellectually disabled.
Dr Heng’s work, on pre-clinical models, builds on previous research in which another transcription factor, Neurog2, operated as the “on-switch” for the crucial process of early brain development whereby stem cells become neurons.
Neurog2 switches on the expression of another gene, Rnd2, to control how new nerve cells of the developing brain find their appropriate location and go on to establish their proper connections. However, too much Rnd2 can impair the path-finding of new neurons, and so the researchers theorised that an “off-switch” controlled the process.
Dr Heng said that the discovery of RP58 was the proof needed to demonstrate that genes such as Rnd2 must be switched on, and then off in order for brain cells to assemble properly.
“Together with a collaborative study we published with our colleagues earlier in the year, this research demonstrates that loss of RP58 impairs the development of new nerve cells in the embryonic mouse brain, including their path-finding,” Dr Heng said.
“Since the early steps of nerve cell production during brain development are comparable between mice and humans, we believe that RP58 carries out similar functions in the foetal human brain as well. This strengthens the notion that disruptions to this gene can cause brain developmental disease.”
Recently, a study led by researchers at Stanford University in the United States provided evidence showing that RP58 (also known as ZFP238) is crucial for the maturation of new human nerve cells.
Dr Heng believes his discoveries could be used in the context of regenerative medicine.
“Ultimately, the goal of our research is to understand the fundamental properties which control the production and maturation of new nerve cells in the brain. Understanding the function of switches like RP58 is crucial to this process,” Dr Heng said.
"In the future, we will use this knowledge to develop novel cell-based therapies to treat neurodegenerative disorders and brain injury.”
Scientists discover two proteins that control chandelier cell architecture
Chandelier cells are neurons that use their unique shape to act like master circuit breakers in the brain’s cerebral cortex. These cells have dozens, often hundreds, of branching axonal projections – output channels from the cell body of the neuron – that lend the full structure of a chandelier-like appearance. Each of those projections extends to a nearby excitatory neuron. The unique structure allows just one inhibitory chandelier cell to block or modify the output of literally hundreds of other cells at one time.
Without such large-scale inhibition, some circuits in the brain would seize up, as occurs in epilepsy. Abnormal chandelier cell function also has been implicated in schizophrenia. Yet after nearly 40 years of research, little is known about how these important inhibitory neurons develop and function.
In work published today in Cell Reports, a team led by CSHL Professor Linda Van Aelst identifies two proteins that control the structure of chandelier cells, and offers insight into how they are regulated.
To study the architecture of chandelier cells, Van Aelst and colleagues first had to find a way to visualize them. Generally, scientists try to find a unique marker, a sort of molecular signature, to distinguish one type of neuron from the many others in the brain. But no markers are known for chandelier cells. So Van Aelst and Yilin Tai, Ph.D., lead author on the study, developed a way to label chandelier cells within the mouse brain.
Using this new method, the team found two proteins, DOCK7 and ErbB4, whose activity is essential in processes that give chandelier cells their striking shape. When the function of these proteins is disrupted, chandelier cells have fewer, more disorganized, axonal projections. Van Aelst and colleagues used a series of biochemical experiments to explore the relationship between the two proteins. They found that DOCK7 activates ErbB4 through a previously unknown mechanism; this activation must occur if chandelier cells are to develop their characteristic architecture.
Moving forward, Van Aelst says she is interested in exploring the relationship between structure and function of chandelier cells. “We envisage that morphological changes are likely to impact the function of chandelier cells, and consequently, alter the activity of cortical networks. We believe irregularities in these networks contribute to the cognitive abnormalities characteristic of schizophrenia and epilepsy. As we move forward, therefore, we hope that our findings will improve our understanding of these devastating neurological disorders.”