Posts tagged axons
Articles and news from the latest research reports.
(Image caption: A neuron in which the axon originates at a dendrite. Signals arriving at this dendrites become more efficiently forwarded than signals input elsewhere. Credit: Alexei V. Egorov, 2014)
Certain nerve cells take a shortcut for the transmission of information: signals are not conducted via the cell`s center, but around it like on a bypass road. The previously unknown nerve cell shape is now presented in the journal “Neuron" by a research team from Heidelberg, Mannheim and Bonn.
Nerve cells communicate by using electrical signals. Via widely ramified cell structures—the dendrites—, they receive signals from other neurons and then transmit them over a thin cell extension—the axon—to other nerve cells. Axon and dendrites are usually interconnected by the neuron’s cell body. A team of scientists at the Bernstein Center Heidelberg-Mannheim, Heidelberg University, and the University of Bonn has now discovered neurons in which the axon arises directly from one of the dendrites. Similar to taking a bypass road, the signal transmission is thus facilitated within the cell.
“Input signals at this dendrite do not need not be propagated across the cell body,” explains Christian Thome of the Bernstein Center Heidelberg-Mannheim and Heidelberg University, one of the two first authors of the study. For their analyses, the scientists specifically colored the places of origin of axons of so-called pyramidal cells in the hippocampus. This brain region is involved in memory processes. The surprising result: “We found that in more than half of the cells, the axon does not emerge from the cell body, but arises from a lower dendrite,” Thome says.
The researchers then studied the effect of signals received at this special dendrite. For this purpose, they injected a certain form of the neural transmitter substance glutamate into the brain tissue of mice that can be activated by light pulses. A high-resolution microscope allowed the neuroscientists to direct the light beam directly to a specific dendrite. By the subsequent activation of the messenger substance, they simulated an exciting input signal.
“Our measurements indicate that dendrites that are directly connected to the axon, actively propagate even small input stimuli and activate the neuron,” says second first author Tony Kelly, a member of the Sonderforschungsbereich (SFB) 1089 at the University of Bonn. A computer simulation of the scientists predicts that this effect is particularly pronounced when the information flow from other dendrites to the axon is suppressed by inhibitory input signals at the cell body.
“That way, information transmitted by this special dendrite influences the behavior of the nerve cell more than input from any other dendrite,” Kelly says. In a future step, the researchers attempt to figure out which biological function is actually strengthened through the specific dendrite—and what therefore might be the reason for the unusual shape of these neurons.
Nerve impulses can collide and continue unaffected
According to the traditional theory of nerves, two nerve impulses sent from opposite ends of a nerve annihilate when they collide. New research from the Niels Bohr Institute now shows that two colliding nerve impulses simply pass through each other and continue unaffected. This supports the theory that nerves function as sound pulses. The results are published in the scientific journal Physical Review X.
Nerve signals control the communication between the billions of cells in an organism and enable them to work together in neural networks. But how do nerve signals work?
Old model
In 1952, Hodgkin and Huxley introduced a model in which nerve signals were described as an electric current along the nerve produced by the flow of ions. The mechanism is produced by layers of electrically charged particles (ions of sodium and potassium) on either side of the nerve membrane that change places when stimulated. This change in charge creates an electric current.
This model has enjoyed general acceptance. For more than 60 years, all medical and biology textbooks have said that nerves function is due to an electric current along the nerve pathway. However, this model cannot explain a number of phenomena that are known about nerve function.
New model
Researchers at the Niels Bohr Institute at the University of Copenhagen have now conducted experiments that raise doubts about this well-established model of electrical impulses along the nerve pathway.
“According to the theory of this ion mechanism, the electrical signal leaves an inactive region in its wake, and the nerve can only support new signals after a short recovery period of inactivity. Therefore, two electrical impulses sent from opposite ends of the nerve should be stopped after colliding and running into these inactive regions,” explains Thomas Heimburg, Professor and head of the Membrane Biophysics Group at the Niels Bohr Institute at the University of Copenhagen.
Thomas Heimburg and his research group conducted experiment in the laboratory using nerves from earthworms and lobsters. The nerves were removed and used in an experiment which allowed the researchers to stimulate the nerve fibres with electrodes on both ends. Then they measured the signals en route.
“Our study showed that the signals passed through each other completely unhindered and unaltered. That’s how sound waves work. A sound wave doesn’t stop when it meets another sound wave. Both waves continue on unimpeded. The nerve impulse can therefore be explained by the fact that the pulse is a mechanical wave in the form of a sound pulse, a soliton, that moves along the nerve membrane,” explains Thomas Heimburg.
The theory is confirmed
When the sound pulse moves through the nerve pathway, the membrane changes locally from a liquid to a more solid form. The membrane is compressed slightly, and this change leads to an electrical pulse as a consequence of the piezoelectric effect.
“The electrical signal is thus not based on an electric current but is caused by a mechanical force,” points out Thomas Heimburg.
Thomas Heimburg, along with Professor Andrew Jackson, first proposed the theory that nerves function by sound pulses in 2005. Their research has since provided support for this theory, and the new experiments offer additional confirmation for the theory that nerve signals are sound pulses.
Scientists unravel mystery of brain cell growth
In the developing brain, special proteins that act like molecular tugboats push or pull on growing nerve cells, or neurons, helping them navigate to their assigned places amidst the brain’s wiring.
How a single protein can exert both a push and a pull force to nudge a neuron in the desired direction is a longstanding mystery that has now been solved by scientists from Dana-Farber Cancer Institute and collaborators in Europe and China.
Jia-huai Wang, PhD, who led the work at Dana-Farber and Peking University in Beijing, is a corresponding author of a report published in the August 7 online edition of Neuron that explains how one guidance protein, netrin-1, can either attract or repel a brain cell to steer it along its course. Wang and co-authors at the European Molecular Biology Laboratory (EMBL) in Hamburg, Germany, used X-ray crystallography to reveal the three-dimensional atomic structure of netrin-1 as it bound to a docking molecule, called DCC, on the axon of a neuron. The axon is the long, thin extension of a neuron that connects to other neurons or to muscle cells.
As connections between neurons are established – in the developing brain and throughout life – axons grow out from a neuron and extend through the brain until they reach the neuron they are connecting to. To choose its path, a growing axon senses and reacts to different molecules it encounters along the way. One of these molecules, netrin-1, posed an interesting puzzle: an axon can be both attracted to and repelled from this cue. The axon’s behavior is determined by two types of receptors on its tip: DCC drives attraction, while UNC5 in combination with DCC drives repulsion.
“How netrin works at the molecular level has long been a puzzle in neuroscience field,” said Wang, “We now provide structure evidences that reveal a novel mechanism of this important guidance cue molecule.” The structure showed that netrin-1 binds not to one, but to two DCC molecules. And most surprisingly, it binds those two molecules in different ways.
“Normally a receptor and a signal are like lock-and-key, they have evolved to bind each other and are highly specific – and that’s what we see in one netrin site,” said Meijers. “But the second binding site is a very unusual one, which is not specific for DCC.”
Not all of the second binding site connects directly to a receptor. Instead, in a large portion of the binding interface, it requires small molecules that act as middle-men. These intermediary molecules seem to have a preference for UNC5, so if the axon has both UNC5 and DCC receptors, netrin-1 will bind to one copy of UNC5 via those molecules and the other copy of DCC at the DCC-specific site. This triggers a cascade of events inside the cell that ultimately drives the axon away from the source of netrin-1, author Yan Zhang’s lab at Peking University found. The researchers surmised that, if an axon has only DCC receptors, each netrin-1 molecule binds two DCC molecules, which results in the axon being attracted to netrin-1. “By controlling whether or not UNC5 is present on its tip, an axon can switch from moving toward netrin to moving away from it, weaving through the brain to establish the right connection,” said Zhang.
Knowing how neurons switch from being attracted to netrin to being repelled opens the door to devise ways of activating that switch in other cells that respond to netrin cues, too. For instance, many cancer cells produce netrin to attract growing blood vessels that bring them nourishment and allow the tumor to grow, so switching off that attraction could starve the tumor, or at least prevent it from growing.
On the other hand, when cancers metastasize they often stop being responsive to netrin. In fact, the DCC receptor was first identified as a marker for an aggressive form of colon cancer, and DCC stands for “deleted in colorectal cancer.” Since colorectal cancer cells have no DCC, they are ‘immune’ to the programmed cell death that would normally follow once they move away from the lining of the gut and no longer have access to netrin. As a result, these tumor cells continue to move into the bloodstream, and metastasize to other tissues. “Therefore, to understand the molecular mechanism of how netrin works should also have a good impact in cancer biology,” said Wang.
The guidance issue is a very complicated cell biology problem. Meijers, Zhang, Wang and their colleagues are now investigating how other receptors bind to netrin-1, exactly how the intermediary molecules ‘choose’ their preferred receptor, how other guidance molecule binds to DCC, and how the system is regulated. The answers could one day enable researchers to steer a cell’s response to netrin and other guidance cues, ultimately changing its fate.
Mechanism explains complex brain wiring
How neurons are created and integrate with each other is one of biology’s greatest riddles. Researcher Dietmar Schmucker from VIB-KU Leuven unravels a part of the mystery in Science magazine. He describes a mechanism that explains novel aspects of how the wiring of highly branched neurons in the brain works. These new insights into how complex neural networks are formed are very important for understanding and treating neurological diseases.
Neurons, or nerve cells
It is estimated that a person has 100 billion neurons, or nerve cells. These neurons have thin, elongated, highly branched offshoots called dendrites and axons. They are the body’s information and signal processors. The dendrites receive electrical impulses from the other neurons and conduct these to the cell body. The cell body then decides whether stimuli will or will not be transferred to other cells via the axon.
The brain’s wiring is very complex. Although the molecular mechanisms that explain the linear connection between neurons have already been described numerous times, little is as yet known about how the branched wiring works in the brain.
The connections between nerve cells
Prior research by Dietmar Schmucker and his team lead to the identification of the Dscam1 protein in the fruit fly. The neuron can create many different protein variations, or isoforms, from this same protein. The specific set of isoforms that occurs on a neuron’s cell surface determines the neuron’s unique molecular identity and plays an important role in the establishment of accurate connections. In other words, it describes why certain neurons either come into contact with each other or reject each other.
Recent work by Haihuai He and Yoshiaki Kise from Dietmar’s team indicates that different sets of Dscam1 isoforms occur inside one axon, between the newly formed offshoots amongst each other. If this was not the case, then only linear connections could come about between neurons. These results indicate for the first time the significance of why different sets of the same protein variations can occur in one neuron and it could explain mechanistically how this contributes to the complex wiring in our brain.
Clinical impact
Although this research was done with fruit flies, it also provides new insights that help explain the wiring and complex interactions of the human brain and shine a new light on neurological development disorders such as autism. Thorough knowledge of nerve cell creation and their neural interactions is considered essential knowledge for the future possibility of using stem cell therapy as standard treatment for certain nervous system disorders.
Questions
Given that this research can raise many questions, we would like to refer your questions in your report or article to the email address that the VIB has made available for this purpose. All questions regarding this and other medical research can be directed to: patients@vib.be.
Relevant scientific publication
The above-mentioned research was published in the prominent magazine Science.
(Source: vib.be)
Research details how developing neurons sense a chemical cue
Symmetry is an inherent part of development. As an embryo, an organism’s brain and spinal cord, like the rest of its body, organize themselves into left and right halves as they grow. But a certain set of nerve cells do something unusual: they cross from one side to the other. New research in mice delves into the details of the molecular interactions that help guide these neurons toward this anatomical boundary.
In an embryo, a neuron’s branches, or axons, have special structures on their tips that sense chemical cues telling them where to grow. The new findings, by researchers at Memorial Sloan Kettering Cancer Center and The Rockefeller University, reveal the structural details of how one such cue, Netrin-1, interacts with two sensing molecules on the axons, DCC and a previously less well characterized player known as neogenin, as a part of this process.
“Our work provides the first high-resolution view of the molecular complexes that form on the surface of a developing axon and tell it to move in one direction or another,” says Dimitar Nikolov, a structural biologist at Memorial Sloan Kettering. “This detailed understanding of these assemblies helps us better understand neural wiring, and may one day be useful in the development of drugs to treat spinal cord or brain injuries.”
In a developing nervous system, the signaling molecule, Netrin-1, identified by Rockefeller University Professor Marc Tessier-Lavigne and colleagues, can guide neurons by attracting or repulsing them. In the case of axons that cross from one side to the other, extended by so-called commissural neurons, Netrin-1 attracts them toward the middle.
With a technique that uses X-rays to visualize the structure of crystalized proteins, research scientist Kai Xu and colleagues in Nikolov’s laboratory revealed that Netrin-1 has two separate binding sites on opposite ends, enabling it to simultaneously bind to different receptors. This may explain how Netrin-1, which is an important axon-guiding molecule, can affect in different ways neurons that express different combinations of receptors, Nikolov says.
For some time, scientists have known commissural neurons used the receptor molecule DCC to detect Netrin-1. Neogenin has a structure similar to DCC, and this research, described today in Science, confirms neogenin too acts as a sensing molecule for commissural neurons in mammals.
In experiments that complemented the structural work, conducted by Nicolas Renier and Zhuhao Wu in Tessier-Lavigne’s lab, the researchers confirmed that, like DCC, neogenin senses Netrin-1 for the growing commissural neurons in mice.
These neurons are part of the system by which one side of the brain controls movement on the opposite side of the body. As a result, a mutation in the gene responsible for DCC interferes with this coordination, causing congenital mirror movement disorder. People with this disorder cannot move one side of the body in isolation; for example, a right-handed wave is mirrored by a similar gesture by the left hand.
The work also has implications for understanding why DCC, neogenin and other cell-surface receptors come in slightly different forms, called splice isoforms. The structural research revealed these isoforms bind differently to Netrin-1. However, it is not yet clear what this means for neuron wiring, Nikolov says.
“With this structural knowledge, and with the identification of an additional receptor involved in axon guidance in the spinal cord, we are gaining deeper insight into the mechanisms through which neurons make connections that produce a functioning nervous system, as well as the dysfunction that arises from miswiring of connections” says Tessier-Lavigne.
(Source: newswire.rockefeller.edu)
Scientists identify clue to regrowing nerve cells
Researchers at Washington University School of Medicine in St. Louis have identified a chain reaction that triggers the regrowth of some damaged nerve cell branches, a discovery that one day may help improve treatments for nerve injuries that can cause loss of sensation or paralysis.
The scientists also showed that nerve cells in the brain and spinal cord are missing a link in this chain reaction. The link, a protein called HDAC5, may help explain why these cells are unlikely to regrow lost branches on their own. The new research suggests that activating HDAC5 in the central nervous system may turn on regeneration of nerve cell branches in this region, where injuries often cause lasting paralysis.
“We knew several genes that contribute to the regrowth of these nerve cell branches, which are called axons, but until now we didn’t know what activated the expression of these genes and, hence, the repair process,” said senior author Valeria Cavalli, PhD, assistant professor of neurobiology. “This puts us a step closer to one day being able to develop treatments that enhance axon regrowth.”
The research appears Nov. 7 in the journal Cell.
Axons are the branches of nerve cells that send messages. They typically are much longer and more vulnerable to injury than dendrites, the branches that receive messages.
In the peripheral nervous system — the network of nerve cells outside the brain and spinal column — cells sometimes naturally regenerate damaged axons. But in the central nervous system, comprised of the brain and spinal cord, injured nerve cells typically do not replace lost axons.
Working with peripheral nervous system cells grown in the laboratory, Yongcheol Cho, PhD, a postdoctoral research associate in Cavalli’s laboratory, severed the cells’ axons. He and his colleagues learned that this causes a surge of calcium to travel backward along the axon to the body of the cell. The surge is the first step in a series of reactions that activate axon repair mechanisms.
In peripheral nerve cells, one of the most important steps in this chain reaction is the release of a protein, HDAC5, from the cell nucleus, the central compartment where DNA is kept. The researchers learned that after leaving the nucleus, HDAC5 turns on a number of genes involved in the regrowth process. HDAC5 also travels to the site of the injury to assist in the creation of microtubules, rigid tubes that act as support structures for the cell and help establish the structure of the replacement axon.
When the researchers genetically modified the HDAC5 gene to keep its protein trapped in the nuclei of peripheral nerve cells, axons did not regenerate in cell cultures. The scientists also showed they could encourage axon regrowth in cell cultures and in animals by dosing the cells with drugs that made it easier for HDAC5 to leave the nucleus.
When the scientists looked for the same chain reaction in central nervous system cells, they found that HDAC5 never left the nuclei of the cells and did not travel to the site of the injury. They believe that failure to get this essential player out of the nucleus may be one of the most important reasons why central nervous system cells do not regenerate axons.
“This gives us the hope that if we can find ways to manipulate this system in brain and spinal cord neurons, we can help the cells of the central nervous system regrow lost branches,” Cavalli said. “We’re working on that now.”
Pulse propagation and signal transduction in the hydraulic brain
When Descartes turned his critical eye to the nervous system, he reasoned that the nerves must transduce hydraulic power to control the musculature. In the circulatory system, blood is pushed comparatively slowly through the aorta, perhaps around 0.3 meters per second. Superimposed on that flow, however, is an arterial pulse wave which propagates much faster, both through the blood and the walls of the vessel. For compliant and healthy vessels that speed might be around 10 meters per second, while for more hardened arteries, it could be 15 or higher. Modern day electrophysiologists have since replaced the hydraulic model with the idea that nerves really only transmit information—electrical information no less. Yet when looking at the power supply to the leg, for example, it is still hard to ignore the fact that the main femoral artery, at a diameter scarcely a half of an inch, looks rather meager next to the “information-supplying” sciatic nerve, which may actually be more like three-quarters of an inch. A conflux of ideas from a variety of disciplines has recently led to a critical re-emergence of the more mechanical side of the nervous system. To that point, two German scientists have just published a paper in the journal, Medical Hypotheses, where they suggest that the pulse wave is the main event in nervous conduction, while the electrical show is mere epiphenomenon.
We recently discussed the increasingly popular idea that action potentials may actually be soliton waves which propagate in the membranes of axons as phase transitions with minimal loss in energy. Convincing biologists that these subtle creatures could exist in the chaotic and varied conditions inside neurons has been a challenge. However, it is harder to argue against the fact that any kind of electrochemical spike based on the rapid influx of ions will be accompanied by a significant pressure pulse. The idea that the German researchers have supported, is that these as the pressure pulses naturally decay in the viscoelastic medium of the nerve, they are refreshed by ionic input at the nodes between myelinated axon segments, or continuously in unmyelinated axons.
If you have ever been absent-minded enough to grab a live wire, or even brush up strongly against one, the sensation is unforgettable. It is not such a stretch to acknowledge that when you slam your funny bone, or more precisely the Ulnar nerve (largest unprotected nerve in your body), the resultant vibe and decay feels almost identical to a real electrical assault. Similarly, the so-called “stingers” that run down the limbs after a sharp blow to the head are familiar to most footballers, and can give one quite a shock. Unfortunately these (albeit very simplistic) macroscopic intuitions don’t hold up so well when extended to the microscopic domain. Granted, when the electrochemical mechanisms that are assumed to underlie nervous conduction are looked at in detail, it becomes more difficult to disentangle the mechanical from the electric. However, as the authors observe, at some point, an attentive electrophysiologist must ask his or herself, “why are so many ion channels mechanosensitive” ?
One unexpected finding of the patch clamp recording technique was that the dilation of the membrane caused by local tension leads to considerable increase in transmembrane ion flow. Impulse waves causing short extensions in the membrane can directly induce opening and closing of both voltage and ligand gated channels. The idea that the pore in these channels is a rigid tube isolated from larger membrane events is difficult to support in this context. According to the authors, it is quite likely that common mechanoreceptor devices, like the pressure- or vibration-sensitive Vater-Pacinian corpuscles of the skin, conduct signals to initiate high-speed polysynaptic muscle reflex circuits without any classical intermediary electrical conversion.
The exact conduction velocity of mechanical impulses in nerve fibers remains unknown. It is estimated that under physiologic conditions, an unamplified axoplasmic pressure pulse would decay over roughly 1 mm due to viscosity, depending on the distensibility of the axon wall. When compared to the theoretical case of an absolutely rigid wall, a typical myelin sheath may be rigid enough to support pulse speeds up to one-fifth of the estimated maximum. That speed is not to shabby when compared with some rough estimates from previous authors, which put the maximum pulse velocity under an indistensible membrane somewhere upwards of 1500 meters per second. Suddenly, the quicker than life eyeblink response, or speed of the tenderfoot stepping on a sharp shard, become a little more comprehensible.
The theory as it stands is incomplete and needs to be adapted for specific cases with real biology in mind. In different animals, and in different regions of their brains, conduction in neurons goes by different names. For example, in the cerebellum, the unmyelinated parallel fibers pack to extreme densities in a regular crystalline lattice whose reason to be defies physiologic explanation to this day. Just as we currently have no good explanation for how signals could be properly isolated in nerve bundles where seemingly random nodes of Ranvier overlap in extent and influence, it is hard to imagine parallel fibers could maintain their electrochemical, or even mechanical, autonomy within this geometry.
The pressure wave theory wields considerable predictive power when it comes to explaining some of the unique synaptic specializations found throughout the brain. When considered only from an electrochemical point of view, the huge structural synaptic investments, like those found at the neuromuscular junction (NMJ), can hardly be imagined to be driven by local, and weak, current or field effects. One might need look no further than simple-to-recreate Chaldni patterns set up in two dimensions on the surface of a taunt drum, to make the imaginative leap to a three dimensional system, with multiple vibrating players, where more extreme patterns might easily be set up to provide authorship to repeatable complex structure. For the NMJ in particular, the case has been made that at the end-plate, the comparatively enormous efflux of acetylcholine to the deeply-guttered cleft, and propagation of excitation through the transverse tubule system, are all components of a continuous mechanical amplifier.
The apparent ease with which evolving organisms manage to cobble together all manner of sensitive hearing devices becomes infinitely more explicable once we see that nature has apparently been doing this kind of thing all alone inside of neurons. The amplification and transduction through liquid channels, of barely noticeable vibrations against a background of thermal noise much greater in magnitude, is in this light, no evolutionary stumble-upon, but rather the bread and butter of neural systems, and perhaps many aspects of life in general.
Predicting Who Will Have Chronic Pain
Abnormalities in brain axons predispose people to chronic back pain after injury
Abnormalities in the structure of the brain predispose people to develop chronic pain after a lower back injury, according to new Northwestern Medicine® research. The findings could lead to changes in the way physicians treat patients’ pain.
Most scientists and clinicians have assumed chronic back pain stems from the site of the original injury.
“We’ve found the pain is triggered by these irregularities in the brain,” said A. Vania Apkarian, senior author of the study and a professor of physiology at Northwestern University Feinberg School of Medicine. “We’ve shown abnormalities in brain structure connections may be enough to push someone to develop chronic pain once they have an injury.”
Based on MRI brain scans of people who had a new lower back injury, Northwestern scientists could predict with about 85 percent accuracy which patients’ pain would persist. The predictor was a specific irregularity or marker the scientists identified in the axons, pathways in the brain’s white matter that connect brain cells so they can communicate with each other.
The findings provide a new view of treating chronic pain, which affects nearly 100 million Americans and costs up to $635 billion a year to treat.
“We think the people who are vulnerable need to be treated aggressively with medication early on to prevent their pain from becoming chronic,” Apkarian said. “Last year, we showed people who take medication early on had a better chance of recovering. Medication does help.” Apkarian also is a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
The research, funded by the National Institutes of Health, was published Sept. 16 in the journal Pain.
Brain abnormalities have been observed in other long-term chronic pain conditions. Apkarian’s study is the first to show brain structure abnormalities are a marker of a predisposition to the chronic pain, not a result of living with it.
The lead author of the study is Ali Mansour, M.D., formerly a postdoctoral fellow in Apkarian’s lab.
Apkarian’s research focuses on the relationship between chronic pain and the brain. One of his previous studies showed chronic pain patients lose gray matter volume over time.
Chronic pain is one of the most expensive health care conditions in the U.S. and takes an enormous toll on quality of life, yet there still is not a scientifically validated therapy for the condition. Lower back pain represents 28 percent of all causes of pain in the U.S.; about 23 percent of these patients suffer long-term pain.
The abnormalities identified in the study were found in multiple white matter axon bundles, some surrounding the nucleus accumbens and medial prefrontal cortex, two brain regions involved in processing emotion and pain. Last year, the Apkarian group showed that the physiological properties of these two regions identify which patients will persist with back pain. The new results identify a pre-existing culprit for these physiological responses to the injury.
“The brain abnormalities exist in the general population, but only those people with a back injury go on to develop the chronic pain,” Apkarian said.
For the study, Apkarian and his colleagues scanned the brains of 46 people who had an episode of lower back pain for at least four weeks and had not experienced any pain for at least one year before that. Their pain had to be rated at least five out of 10 on a pain scale for them to be included in the study.
Scientists followed the patients for a year, scanning their brains at the onset of study and one year later. After a year about half of them had improved, regardless of whether they took anything to treat the pain, and half of them continued to have pain. Those with the persistent pain had the same structural abnormalities in their white matter at the onset of the injury and after one year.
“The abnormality makes them vulnerable and predisposes them to enhanced emotional learning that then amplifies the pain and makes it more emotionally significant,” Apkarian said.
“Pain is becoming an enormous burden on the public,” said Linda Porter, the pain policy advisor at National Institute of Neurological Disorders and Stroke (NINDS) and a leader of the National Institutes of Health (NIH) Pain Consortium. “The U.S. government recently outlined steps to reduce the future burden of pain through broad-ranging efforts, including enhanced research. This study is a good example of the kind of innovative research we hope will reduce chronic pain, which affects a huge portion of the population.”
(Image: Shutterstock)
Two different versions of the same signaling protein tell a nerve cell which end is which, UA researchers have discovered. The findings could help improve therapies for spinal injuries and neurodegenerative diseases.
University of Arizona scientists have discovered an unknown mechanism that establishes polarity in developing nerve cells. Understanding how nerve cells make connections is an important step in developing cures for nerve damage resulting from spinal cord injuries or neurodegenerative diseases such as Alzheimer’s.
In a study published on Aug. 12 in the journal Proceedings of the National Academy of Sciences, UA doctoral student Sara Parker and her adviser, assistant professor of cellular and molecular medicine Sourav Ghosh, report that the decision which will be the “plus” and the “minus” end in a newborn nerve cell is made by a long and a short version of the same signaling molecule.
Nerve cells – or neurons – differ from many other cells by their highly asymmetric shape: Vaguely resembling a tree, a neuron has one long, trunk-like extension ending in a tuft of root-like bristles. This is called the axon. From the opposite end of the cell body sprout branch-like structures known as dendrites. By connecting the “branches” of their dendrites to the “root tips” of other neurons’ axons, nerve cells form networks, which can be as simple as the few connections involved in the knee-jerk reflex or as complex as those in the human brain.
Parker and her team found that embryonic nerve cells manufacture a well-known signaling enzyme called Atypical Protein Kinase C (aPKC) in two varieties: a full-length one and a truncated one. Both varieties compete to bind the same molecular partner, a protein called Par3. If the short form of aPKC pairs up with Par3, it tells the cell to grow a dendrite, and if the long one pairs up with Par3, it will make an axon instead.
When the researchers blocked the production of the short form, the nerve cell grew multiple axons and no dendrites. When they created an artificial abundance of the short form, dendrites formed at the expense of axons. UA undergraduate student Sophie Hapak performed many of the experiments revealing how the two isoforms compete for Par3.
"We show that wiring a neuronal circuit is much more complex than previously thought," said Ghosh. "The process has a built-in robustness that explicitly defines which part of the cell is ‘positive’ and which is ‘negative.’"
"In order to have a functioning neuronal circuit, you have to have receiving and sending ends," Parker said. "Initially, when a neuron is formed, it lacks the polarity it needs once it develops into a part of a circuit. The mechanism we discovered establishes that polarity."
"How the various brain regions are wired is the basis of emotion, memory and all cognitive functions," said Ghosh, who is a member of the UA’s BIO5 Institute. "Establishing neuronal polarity in single neurons is absolutely essential for neuronal circuits to form."
"If we understand this mechanism, we could think about methods to spur new axons after the original ones were severed in a traumatic spinal cord injury, for example," Ghosh said.
The findings defy conventional wisdom, which maintains that a developing neuron will make dendrites by default unless instructed by the long form of aPKC to make an axon instead. By cultivating and studying neurons just after they formed, Parker and her group found that both forms of aPKC, long and short, are initially distributed equally throughout the cell. These forms subsequently segregate into different parts of the cell as the neuron matures and establishes polarity.
Because the cells were isolated from rat brains and kept in culture, the researchers could demonstrate that no external clues from other cells are needed to instruct a developing neuron. Whether the establishment of polarity is a random process or whether other signals yet to be identified play a role in regulating the abundance of the two aPKC varieties is not known.
Splice this: End-to-end annealing demonstrated in neuronal neurofilaments
While popularly publicized neuroscience research focuses on structural and functional connectomes, timing patterns of axonal spikes, neural plasticity, and other areas of inquiry, the intraneuronal environment also receives a great deal of investigative attention.
One example is the study of cytoskeletal polymers called neurofilaments –intermediate filaments of nerve cells that and a major component of the neuronal cytoskeleton believed to provide the axon with structural support. Neurofilaments are transported into axons where they accumulate during development, causing the axons to expand in girth. This is important because the cross-sectional area of an axon influences the rate of propagation of the nerve impulse. The space-filling properties of these polymers are maximized by spoke-like projection domains called side-arms that function to space the polymers apart. Once in the axons these polymers (which are barely 10 nm in diameter) can grow to reach remarkably long lengths – 100,000 nm (0.1 mm) or more – but how they attain such lengths and how their length is regulated is not known. Recently, scientists at The Ohio State University – who previously showed that neurofilaments and vimentin filaments expressed in nonneuronal cell lines can lengthen by joining ends in a process known as end-to-end annealing – demonstrated robust and efficient end-to-end annealing of neurofilaments in nerve cells. In additions, the researchers reported evidence for a neurofilament-severing mechanism.