Posts tagged neuron

July 16, 2012

For more than 20 years, doctors have been using cells from blood that remains in the placenta and umbilical cord after childbirth to treat a variety of illnesses, from cancer and immune disorders to blood and metabolic diseases.

This microscope image shows a colony of neurons derived from cord-blood cells using stem cell reprogramming technology. The green and red glow indicates that the cells are producing protein makers found in neurons, evidence that the cord-blood cells did in fact morph into neurons. The blue glow marks the nuclei of the neurons. Credit: Image: Courtesy of Alessandra Giorgetti

Now, scientists at the Salk Institute for Biological Studies have found a new way-using a single protein, known as a transcription factor-to convert cord blood (CB) cells into neuron-like cells that may prove valuable for the treatment of a wide range of neurological conditions, including stroke, traumatic brain injury and spinal cord injury.

The researchers demonstrated that these CB cells, which come from the mesoderm, the middle layer of embryonic germ cells, can be switched to ectodermal cells, outer layer cells from which brain, spinal and nerve cells arise. “This study shows for the first time the direct conversion of a pure population of human cord blood cells into cells of neuronal lineage by the forced expression of a single transcription factor,” says Juan Carlos Izpisua Belmonte, a professor in Salk’s Gene Expression Laboratory, who led the research team. The study, a collaboration with Fred H. Gage, a professor in Salk’s Laboratory of Genetics, and his team, was published on July 16 in the Proceedings of the National Academy of Sciences.

"Unlike previous studies, where multiple transcription factors were necessary to convert skin cells into neurons, our method requires only one transcription factor to convert CB cells into functional neurons," says Gage.

The Salk researchers used a retrovirus to introduce Sox2, a transcription factor that acts as a switch in neuronal development, into CB cells. After culturing them in the laboratory, they discovered colonies of cells expressing neuronal markers. Using a variety of tests, they determined that the new cells, called induced neuronal-like cells (iNC), could transmit electrical impulses, signaling that the cells were mature and functional neurons. Additionally, they transferred the Sox2-infused CB cells to a mouse brain and found that they integrated into the existing mouse neuronal network and were capable of transmitting electrical signals like mature functional neurons.

"We also show that the CB-derived neuronal cells can be expanded under certain conditions and still retain the ability to differentiate into more mature neurons both in the lab and in a mouse brain," says Mo Li, a scientist in Belmonte’s lab and a co-first author on the paper with Alessandra Giorgetti, of the Center for Regenerative Medicine, in Barcelona, and Carol Marchetto of Gage’s lab. "Although the cells we developed were not for a specific lineage-for example, motor neurons or mid-brain neurons-we hope to generate clinically relevant neuronal subtypes in the future."

Importantly, says Marchetto, “We could use these cells in the future for modeling neurological diseases such as autism, schizophrenia, Parkinson’s or Alzheimer’s disease.”

Cord blood cells, says Giorgetti, offer a number of advantages over other types of stem cells. First, they are not embryonic stem cells and thus they are not controversial. They are more plastic, or flexible, than adult stem cells from sources like bone marrow, which may make them easier to convert into specific cell lineages. The collection of CB cells is safe and painless and poses no risk to the donor, and they can be stored in blood banks for later use.

"If our protocol is developed into a clinical application, it could aid in future cell-replacement therapies," says Li. "You could search all the cord blood banks in the country to look for a suitable match."

Provided by Salk Institute

Source: medicalxpress.com

July 16, 2012

One of the marvels of brain development is the mass migration of nerve cells to their functional position. European research has investigated the molecules required for their successful navigation.

Credit: Thinkstock

Formation of the cerebral cortex during embryonic development requires the migration of billions of cells from their birth position to their final destination. A motile nerve cell must have internal polarity to move in the specified direction. What is more, neurons then have to extend neurites or projections from the cell body to communicate with each other.

The key to this extraordinary feat of organisation lies in cell signalling pathways. The EU-funded Neuronal Polarity project aimed to characterise these cascades important in cerebral cortex development. At a later stage, defective cortical architecture can be responsible for brain pathologies including microcephaly, epilepsy and schizophrenia.

Project scientists showed that in vivo the guanine triphosphatase GTPase Ras-proximate-1 (Rap 1) caused an accumulation of neurons halfway to their destination. The team used time-lapse video microscopy and immunostaining to show that the problem does not lie with motility of the neurons but in a defect in their polarity. Other evidence from motility tests in vitro and the fact that some neurons do actually make it to their destination, albeit slowly, suggest Rap 1 is important for initial polarisation of the neurons.

The transmembrane receptor N-cadherin (Ncad) also has an important function in polarising cortical neurons. Experimental data confirmed that this receptor is involved downstream from Rap 1. Overall, inhibition of Rap 1 reduces Ncad presence.

Neuronal Polarity scientists suggest that Rap 1 activity is important in migrating neurons to maintain a high level of Ncad at the plasma membrane for nerve cells to polarise correctly.

Exactly how Ncad interacts with molecular cascades for neuron polarisation is still under investigation. The Neuronal Polarity project accumulated data on which to base a concrete research path for future investigation.

Provided by CORDIS

Source: medicalxpress.com

July 11, 2012

(Medical Xpress) — Johns Hopkins researchers say they have discovered that the central nervous system’s oligodendroglia cells, long believed to simply insulate nerves as they “fire” signals, are unexpectedly also vital to the survival of neurons. Damage to these insulators appears to contribute to brain injury in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease for the Yankee baseball great who died from the disease.

The discovery, described online in the journal Nature, suggests that a previously unknown — and unexpected — function of these cells is to supply nutrition to the principal brain cells, neurons. This new pathway may prove to be an important and novel therapeutic target for ALS, the researchers say, and potentially other diseases that attack the body’s nerve fibers, such as multiple sclerosis.

"More than 100 years after their discovery, we have now found a fundamentally new property in the way oligodendroglia work in the brain, laying the foundation for a new approach to try to treat debilitating neurodegenerative diseases,” says Jeffrey D. Rothstein, M.D., Ph.D., a professor of neurology and neuroscience at the Johns Hopkins University School of Medicine, and the study’s leader. “We’ve added a whole new category to what they do in the brain.”

The cells responsible for the transfer of information and electrical impulses around the body, neurons work by transferring electrical charges from neuron to neuron. Axons, the wire-like extensions of the neurons, help move the messages, in some cases over many feet, from cell to cell. Oligodendroglia insulate axons, like rubber coating around an electrical wire, to speed up the conduction of information. Axonal death is a hallmark of ALS and most other neurodegenerative disorders, Rothstein says.

Rothstein and his colleagues say the other principal brain cells, the astroglia, were believed to be primarily responsible for providing energy to neurons in the form of glucose, but their experiments show that oligodendroglia are surprisingly crucial in feeding neurons — in the form of less energy-rich lactate, without which neurons and their axons die. Lactate has long been seen as a minor player in this process, but the Johns Hopkins team says it appears to be far more important to nerve cell survival. Moreover, they found that the protein MCT1, the dominant transporter of lactate in the brain, is only found in oligodendroglia.

Rothstein says their discovery was rooted in experiments during which scientists, using mice, knocked out the gene that makes the MCT1 protein and saw axons begin to die, even though they were still getting plenty of glucose.

As part of these experiments, the researchers engineered mice whose cells would light up if they were expressing MCT1. The scientists then determined that only oligodendroglia cells lit up, showing that MCTI is located on this type of cell alone. They also knocked out the MCT1 in cell cultures and found that neurons would begin to die, but would recover when fed lactate, proving the importance of MCT1 in providing this nutritional compound. They conducted the same experiments in mice and got similar results.

Finally, the researchers turned their attention to ALS, a disease where they had recently uncovered abnormalities related to oligodendroglia. In ALS mice, they found that MCT1 was missing in brain cells well before the disease developed, and they found similar results in ALS patients. Rothstein says the findings suggest that oligodendroglia injury — specifically injury to the mechanism that produces MCT1 — may be an important event in the onset and progression of ALS.

Rothstein, who is director of the Johns Hopkins University School of Medicine’s Brain Science Institute, says he hopes further research can establish that the activation of MCT1 in people will protect axons in those with ALS and other degenerative diseases.

Provided by Johns Hopkins University School of Medicine

Source: medicalxpress.com

June 26, 2012

The inexorable spread of Alzheimer’s disease through the brain leaves dead neurons and forgotten thoughts in its wake. Researchers at Linköping University in Sweden are the first to show how toxic proteins are transferred from neuron to neuron.

Two nerve cells, each about 10 micrometers large, are visible as shadows in this picture. From the beginning only the right one (yellow arrow) contained the toxic, red stained, oligomeric beta-amyloid. When these sick cells make contacts with the healthy, green labeled cells (black arrow), toxic beta-amyloid will spread through the neuronal projections (white arrow). Subsequently, also the green cell will become sick. Credit: Martin Hallbeck

Through experiments on stained neurons, the research team – under the leadership of Martin Hallbeck, associate professor of Pathology – has been able to depict the process of neurons being invaded by diseased proteins that are then passed on to nearby cells.

"The spread of Alzheimer’s, which can be studied in the brains of diseased patients, always follows the same pattern. But until now how and why this happens has not been understood," says Hallbeck, who along with his research group has now published their results in The Journal of Neuroscience.

The illness starts in the entorhinal cortex – a part of the cerebral cortex, and then spreads to the hippocampus. Both of these areas are important for memory. Gradually, pathological changes take place in more and more areas of the brain, while the patient becomes even sicker.

Two proteins have been identified in connection with Alzheimer’s: beta amyloid and tau. Normally tau is found in the axons – the outgrowths that connect between neurons – where it has a stabilising function, while beta amyloid seems to have a role in the synapses where the neurons transfer signal substances to each other. But in Alzheimer’s patients, something happens with these proteins; autopsies reveal abnormal accumulations of both.

Why they become abnormal is still unknown, but what is known is that it’s not the large accumulations, or plaques, that damage the neurons. Instead, smaller groups of beta amyloid – called oligomeres – seem to be the toxic form that gradually destroy the neurons and shrink the brain.

"We wanted to investigate whether these oligomeres can spread from neuron to neuron, something many researchers tried earlier but didn’t succeed," Hallbeck says.

The study was inaugurated with an experiment on neuron cultures, where researchers injected oligomeres stained with a phosphorescent red substance called TMR using a very thin needle. The next day the neighbouring, connected neurons were also red, which showed that the oligomeres had spread.

To test whether a sick neuron can “infect” others, they conducted a round of experiments with mature human neurons stained green and mixed with others that were red after having taken up stained oligomeres. After a day, approximately half of the green cells had been in contact with a few of the red ones. After two more days, the axons had lost their shape and organelles in the cell nucleus had started to leak.

"Gradually more and more of the green cells became sick. Those that hadn’t taken up the oligomeres, on the other hand, weren’t affected," Hallbeck says.

The study is a breakthrough in understanding Alzheimer’s and its progress. If a way of stopping the transfer can be found, it could lead to a more effective inhibitor against the disease.

Provided by Linköping University

Source: medicalxpress.com

ScienceDaily (June 24, 2012) — Researchers at Yale School of Medicine have zeroed in on a set of neurons in the part of the brain that controls hunger, and found that these neurons are not only associated with overeating, but also linked to non-food associated behaviors, like novelty-seeking and drug addiction.

A lean animal and a control were both exposed to a novelty item (center). The lean animal spent more time exploring the novelty, as shown by the higher concentration of yellow in the slide. (Credit: Image courtesy of Yale University)

Published in the June 24 online issue of Nature Neuroscience, the study was led by Marcelo O. Dietrich, postdoctoral associate, and Tamas L. Horvath, the Jean and David W. Wallace Professor of Biomedical Research and chair of comparative medicine at Yale School of Medicine.

In attempts to develop treatments for metabolic disorders such as obesity and diabetes, researchers have paid increasing attention to the brain’s reward circuits located in the midbrain, with the notion that in these patients, food may become a type of “drug of abuse” similar to cocaine. Dietrich notes, however, that this study flips the common wisdom on its head.

"Using genetic approaches, we found that increased appetite for food can actually be associated with decreased interest in novelty as well as in cocaine, and on the other hand, less interest in food can predict increased interest in cocaine," said Dietrich.

Horvath and his team studied two sets of transgenic mice. In one set, they knocked out a signaling molecule that controls hunger-promoting neurons in the hypothalamus. In the other set, they interfered with the same neurons by eliminating them selectively during development using diphtheria toxin. The mice were given various non-invasive tests that measured how they respond to novelty, and anxiety, and how they react to cocaine.

"We found that animals that have less interest in food are more interested in novelty-seeking behaviors and drugs like cocaine," said Horvath. "This suggests that there may be individuals with increased drive of the reward circuitry, but who are still lean. This is a complex trait that arises from the activity of the basic feeding circuits during development, which then impacts the adult response to drugs and novelty in the environment."

Horvath and his team argue that the hypothalamus, which controls vital functions such as body temperature, hunger, thirst fatigue and sleep, is key to the development of higher brain functions. “These hunger-promoting neurons are critically important during development to establish the set point of higher brain functions, and their impaired function may be the underlying cause for altered motivated and cognitive behaviors,” he said.

"There is this contemporary view that obesity is associated with the increased drive of the reward circuitry," Horvath added. "But here, we provide a contrasting view: that the reward aspect can be very high, but subjects can still be very lean. At the same time, it indicates that a set of people who have no interest in food, might be more prone to drug addiction."

Source: Science Daily

June 20, 2012

Neurons come in an astounding assortment of shapes and sizes, forming a thick inter-connected jungle of cells. Now, UCL neuroscientists have found that there is a simple pattern that describes the tree-like shape of all neurons.

Neurons look remarkably like trees, and connect to other cells with many branches that effectively act like wires in an electrical circuit, carrying impulses that represent sensation, emotion, thought and action.

Over 100 years ago, Santiago Ramon y Cajal, the father of modern neuroscience, sought to systematically describe the shapes of neurons, and was convinced that there must be a unifying principle underlying their diversity.

Cajal proposed that neurons spread out their branches so as to use as little wiring as possible to reach other cells in the network. Reducing the amount of wiring between cells provides additional space to pack more neurons into the brain, and therefore increases its processing power.

New work by UCL neuroscientists, published today in Proceedings of the National Academy of Sciences, has revisited this century-old hypothesis using modern computational methods. They show that a simple computer program which connects points with as little wiring as possible can produce tree-like shapes which are indistinguishable from real neurons - and also happen to be very beautiful. They also show that the shape of neurons follows a simple mathematical relationship called a power law.

Power laws have been shown to be common across the natural world, and often point to simple rules underlying complex structures. Dr Herman Cuntz (UCL Wolfson Institute for Biomedical Research) and colleagues find that the power law holds true for many types of neurons gathered from across the animal kingdom, providing strong evidence for Ramon y Cajal’s general principle.

The UCL team further tested the theory by examining neurons in the olfactory bulb, a part of the brain where new brain cells are constantly being formed. These neurons grow and form new connections even in the adult brain, and therefore provide a unique window into the rules behind the development of neural trees in a mature neural circuit.

The team analysed the change in shape of the newborn olfactory neurons over several days, and found that the growth of these neurons also follow the power law, providing further evidence to support the theory.

Dr Hermann Cuntz said: “The ultimate goal of neuroscience is to understand how the impenetrable neural jungle can give rise to the complexity of behaviour.

"Our findings confirm Cajal’s original far-reaching insight that there is a simple pattern behind the circuitry, and provides hope that neuroscientists will someday be able to see the forest for the trees."

Provided by University College London

Source: medicalxpress.com