Posts tagged nerve cells
Articles and news from the latest research reports.
First to measure the concerted activity of a neuronal circuit
Neurobiologists from the Friedrich Miescher Institute for Biomedical Research have been the first to measure the concerted activity of a neuronal circuit in the retina as it extracts information about a moving object. With their novel and powerful approach they can now not only visualize networks of neurons but can also measure functional aspects. These insights are direly needed for a better understanding of the processes in the brain in health and disease.
For many decades electrophysiology and genetics have been the main tools in the toolbox of approaches to study individual neurons in the central nervous system to understand perception and behavior. In the last five years however, neurobiology has been riding a wave of technological advances that brought unprecedented insights: Optogenetics and genetically encoded activity sensors has allowed scientists to control and measure the activity of clearly defined neurons; the application of rabies viruses enabled the visualization of networks of interconnected nerve cells. What was still missing, was the link between neural circuit and monitoring of activity.
Scientists from the Friedrich Miescher Institute for Biomedical Research have now been the first to measure the concerted activity of a neuronal circuit in the retina as it extracts information about the movement of an object.
In a world defined through eyesight, it is crucial to be able to discern whether something moves towards us, moves away or moves next to us. It comes as no surprise then that in the retina several parallel neuronal circuits are reserved for the extraction of information about movement and that most of them are dedicated to the analysis of the direction of motion.
As they report online in Neuron, Keisuke Yonehara and Karl Farrow, two Postdoctoral Fellows in Botond Roska’s team at the FMI, have now been able to monitor the activity of all circuit elements in a motion sensitive retinal circuit at once, and pinpoint the site, at a subcellular level, where the information about the direction of the movement becomes encoded. To achieve this, they used genetically altered rabies viruses expressing calcium sensors developed by the laboratory of Klaus Conzelmann in Munich. The special property of rabies viruses is that they move across connected neurons and therefore are able to deliver the sensors to all circuit elements within a defined neuronal circuit. Simultaneous two-photon imaging allowed them then to monitor activity in every part of the neuronal circuit at once, even in subcellular compartments, such as axons, synapses and dendrites.
"We are extremely thrilled that with this new method, which combines the power of genetically altered rabies viruses with very powerful two-photon microscopy, we are now able to link circuit architecture with activity and ultimately function," comments Yonehara. "We have illustrated the power of the method for a better understanding of the perception of movement and are convinced that the method will allow us to reach a better understanding of many processes in the retina and in other parts of the brain."
(Source: medicalxpress.com)
How brain microcircuits integrate information from different senses
A new publication in the top-ranked journal Neuron sheds new light onto the unknown processes on how the brain integrates the inputs from the different senses in the complex circuits formed by molecularly distinct types of nerve cells. The work was led by new Umeå University associate professor Paolo Medini.
One of the biggest challenges in Neuroscience is to understand how the cerebral cortex of the brain processes and integrates the inputs from the different senses (like vision, hearing and touch) to control for example, that we can respond to an event in the environment with precise movement of our body.
The brain cortex is composed by morphologically and functionally different types of nerve cells, e.g. excitatory, inhibitory, that connect in very precise ways. Paolo Medini and co-workers show that the integration of inputs from different senses in the brain occurs differently in excitatory and inhibitory cells, as well as in superficial and in the deep layers of the cortex, the latter ones being those that send electrical signals out from the cortex to other brain structures.
“The relevance and the innovation of this work is that by combining advanced techniques to visualize the functional activity of many nerve cells in the brain and new molecular genetic techniques that allows us to change the electrical activity of different cell types, we can for the first time understand how the different nerve cells composing brain circuits communicate with each other”, says Paolo Medini.
The new knowledge is essential to design much needed future strategies to stimulate brain repair. It is not enough to transplant nerve cells in the lesion site, as the biggest challenge is to re-create or re-activate these precise circuits made by nerve cells.
Paolo Medini has a Medical background and worked in Germany at the Max Planck Institute for Medical Research of Heidelberg, as well as a Team leader at the Italian Institute of Technology in Genova, Italy. He recently started on the Associate Professor position in Cellular and Molecular Physiology at the Molecular Biology Department.
He is now leading a brand new Brain Circuits Lab with state of state-of-the-art techniques such as two-photon microscopy, optogenetics and electrophysiology to investigate the circuit functioning and repair in the brain cortex. This investment has been possible by a generous contribution from the Kempe Foundation and by the combined effort of Umeå University.
“By combining cell physiology knowledge in the intact brain with molecular biology expertise, we plan to pave the way for this kind of innovative research that is new to Umeå University and nationally”, says Paolo Medini.
(Source: teknat.umu.se)
A ‘Rocking’ Receptor: Crucial Brain-Signaling Molecule Requires Coordinated Motion to Turn On
Study could help yield new drugs for brain disorders
Johns Hopkins biophysicists have discovered that full activation of a protein ensemble essential for communication between nerve cells in the brain and spinal cord requires a lot of organized back-and-forth motion of some of the ensemble’s segments. Their research, they say, may reveal multiple sites within the protein ensemble that could be used as drug targets to normalize its activity in such neurological disorders as epilepsy, schizophrenia, Parkinson’s and Alzheimer’s disease.
The glutamate-binding segments (blue, yellow) of ionotropic glutamate receptors undergo a “rocking” motion during activation by glutamate (red). (The dotted line provides a point of reference.)
A summary of the results, published online in the journal Neuron on Aug. 7, shows that full activation of so-called ionotropic glutamate receptors is more complex than previously envisioned. In addition to the expected shape changes that occur when the receptor “receives” and clamps down on glutamate messenger molecules, the four segments of the protein ensemble also rock back and forth in relation to each other when fewer than four glutamates are bound.
“We believe that our study is the first to show the molecular architecture and behavior of a prominent neural receptor protein ensemble in a state of partial activation,” says Albert Lau, Ph.D., assistant professor of biophysics and biophysical chemistry at the Johns Hopkins University School of Medicine.
Glutamate receptors reside in the outer envelope of every nerve cell in the brain and spinal cord, Lau notes, and are responsible for changing chemical information — the release of glutamate molecules from a neighboring nerve cell — into electrical information, the flow of charged particles into the receiving nerve cell. There would be sharply reduced communication between nerve cells in our brains if these receptors were disabled, he added, and thought and normal brain function in general would be severely compromised. Malfunctioning receptors, says Lau, have been linked with numerous neurological disorders and are therefore potential targets for drug therapies.
Lau explained that each glutamate receptor is a united group of four protein segments that has a pocket for clamping down on glutamate like a Venus fly trap snaring a bug. Below the glutamate-binding segments are four other segments embedded in the cell’s outer envelope to form a channel for charged particles to flow through. When no glutamates are bound to the receptor, the channel is closed; full activation of the receptor and full opening of the channel occur when four glutamates are bound, each to a difference pocket.
Previously, Lau says, investigators thought that the level of receptor activation simply corresponded to the degree to which each glutamate-binding segment changed shape during the glutamate-binding process. Using a combination of computer modeling, biophysical “imaging” of molecular structure, biochemical analysis and electrical monitoring of individual cells, the researchers teased apart some of the steps in between zero activation and full activation. They were able to show that the four glutamate-binding segments, in addition to clamping down on glutamate, also rock back and forth in pairs when fewer than four glutamates are bound.
“It isn’t clear yet how this rocking motion affects receptor function, but we now know that activation depends on more than how much each glutamate-binding segment clamps down,” says Lau. Previous development of drugs targeting the receptor focused on the four glutamate-binding pockets. “Our discovery of this molecular motion could aid the development of drugs by revealing additional drug-binding sites on the receptor,” he adds.
(Source: hopkinsmedicine.org)
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.
For a healthy brain, don’t let the trash pile up
Recycling is not only good for the environment, it’s good for the brain. A study using rat cells indicates that quickly clearing out defective proteins in the brain may prevent loss of brain cells.
Results of a study in Nature Chemical Biology suggest that the speed at which damaged proteins are cleared from neurons may affect cell survival and may explain why some cells are targeted for death in neurodegenerative disorders. The research was supported by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.
One of the mysteries surrounding neurodegenerative diseases is why some nerve cells are marked for destruction whereas their neighbors are spared. It is especially puzzling because the protein thought to be responsible for cell death is found throughout the brain in many of these diseases, yet only certain brain areas or cell types are affected.
In Huntington’s disease and many other neurodegenerative disorders, proteins that are misfolded (have abnormal shapes), accumulate inside and around neurons and are thought to damage and kill nearby brain cells. Normally, cells sense the presence of malformed proteins and clear them away before they do any damage. This is regulated by a process called proteostasis, which the cell uses to control protein levels and quality.
In the study, Andrey S. Tsvetkov and his colleagues from the University of California, San Francisco (UCSF) and Duke University, Durham, N.C., showed that differences in the rate of proteostasis may be the clue to understanding why certain nerve cells die in Huntington’s, a genetic brain disorder that leads to uncontrolled movements and death.
To measure how quickly proteins are cleared away from cells, the researchers developed a new technique called optical pulse-labeling, allowing them to follow specific proteins in individual living cells. To test the technique, they grew brain cells in a dish and turned on Dendra2, a photoswitchable protein that glows from green to red after being hit by a specific type of light. Both the red and green glow can be followed until the protein is cleared from the cell. In this way, the researchers could track the lifetime of newly produced Dendra2 (which glows green) and older, photoswitched Dendra2 (which glows red) until the protein was cleared away from the cell.
"Before this new technique, there was no way to look at individual neurons and their capacity to handle proteins. This method provides a real-time readout of how fast proteins are turned over in neurons and gives us a look at some of the mechanisms involved," said Margaret Sutherland, Ph.D., program director at NINDS.
The researchers followed Dendra2 in a set of striatal neurons, which they obtained from rats. The striatum (where striatal neurons are located) is a brain region involved in a number of brain functions including planning movements and is most heavily affected in Huntington’s disease. They discovered that the mean lifetime of the protein (how long it remained in the cell) varied three- to fourfold, suggesting that rates of proteostasis were different among individual neurons. In other words, some cells may process an identical protein much slower than others.
Then, the researchers investigated how cells deal with different forms of huntingtin, the protein involved in Huntington’s. They fused Dendra2 on the end of a normal or mutant version of huntingtin to track how long the protein remained in cells. The mutant version of huntingtin is longer, and contains three building blocks of the protein repeated an abnormal number of times. These repeats in huntingtin are what cause it to misfold, eventually leading to neuron death and the symptoms of the disease. As predicted, in their experiments, the mutant form of huntingtin caused more rat cells to die than did the normal form of the protein.
The researchers found that the amount of time the mutant protein remained in the cell predicted neuronal survival: shorter mean lifetimes of mutant huntingtin were associated with longer neuronal survival. A shorter mean lifetime indicates that a protein does not remain in the cell for a long time, and that proteostasis is working effectively to clear it away. This suggests that improving proteostasis in Huntington’s brains may improve neuronal survival.
To test this idea, the researchers activated Nrf2, a protein known to regulate protein processing. When Nrf2 was turned on, the mean lifetime of huntingtin was shortened, and the neuron lived longer.
"Nrf2 seems like a potentially exciting therapeutic target. It is profoundly neuroprotective in our Huntington’s model and it accelerates the clearance of mutant huntingtin," said Dr. Steven Finkbeiner, senior author of the paper.
Although both striatal and cortical neurons are affected by mutant huntingtin, striatal neurons are more susceptible to cell death. The investigators found that striatal neurons were not as effective as cortical neurons in recognizing and clearing away the mutant protein.
"One surprising finding from these experiments was the significance of single cells’ ability to clear mutant huntingtin. It turned out that this ability largely predicted their susceptibility, whether that neuron came from the most vulnerable region of the brain – the striatum, or the cortex, which is less vulnerable," said Dr. Finkbeiner. The findings indicate that the toxicity of the damaged proteins may cause neurodegeneration by interfering with the proteostasis system, affecting how quickly they are cleared from neurons.
"The results should remind us that focusing on the disease-causing proteins is only one side of the coin. To understand why some cells die and others are spared, we may need to recognize that there are major, largely unrecognized cell-specific differences in the ways that various types of neurons recognize and dispose of disease-causing proteins," continued Dr. Finkbeiner.
The researchers explored potential mechanisms behind differences in proteostasis. One way that cells normally get rid of proteins is through autophagy — a process in which proteins are packed up into spheres and then broken down. Results in this paper suggested that neurons increased the rate of autophagy when they sensed that the mutant form of huntingtin was accumulating, indicating the autophagy system may be a drug target.
"These findings provide evidence that our brains have powerful coping mechanisms to deal with disease-causing proteins. The fact that some of these diseases don’t cause symptoms we can detect until the fourth or fifth decade of life, even when the gene has been present since birth, suggests that those mechanisms are pretty good," said Dr. Finkbeiner.
Future research is needed to determine why coping mechanisms fail as brain cells age and how neurons in the healthy brain keep the proteostasis system functioning.
"New research methods that help us understand how individual neurons function will increase our understanding of central nervous system disorders and help identify new treatments. It is critical to continue working on the methods such as those described in this paper," said Dr. Sutherland.
(Source: eurekalert.org)
New tissue engineering breakthrough encourages nerve repair
A new combination of tissue engineering techniques could reduce the need for nerve grafts, according to new research by The Open University. Regeneration of nerves is challenging when the damaged area is extensive, and surgeons currently have to take a nerve graft from elsewhere in the body, leaving a second site of damage. Nerve grafts contain aligned tissue structures and Schwann cells that support and guide neuron growth through the damaged area, encouraging function to be restored. The research, published in Biomaterials, reported a way to manufacture artificial nerve tissue with the potential to be used as an alternative to nerve grafts.
Pieces of Engineered Neural Tissue (EngNT) are formed by controlling natural Schwann cell behaviour in a three-dimensional collagen gel so that the cells elongate and align, then a stabilisation process removes excess fluid to leave robust artificial tissues. These living biomaterials contain aligned Schwann cells in an aligned collagen environment, recreating key features of normal nerve tissue.
Incorrect orientation of regenerating nerve cells can lead to delays in repair, scarring and poor restoration of nerve function. Much research has taken place into how support cells (Schwann cells) can be combined with materials to guide nerve regeneration. The new technology from The Open University avoids the use of synthetic materials by building neural tissue from collagen, a protein that is abundant in normal nerve tissue. Building the artificial tissue from natural proteins and directing the cellular alignment using normal cell-material interactions means the EngNT can integrate effectively at the repair site.
Dr James Phillips, Lecturer in Health Sciences at The Open University, said: “We previously reported how self-alignment of Schwann cells could be achieved by using a tethered collagen hydrogel, which exploited cells’ natural ability to orientate in the appropriate direction by using their internal contraction forces. Our current research shows that cell-alignment in the hydrogel can be stabilised using plastic compression. The compression removes fluid from the gels, leaving a strong and stable aligned structure that has many features in common with nerve tissue.”
The team incorporated Schwann cells within the aligned material to form artificial neural tissue that could potentially be used in peripheral nerve repair. The technique could be applied to other regenerative medicine scenarios, where a stable artificial tissue containing aligned cellular architecture would be of benefit.
(Source: www3.open.ac.uk)
Hearing loss from loud blasts may be treatable
Long-term hearing loss from loud explosions, such as blasts from roadside bombs, may not be as irreversible as previously thought, according to a new study by researchers at the Stanford University School of Medicine.
Using a mouse model, the study found that loud blasts actually cause hair-cell and nerve-cell damage, rather than structural damage, to the cochlea, which is the auditory portion of the inner ear. This could be good news for the millions of soldiers and civilians who, after surviving these often devastating bombs, suffer long-term hearing damage.
“It means we could potentially try to reduce this damage,” said John Oghalai, MD, associate professor of otolaryngology and senior author of the study, published July 1 in PLOS ONE. If the cochlea, an extremely delicate structure, had been shredded and ripped apart by a large blast, as earlier studies have asserted, the damage would be irreversible. (Researchers presume that the damage seen in these previous studies may have been due to the use of older, less sophisticated imaging techniques.)
“The most common issue we see veterans for is hearing loss,” said Oghalai, a scientist and clinician who treats patients at Stanford Hospital & Clinics and directs the hearing center at Lucile Packard Children’s Hospital.
The increasingly common use of improvised explosive devices, or IEDs, around the world provided the impetus for the new study, which was primarily funded by the U.S. Department of Defense. Among veterans with service-connected disabilities, tinnitus — a constant ringing in the ears — is the most prevalent condition. Hearing loss is the second-most-prevalent condition. But the results of the study would prove true for anyone who is exposed to loud blasts from other sources, such as jet engines, air bags or gunfire.
More than 60 percent of wounded-in-action service members have eardrum injuries, tinnitus or hearing loss, or some combination of these, the study says. Twenty-eight percent of all military personnel experience some degree of hearing loss post-deployment. The most devastating effect of blast injury to the ear is permanent hearing loss due to trauma to the cochlea. But exactly how this damage is caused has not been well understood.
The ears are extremely fragile instruments. Sound waves enter the ear, causing the eardrums to vibrate. These vibrations get sent to the cochlea in the inner ear, where fluid carries them to rows of hair cells, which in turn stimulate auditory nerve fibers. These impulses are then sent to the brain via the auditory nerve, where they get interpreted as sounds.
Permanent hearing loss from loud noise begins at about 85 decibels, typical of a hair dryer or a food blender. IEDs have noise levels approaching 170 decibels.
Damage to the eardrum is known to be common after large blasts, but this is easily detected during a clinical exam and usually can heal itself — or is surgically repairable — and is thus not typically the cause of long-term hearing loss.
In order to determine exactly what is causing the permanent hearing loss, Stanford researchers created a mouse model to study the effects of noise blasts on the ear.
After exposing anesthetized mice to loud blasts, researchers examined the inner workings of the mouse ear from the eardrum to the cochlea. The ears were examined from day one through three months. A micro-CT scanner was used to image the workings of the ear after dissection.
“When we looked inside the cochlea, we saw the hair-cell loss and auditory-nerve-cell loss,” Oghalai said.
“With one loud blast, you lose a huge number of these cells. What’s nice is that the hair cells and nerve cells are not immediately gone. The theory now is that if the ear could be treated with certain medications right after the blast, that might limit the damage.”
Previous studies on larger animals had found that the cochlea was torn apart and shredded after exposure to a loud blast. Stanford scientists did not find this in the mouse model and speculate that the use of older research techniques may have caused the damage.
“We found that the blast trauma is similar to what we see from more lower noise exposure over time,” said Oghalai. “We lose the sensory hair cells that convert sound vibrations into electrical signals, and also the auditory nerve cells.”
Much of the resulting hearing loss after such blast damage to the ear is actually caused by the body’s immune response to the injured cells, Oghalai said. The creation of scar tissue to help heal the injury is a particular problem in the ear because the organ needs to vibrate to allow the hearing mechanism to work. Scar tissue damages that ability.
“There is going to be a window where we could stop whatever the body’s inflammatory response would be right after the blast,” Oghalai said. “We might be able to stop the damage. This will determine future research.”
Carbon Nanotube Harpoon Catches Individual Brain Cell Signals
Neuroscientists may soon be modern-day harpooners, snaring individual brain-cell signals instead of whales with tiny spears made of carbon nanotubes.
(This image, taken with a scanning electron microscope, shows a new brain electrode that tapers to a point as thick as a single carbon nanotube. Credit: Inho Yoon and Bruce Donald, Duke)
The new brain cell spear is a millimeter long, only a few nanometers wide and harnesses the superior electromechanical properties of carbon nanotubes to capture electrical signals from individual neurons.
"To our knowledge, this is the first time scientists have used carbon nanotubes to record signals from individual neurons, what we call intracellular recordings, in brain slices or intact brains of vertebrates," said Bruce Donald, a professor of computer science and biochemistry at Duke University who helped developed the probe.
He and his collaborators describe the carbon nanotube probes June 19 in PLOS ONE.
"The results are a good proof of principle that carbon nanotubes could be used for studying signals from individual nerve cells," said Duke neurobiologist Richard Mooney, a study co-author. "If the technology continues to develop, it could be quite helpful for studying the brain."
Scientists want to study signals from individual neurons and their interactions with other brain cells to better understand the computational complexity of the brain.
Currently, they use two main types of electrodes, metal and glass, to record signals from brain cells. Metal electrodes record spikes from a population of brain cells and work well in live animals. Glass electrodes also measure spikes, as well as the computations individual cells perform, but are delicate and break easily.
"The new carbon nanotubes combine the best features of both metal and glass electrodes. They record well both inside and outside brain cells, and they are quite flexible. Because they won’t shatter, scientists could use them to record signals from individual brain cells of live animals," said Duke neurobiologist Michael Platt, who was not involved in the study.
In the past, other scientists have experimented with carbon nanotube probes. But the electrodes were thick, causing tissue damage, or they were short, limiting how far they could penetrate into brain tissue. They could not probe inside individual neurons.
To change this, Donald began working on a harpoon-like carbon-nanotube probe with Duke neurobiologist Richard Mooney five years ago. The two met during their first year at Yale in the 1976, kept in touch throughout graduate school and began meeting to talk about their research after they both came to Duke.
Mooney told Donald about his work recording brain signals from live zebra finches and mice. The work was challenging, he said, because the probes and machinery to do the studies were large and bulky on the small head of a mouse or bird.
With Donald’s expertise in nanotechnology and robotics and Mooney’s in neurobiology, the two thought they could work together to shrink the machinery and improve the probes with nano-materials.
To make the probe, graduate student Inho Yoon and Duke physicist Gleb Finkelstein used the tip of an electrochemically sharpened tungsten wire as the base and extended it with self-entangled multi-wall carbon nanotubes to create a millimeter-long rod. The scientists then sharpened the nanotubes into a tiny harpoon using a focused ion beam at North Carolina State University.
Yoon then took the nano-harpoon to Mooney’s lab and jabbed it into slices of mouse brain tissue and then into the brains of anesthetized mice. The results show that the probe transmits brain signals as well as, and sometimes better than, conventional glass electrodes and is less likely to break off in the tissue. The new probe also penetrates individual neurons, recording the signals of a single cell rather than the nearest population of them.
Based on the results, the team has applied for a patent on the nano-harpoon. Platt said scientists might use the probes in a range of applications, from basic science to human brain-computer interfaces and brain prostheses.
Donald said the new probe makes advances in those directions, but the insulation layers, electrical recording abilities and geometry of the device still need improvement.
A Peptide to Protect Brain Function
TAU researcher develops a protein to protect and restore nerve cell communications
A structure called “the microtubule network” is a crucial part of our nervous system. It acts as a transportation system within nerve cells, carrying essential proteins and enabling cell-to-cell communications. But in neurodegenerative diseases like Alzheimer’s, ALS, and Parkinson’s, this network breaks down, hindering motor abilities and cognitive function.
Now Prof. Illana Gozes of Tel Aviv University’s Sackler Faculty of Medicine has developed a new peptide in her lab, called NAP or Davunetide, that has the capacity to both protect and restore microtubule function. The peptide is a compound derived from the protein ADNP, which regulates more than 400 genes and is essential for brain formation, memory, and behavior.
Prof. Gozes and her team of researchers, including Dr. Yan Jouroukhin and graduate student Regin Ostritsky of TAU, observed that in animal models with microtubule damage, NAP was able to maintain or revive the transport of proteins and other materials in cells, ameliorating symptoms associated with neurodegeneration. These findings, which were reported in the journal Neurobiology of Disease, indicate that NAP could be an effective tool in fighting some of the most debilitating effects of neurodegenerative diseases.
Prof. Gozes is the director of TAU’s Adams Super Center for Brain Studies and holds the Lily and Avraham Gildor Chair for the Investigation of Growth Factors.
Securing passage through the brain
In their investigation, the researchers used two different animal models with microtubule damage. The first group was made up of normal mice whose microtubule system was broken down through the use of a compound. The second group were genetically-engineered mouse models of ALS, in which the microtubule system was chronically damaged. In both groups, half the mice were given a single NAP injection, while the control half were not.
To determine the impact of NAP on nerve cell communications, the researchers administered the chemical element manganese to all animal models and tracked its movement through the brain using an MRI. In the mice treated with NAP, researchers observed that the manganese was able to travel through the brain normally — the microtubule system had been protected from damage or restored to normal use. Those mice that did not receive the peptide experienced the usual breakdown or continued dysfunction of the microtubule system.
These findings were corroborated by a subsequent study conducted in the UK, published in the journal Molecular Psychiatry, which found that NAP was able to ameliorate damage in fruit fly models of microtubule deficiency, repairing nerve cell dysfunction.
Slowing down cognitive dysfunction
NAP appears to have widespread potential in terms of neuroprotection, says Prof. Gozes, who was recently awarded the Meitner-Humblodt Research Award for her lifelong contribution to the field of brain sciences.
Previous studies on the peptide, conducted through a collaboration between Allon Therapeutics and Ramot, TAU’s technology transfer arm, have shown that patients suffering from cognitive dysfunction — a precursor to Alzheimer’s Disease — showed significant improvements in their cognitive scores when treated with NAP. Additional studies have also shown that NAP has a positive impact on rectifying microtubule deficiencies in schizophrenia patients.
Prof. Gozes notes that more research must be conducted to discover how to optimize the use of NAP as a treatment, including which patients can benefit most from the intervention.
(Source: aftau.org)
Laura Wong has coaxed damaged nerve cells to grow and send messages to the brain again
“An ailment not to be treated,” read the prescription for a spinal cord injury on an Egyptian papyrus in 1,700 B.C. Not much has changed in the intervening millennia. Despite decades of research, modern medicine has made little headway in its quest to reverse damage to the central nervous system.
That is not to say, however, that there isn’t a glimmer of hope. Laura Wong, an M.D./Ph.D. student in Professor Eric Frank’s molecular physiology lab at the Sackler School, has been able to coax damaged nerve cells known as sensory neurons to regenerate, growing as much as 10 times longer than previously documented. What’s more, the new neurons make organized connections with their counterparts inside the spinal cord and brain stem, ensuring information from the outside world paints an accurate picture inside the brain.
“All the regeneration in the world isn’t going to make any difference if they don’t reconnect. You’re still not going to get any function,” says Wong, who has worked since 2010 in Frank’s lab, which is trying to develop therapies for spinal cord injuries.
Her findings, which she presented at the annual meeting of the Society for Neuroscience in 2011 and 2012, shed light on the complex processes behind nerve cell growth and regeneration. If those results can be replicated in patients, it could prevent certain types of nerve damage and improve quality of life for some.
Going the Distance
Unlike tissues such as skin and bone, the cells of the central nervous system in an adult are notoriously resistant to healing. Not only does the supply of natural growth stimulants decline as we age, but the body also produces chemicals that discourage nerve cells from regenerating. Worse, the scar tissue that starts to form immediately after a spinal cord injury also contains compounds that hinder nerve cell growth.
Researchers in Frank’s lab have been seeking ways to either stimulate growth or block the mechanisms that inhibit nerve cell growth—or both—since 2005. Wong’s predecessor in the lab, Pamela Harvey, a 2009 graduate of the Sackler School, tested a synthetic version of a nerve cell growth factor, called artemin, on crushed sensory neurons that relay information from the hands, arms and shoulders to the brain.
The damage mimics a common injury called Erb’s palsy, which can occur when a baby’s shoulder gets caught behind the mother’s pelvis during labor and delivery, creating undue strain on nerves in the newborn’s neck. Riders thrown head first off a motorcycle or snowmobile can suffer similar injuries.
“Anytime the shoulder goes one way and the head and neck go the other, that’s when you see these injuries,” Wong says.
In earlier experiments, Harvey and Frank found that treating with artemin did indeed stimulate the sensory nerve fibers to regenerate and grow back into the spinal cord over the course of about six weeks. In her follow-up experiments, Wong showed that artemin could induce those nerve fibers to grow the 3- to 4-centimeter distance from there up to the brainstem, where the brain and the spinal cord meet. That’s a little more than an inch—or roughly 10 times longer than any other researchers have been able to demonstrate with artemin or any other growth factor.
“A lot of other researchers just haven’t seen this length,” notes Wong, who saw the artemin-induced growth occur over a period of three to six months.
That’s important, because while axons only have to grow across microscopic distances in a developing embryo, they would have to bridge much wider gaps—depending on the site of the injury—to heal a neural injury in an adult, Wong says. Nerves that extend from the spine to the foot or toe can reach lengths of about 60 centimeters, she adds.
But Wong’s artemin-treated nerve fibers achieved more than unprecedented growth. They also reestablished connections with correct regions in the brain stem, just as Harvey had seen the nerve cells do in the spinal cord. That is, the axons essentially plugged themselves back in just as they were prior to the injury, and, like an old-fashioned telephone switchboard, they sent the right messages to the right parts of the brain.
That’s crucial because should the sensory nerves that relay pain signals become crossed, for example, it could result in a patient feeling phantom pain or the sensation of pain from something that shouldn’t cause discomfort at all.
“With some other growth-promoting compounds you get regeneration, but you see those axons growing kind of willy-nilly,” says Wong. “You can see where it would be just as detrimental to have things wired incorrectly as it would be to have things not wired at all.”
Just a Start
Artemin isn’t a panacea for spinal cord injuries, Wong and Frank stress. To work its cellular magic, the compound must be administered within a day or two, and the sooner the better. Also, artemin promotes growth only in sensory neurons—and so far, only in rats—which means such growth wouldn’t improve motor function for someone who had been paralyzed by a spinal cord injury, for example.
But if the findings, which Wong presented at the Society for Neuroscience meetings in 2011 and 2012, prove applicable to humans, restoring sensation alone could still improve quality of life, even for those living with paralysis. Giving these people the ability to sense heat, cold and pain could help them avoid other accidental injuries, says Frank.
Wong hopes her work with sensory neurons will help unlock the secrets to promoting regeneration of other, more obstinate types of neurons in the brainstem and spinal cord. While she demonstrated that the sensory nerves plugged themselves back into the spinal cord precisely where they should have, it’s not clear how they did that.
Frank speculates that chemical cues guided the cells back into place. Should researchers be able to identify those cues, they potentially could use that knowledge to spark regeneration of other classes of neurons, such as motor neurons.
“There is hope—not proof—that even in humans these guidance molecules will persist into adulthood,” says Frank. “That means if we are able to get neurons to regenerate in patients, we might be able to make them go back to the right place. These experiments suggest we have some reason to believe it may work.”