Posts tagged nerve cells
Articles and news from the latest research reports.
Scientists identify the switch that says it’s time to sleep
The switch works by regulating the activity of a handful of sleep-promoting nerve cells, or neurons, in the brain. The neurons fire when we’re tired and need sleep, and dampen down when we’re fully rested.
‘When you’re tired, these neurons in the brain shout loud and they send you to sleep,’ says Professor Gero Miesenböck of Oxford University, in whose laboratory the new research was performed.
Although the research was carried out in fruit flies, or Drosophila, the scientists say the sleep mechanism is likely to be relevant to humans.
Dr Jeffrey Donlea, one of the lead authors of the study, explains: ‘There is a similar group of neurons in a region of the human brain. These neurons are also electrically active during sleep and, like the flies’ cells, are the targets of general anaesthetics that put us to sleep. It’s therefore likely that a molecular mechanism similar to the one we have discovered in flies also operates in humans.’
The researchers say that pinpointing the sleep switch might help us identify new targets for novel drugs – potentially to improve treatments for sleep disorders.
But there is much still to find out, and further research could give insight into the big unanswered question of why we need to sleep at all, they say.
‘The big question now is to figure out what internal signal the sleep switch responds to,’ says Dr Diogo Pimentel of Oxford University, the other lead author of the study. ‘What do these sleep-promoting cells monitor while we are awake?
‘If we knew what happens in the brain during waking that requires sleep to reset, we might get closer to solving the mystery of why all animals need to sleep.’
The findings are reported in the journal Neuron. The work of the Centre for Neural Circuits and Behaviour is funded by the Wellcome Trust and the Gatsby Charitable Foundation. This study was also supported by the UK Medical Research Council, the US National Institutes of Health, and the Human Frontier Science Program.
The body uses two mechanisms to regulate sleep. One is the body clock, which attunes humans and animals to the 24 hour cycle of day and night. The other mechanism is the sleep ‘homeostat’: a device in the brain that keeps track of your waking hours and puts you to sleep when you need to reset. This mechanism represents an internal nodding off point that is separate from external factors. When it is turned off or out of use, sleep deficits build up.
What makes us go to sleep at night is probably a combination of the two mechanisms,’ says Professor Miesenböck. ‘The body clock says it’s the right time, and the sleep switch has built up pressure during a long waking day.’
The work in fruit flies allowed the critical part of the sleep switch to be discovered. ‘We discovered mutant flies that couldn’t catch up on their lost sleep after they had been kept awake all night,’ says Dr Jeffrey Donlea.
Flies stop moving when they go to sleep and require more disturbance to get them up. Sleep-deprived flies are prone to nodding off and are cognitively impaired – they have severe learning and memory deficits, much as sleep loss in humans leads to problems.
Professor Miesenböck says: ‘The sleep homeostat is similar to the thermostat in your home. A thermostat measures temperature and switches on the heating if it’s too cold. The sleep homeostat measures how long a fly has been awake and switches on a small group of specialized cells in the brain if necessary. It’s the electrical output of these nerve cells that puts the fly to sleep.’
In the mutant flies, the researchers were able to show a key molecular component of the electrical activity switch is broken and the sleep-inducing neurons are always off, causing insomnia.
(Source: ox.ac.uk)
Switching brain development on, and off
The possibility of nerve cell regeneration is a step closer after neuroscientists identified the genetic signals that play a crucial role in normal development - driving stem cells to produce neurons that are correctly positioned and connected neurons within the brain.
Published in Cerebral Cortex, a study led by Dr Julian Heng of the Australian Regenerative Medicine Institute (ARMI) at Monash University, has identified a transcription factor, RP58, which is an important “off switch” for the process of nerve cell formation.
“Known as RP58, this gene switches off Rnd2 expression to control the proper positioning of neurons within the fetal brain - a crucial process,” Dr Heng said.
Absence of RP58 has been linked to a rare brain developmental disorder known as Terminal 1q deletion syndrome, where patients suffer reduced brain growth, experience epileptic seizures and are intellectually disabled.
Dr Heng’s work, on pre-clinical models, builds on previous research in which another transcription factor, Neurog2, operated as the “on-switch” for the crucial process of early brain development whereby stem cells become neurons.
Neurog2 switches on the expression of another gene, Rnd2, to control how new nerve cells of the developing brain find their appropriate location and go on to establish their proper connections. However, too much Rnd2 can impair the path-finding of new neurons, and so the researchers theorised that an “off-switch” controlled the process.
Dr Heng said that the discovery of RP58 was the proof needed to demonstrate that genes such as Rnd2 must be switched on, and then off in order for brain cells to assemble properly.
“Together with a collaborative study we published with our colleagues earlier in the year, this research demonstrates that loss of RP58 impairs the development of new nerve cells in the embryonic mouse brain, including their path-finding,” Dr Heng said.
“Since the early steps of nerve cell production during brain development are comparable between mice and humans, we believe that RP58 carries out similar functions in the foetal human brain as well. This strengthens the notion that disruptions to this gene can cause brain developmental disease.”
Recently, a study led by researchers at Stanford University in the United States provided evidence showing that RP58 (also known as ZFP238) is crucial for the maturation of new human nerve cells.
Dr Heng believes his discoveries could be used in the context of regenerative medicine.
“Ultimately, the goal of our research is to understand the fundamental properties which control the production and maturation of new nerve cells in the brain. Understanding the function of switches like RP58 is crucial to this process,” Dr Heng said.
"In the future, we will use this knowledge to develop novel cell-based therapies to treat neurodegenerative disorders and brain injury.”
Brain Uses Serotonin To Perpetuate Chronic Pain Signals In Local Nerves
Setting the stage for possible advances in pain treatment, researchers at The Johns Hopkins University and the University of Maryland report they have pinpointed two molecules involved in perpetuating chronic pain in mice. The molecules, they say, also appear to have a role in the phenomenon that causes uninjured areas of the body to be more sensitive to pain when an area nearby has been hurt. A summary of the research will be published on Jan. 23 in the journal Neuron.
Image caption: Nerves in mouse skin that are actively responding to the painful stimulus capsaicin have been genetically engineered to glow green. Hairs appear in yellow. Credit: David Rini
"With the identification of these molecules, we have some additional targets that we can try to block to decrease chronic pain," says Xinzhong Dong, Ph.D., associate professor of neuroscience at the Johns Hopkins University School of Medicine and an early career scientist at Howard Hughes Medical Institute. "We found that persistent pain doesn’t always originate in the brain, as some had believed, which is important information for designing less addictive drugs to fight it."
Chronic pain that persists for weeks, months or years after an underlying injury or condition is resolved afflicts an estimated 20 to 25 percent of the population worldwide and about 116 million people in the U.S., costing Americans a total of $600 billion in medical interventions and lost productivity. It can be caused by everything from nerve injuries and osteoarthritis to cancer and stress.
In their new research, the scientists focused on a system of pain-sensing nerves within the faces of mice, known collectively as the trigeminal nerve. The trigeminal nerve is a large bundle of tens of thousands of nerve cells. Each cell is a long “wire” with a hub at its center; the hubs are grouped together into a larger hub. On one side of this hub, three smaller bundles of wires — V1, V2 and V3 — branch off. Each bundle contains individual pain-sensing wires that split off to cover a specific territory of the face. Signals are sent through the wires to the hubs of the cells and then travel to the spinal cord through a separate set of bundles. From the spinal cord, the signals are relayed to the brain, which interprets them as pain.
When the researchers pinched the V2 branch of the trigeminal nerve for a prolonged period of time, they found that the V2 and V3 territories were extra sensitive to additional pain. This spreading of pain to uninjured areas is typical of those experiencing chronic pain, but it can also be experienced during acute injuries, as when a thumb is hit with a hammer and the whole hand throbs with pain.
To figure out why, the researchers studied pain-sensing nerves in the skin of mouse ears. The smaller branches of the trigeminal V3 reach up into the skin of the lower ear. But an entirely different set of nerves is responsible for the skin of the upper ear. This distinction allowed the researchers to compare the responses of two unrelated groups of nerves that are in close proximity to each other.
To overcome the difficulty of monitoring nerve responses, Dong’s team inserted a gene into the DNA of mice so that the primary sensory nerve cells would glow green when activated. The pain-sensing nerves of the face are a subset of these.
When skin patches were then bathed in a dose of capsaicin — the active ingredient in hot peppers — the pain-sensing nerves lit up in both regions of the ear. But the V3 nerves in the lower ear were much brighter than those of the upper ear. The researchers concluded that pinching the connected-but-separate V2 branch of the trigeminal nerve had somehow sensitized the V3 nerves to “overreact” to the same amount of stimulus. (Watch nerves light up in this video.)
Applying capsaicin again to different areas, the researchers found that more nerve branches coming from a pinched V2 nerve lit up than those coming from an uninjured one. This suggests that nerves that don’t normally respond to pain can modify themselves during prolonged injury, adding to the pain signals being sent to the brain.
Knowing from previous studies that the protein TRPV1 is needed to activate pain-sensing nerve cells, the researchers next looked at its activity in the trigeminal nerve. They showed it was hyperactive in injured V2 nerve branches and in uninjured V3 branches, as well as in the branches that extended beyond the hub of the trigeminal nerve cell and into the spinal cord.
Next, University of Maryland experts in the neurological signaling molecule serotonin, aware that serotonin is involved in chronic pain, investigated its role in the TRPV1 activation study. The team, led by Feng Wei, M.D., Ph.D., blocked the production of serotonin, which is released from the brain stem into the spinal cord, and found that TRPV1 hyperactivity nearly disappeared.
Says Dong: “Chronic pain seems to cause serotonin to be released by the brain into the spinal cord. There, it acts on the trigeminal nerve at large, making TRPV1 hyperactive throughout its branches, even causing some non-pain-sensing nerve cells to start responding to pain. Hyperactive TRPV1 causes the nerves to fire more frequently, sending additional pain signals to the brain.”
Unprecedented structural insights reveal how NMDA receptors can be blocked, to limit neurotoxicity
Structural biologists at Cold Spring Harbor Laboratory (CSHL) and collaborators at Emory University have obtained important scientific results likely to advance efforts to develop new drugs targeting NMDA receptors in the brain.
NMDA (N-methyl D-aspartate) receptors are found on the surface of many nerve cells and are involved in signaling that is essential in basic brain functions including learning and memory formation. Problems with their function have been implicated in depression, schizophrenia, Alzheimer’s and Parkinson’s diseases, as well as brain damage caused by stroke.
Normally, NMDA receptors are activated by glutamate, the most common neurotransmitter of excitatory cell-to-cell messages in the brain.
Overactivation of NMDA receptors is a known cause of nerve-cell toxicity. Thus, drug developers have long sought compounds that can selectively block or antagonize NMDA receptors, while not affecting other types of glutamate receptors in the brain, whose function is essential.
However, a basic question — how those compounds bind and antagonize NMDA receptors — has not been understood at the molecular level.
Over a period of years, CSHL Associate Professor Hiro Furukawa and colleagues have taken a step-by-step approach to learn about the precise shape of various subunits of the complex NMDA receptor protein, and demonstrating the relationship between different versions of the receptor’s shape and its function. (see more here) Since the subunits have different biological roles, they have to be specifically targeted by drug compounds to obtain specific effects.
Furukawa’s team has used a technique called x-ray crystallography to map various domains of the protein while it is bound to different chemical compounds, or antagonists, that downregulate its function. Today in the journal Neuron they publish the first crystal structures of two NMDA receptor subunits (called GluN1 and GluN2A) in complex with four different compounds known to have the capacity to inhibit, or antagonize, NMDA receptor function.
Showing this two-unit ligand binding domain (LBD) in complex with NMDA antagonists — potential drugs — reveals that each antagonist has a distinctive mode of binding the LBD. In essence, the “docking port” is held open, but to a different extent when different antagonists are bound. The study also reveals an element in the antagonist binding site that is only present in GluN2A subunit, but not in the others. This previously hidden information, says Furukawa, is critical: “It indicates different strategies to develop therapeutic compounds – ones that bind to a certain type of NMDA receptors very specifically. Being able to target specific subtypes of the receptor is of enormous interest and has great therapeutic potential in a range of illnesses and injuries affecting the brain.”
Two-way traffic in the spinal cord
The progress a baby makes in the first year of life is amazing: a newborn can only wave its arms and legs about randomly, but not so long after the baby can reach out and pick up a crumb from the carpet. What happens in the nervous system that enables this change from random waving to finely coordinated movement? Scientists from the Max Planck Institute of Neurobiology in Martinsried near Munich, working with colleagues from New York and Philadelphia, have described a new type of nerve cell in mice which provides a valuable insight into this developmental phenomenon. During embryonic development, the projections from these cells grow from the spinal cord towards the brain. They may pave the way for other nerve cells which control voluntary movement and which only grow from the brain into the spinal cord after birth.
When we reach out towards an object with our hand or push our foot into a boot, our movements are coordinated and controlled by the brain. For this to be possible there must be a neural pathway for the brain to transmit instructions, for example to the foot; and also in the reverse direction, for stimuli from the surroundings of the foot to be passed back to the brain. Such neural pathways are formed when the projections (axons) grow out from nerve cells during development. Depending on the organism and the body part to be connected, the axons can grow to many centimetres in length. Rüdiger Klein and his team at the Max Planck Institute of Neurobiology investigate how the axons navigate through the body, and which molecules play a part in their pathfinding. In particular, the scientists have been focusing on the signalling molecules known as ephrins and their binding partners, the Eph receptors. Ephrins and Eph receptors are located on the surface of nerve cells, among other places, and help the growing cells find their way and locate their partner cells.
Some time ago, Rüdiger Klein and his team discovered in the mouse that ephrins and Eph receptors play a key role in the development of the neural networks which control our movements. The neurobiologists have been able to demonstrate that the ephrin/Eph system guides nerve cells which, after birth, send their axons from the brain into the spinal cord and direct voluntary movement in the arms and legs. In their investigations into axons which run in the opposite direction, namely from the spinal cord into the brain, the researchers came across a new cell type which also contained Eph receptors. “Just where the ‘descending’ axons were growing, we found the ‘ascending’ axons running in parallel”, says Rüdiger Klein. “That obviously raised the question in our minds as to how this parallel growth is controlled during development.”
Subsequent research by the neurobiologists uncovered something surprising: in contrast with the known cells, the ascending axons of the new cell type did not grow only after birth, but instead already during embryonic development. Moreover, their growth was guided by the same ephrin/Eph signalling system as that involved in the growth of the descending axons. “It would seem that during embryonic development the ascending axons would ‘pre-drill’ a channel for the descending axons which do not grow out until after birth”, explains Rüdiger Klein.
Further investigations into the new, ascending nerve cells have made it clear that they obtain their input from specialised, touch-sensitive cells. A new feedback system could thus be involved here: voluntary movements are refined by signals from touch-sensitive cells, so adapting the intended movement to the environment and your foot slips into the boot. “What we found surprising is the fact that one and the same guidance system directs both the descending and the ascending axons”, says Klein. “This is a wonderful example of how a highly complex nervous system can be built up by making flexible use of individual molecules, and thus a small number of genes.” The next job for the scientists is to find out whether the suspected feedback system actually exists, i.e. whether the ascending and descending cells are connected via synapses. Their aim is to unravel step by step the developmental processes which enable the brain to coordinate sequences of movements.
Picturing pain could help unlock its mysteries and lead to better treatments
Understanding the science behind pain, from a simple “ouch” to the chronic and excruciating, has been an elusive goal for centuries. But now, researchers are reporting a promising step toward studying pain in action. In a study published in the Journal of the American Chemical Society, scientists describe the development of a new technique, which they tested in rats, that could result in better ways to relieve pain and monitor healing.
Sandip Biswal, Frederick T. Chin, Justin Du Bois and colleagues note that current ways to diagnose pain basically involve asking the patient if something hurts. These subjective approaches are fraught with bias and can lead doctors in the wrong direction if a patient doesn’t want to talk about the pain or can’t communicate well. It can also be difficult to tell how well a treatment is really working. No existing method can measure pain intensity objectively or help physicians pinpoint the exact location of the pain. Past research has shown an association between pain and a certain kind of protein, called a sodium channel, that helps nerve cells transmit pain and other sensations to the brain. Certain forms of this channel are overproduced at the site of an injury, so the team set out to develop an imaging method to visualize high concentrations of this protein.
They turned to a small molecule called saxitoxin, produced naturally by certain types of microscopic marine creatures, and attached a signal to it so they could trace it by PET imaging. PET scanners are used in hospitals to diagnose diseases and injuries. When the researchers injected the molecule into rats, often a stand-in for humans in lab tests, they saw that the molecule accumulated where the rats had nerve damage. The rats didn’t show signs of toxic side effects. The work is one of the first attempts to mark these sodium channels in a living animal, they say.
Attractants prevent nerve cell migration
A vision is to implant nerve precursor cells in the diseased brains of patients with Parkinson’s and Huntington’s diseases, whereby these cells are to assume the function of the cells that have died off. However, the implanted nerve cells frequently do not migrate as hoped, rather they hardly move from the site. Scientists at the Institute for Reconstructive Neurobiology at Bonn University have now discovered an important cause of this: Attractants secreted by the precursor cells prevent the maturing nerve cells from migrating into the brain. The results are presented in the journal “Nature Neuroscience.”
One approach for treating patients with Parkinson’s or Huntington’s disease is to replace defective brain cells with fresh cells. To do this, immature precursor cells from neurons are implanted into the diseased brains; these cells are to then mature on-site and take over the function of the defective cells. “However, it has been shown again and again that the nerve cells generated by the transplant barely migrate into the brain but remain largely confined to the implant site,” says Prof. Dr. Oliver Brüstle, Director of the Institute for Reconstructive Neurobiology at Bonn University. Scientists have believed for a long time that this effect is associated with the fact that in the mature brain, there are unfavorable conditions for the uptake of additional nerve cells.
Immature and more mature nerve cells attract each other like magnets
The researchers from the Institute for Reconstructive Neurobiology of Bonn University have now discovered a fully unexpected mechanism to which the deficient migratory behavior of the graft-derived neurons can be attributed. The implanted cells mature at different rates and thus there is a mixture of the two stages. “Like magnets, the precursor cells which are still largely immature attract the nerve cells which have already matured further, which is why there is a sort of agglomeration,” says lead author Dr. Julia Ladewig, who was recently awarded a research prize of 1.25 million Euro by the North Rhine-Westphalian Stem Cell Network, which is supported by State Ministry of Science and Research.
The cause of the attractive force which has remained hidden to date involves chemical attractants which are secreted by the precursor cells. “In this way, the nerve precursor cells prevent the mature brain cells from penetrating further into the tissue,” says Dr. Philipp Koch, who performed the primary work for the study as an additional lead author, together with Dr. Ladewig.
The scientists had initially observed that, the more precursor cells contained in the transplant, the worse the migration of nerve cells is. In a second step, the researchers from the Institute for Reconstructive Neurobiology at Bonn University were able to decode and inactivate the attractants responsible for the agglomeration of mature and immature neurons. When the scientists deactivated the receptor tyrosine kinase ligands FGF2 and VEGF with inhibitors, mature nerve cells migrated better into the animal brains and dispersed over much larger areas.
Promising universal approach for transplants
“This is a promising new approach to solve an old problem in neurotransplantation,” Prof. Brüstle summarizes. Through the inhibition of attractants, the migration of implanted nerve precursor cells into the brain can be significantly improved. As the researchers have shown in various models with precursor cells from animals and humans, the mechanism is a fundamental principle which also functions across species. “However, more research is still needed to transfer the principle into clinical application,” says Prof. Brüstle.
(Source: www3.uni-bonn.de)
Drug Shows Early Promise in Treating Liver Failure-Related Seizures
A study out today in the journal Nature Medicine suggests a potential new treatment for the seizures that often plague children with genetic metabolic disorders and individuals undergoing liver failure. The discovery hinges on a new understanding of the complex molecular chain reaction that occurs when the brain is exposed to too much ammonia.
The study shows that elevated levels of ammonia in the blood overwhelm the brain’s defenses, ultimately causing nerve cells to become overexcited. The researchers have also discovered that bumetanide – a diuretic drug used to treat high blood pressure – can restore normal electrical activity in the brains of mice with the condition and prevent seizures.
“Ammonia is a ubiquitous waste product of regular protein metabolism, but it can accumulate in toxic levels in individuals with metabolic disorders,” said Maiken Nedergaard, M.D., D.M.Sc., co-director of the University of Rochester Medical Center (URMC) Center for Translational Neuromedicine and lead author of the article. “It appears that the key to preventing the debilitating neurological effects of ammonia toxicity is to correct a molecular malfunction which causes nerve cells in the brain to become chemically unbalanced.”
In healthy people, ammonia is processed in the liver, converted to urea, and expelled from the body in urine. Because it is a gas, ammonia can slip through the blood-brain-barrier and make its way into brain tissue. Under normal circumstances, the brain’s housekeeping cells – called astrocytes – sweep up this unwanted ammonia and convert it into a compound called glutamine which can be more easily expelled from the brain.
However, individuals with certain genetic metabolic disorders and people with impaired liver function because of chronic hepatitis, alcoholism, acetaminophen overdose, and other toxic liver conditions cannot remove ammonia from their bodies quickly enough. The result is a larger than normal concentration of ammonia in the blood, a condition called hyperammonemia.
When too much ammonia makes its way into the central nervous system, it can lead to tremors, seizures and, in extreme cases, can cause comas and even lead to death. In children with metabolic disorders the frequent seizures can lead to long-term neurological impairment.
While ammonia has long been assumed to be the culprit behind the neurological problems associated with inherited metabolic disorders and liver failure, the precise mechanisms by which it triggers seizures and comas have not been fully understood. The new study reveals that ammonia causes a chain of events that alters the chemistry and electrical activity of the brain’s nerve cells, causing them to fire in uncontrolled bursts.
One of the keys to unraveling the effects of ammonia on the brain has been new imagining technologies such as two-photon microscopy which allow researchers to watch this phenomenon in real time in the living brains of mice. As suspected, they observed that when high levels of ammonia enter the brain, astrocytes become quickly overwhelmed and cannot remove it fast enough.
The abundant ammonia in the brain mimics the function of potassium, an important player in neurotransmission, and tricks neurons into becoming depolarized. This makes it more likely that electrical activity in the brain will exceed the threshold necessary to trigger seizures.
Furthermore, the researchers observed that one of the neuron’s key molecular gatekeepers – a transporter known as NKCC1 – was also fooled into thinking that the ammonia was potassium. As a result, it went into overdrive, loading neurons with too much chloride. This in turn prevents the cells from stabilizing itself after spikes in activity, keeping the cells in a heightened level of electrical “excitability.”
The team found that the drug bumetanide, a known NKCC1 inhibitor, blocked this process and prevented the cells from overloading with chloride. By knocking down this “secondary” cellular effect of ammonia, the researchers were able to control the seizures in the mice and prolong their survival.
“The neurologic impact of hyperammonemia is a tremendous clinical problem without an effective medical solution,” said Nedergaard. “The fact that bumetanide is already approved for use gives us a tremendous head start in terms of developing a potential treatment for this condition. This study provides a framework to further explore the therapeutic potential of this and other NKCC1 inhibitors.”
(Source: urmc.rochester.edu)
Research gives new insight into how antidepressants work in the brain
Research from Oregon Health & Science University’s Vollum Institute, published in the current issue of Nature (1, 2), is giving scientists a never-before-seen view of how nerve cells communicate with each other. That new view can give scientists a better understanding of how antidepressants work in the human brain — and could lead to the development of better antidepressants with few or no side effects.
The article in today’s edition of Nature came from the lab of Eric Gouaux, Ph.D., a senior scientist at OHSU’s Vollum Institute and a Howard Hughes Medical Institute Investigator. The article describes research that gives a better view of the structural biology of a protein that controls communication between nerve cells. The view is obtained through special structural and biochemical methods Gouaux uses to investigate these neural proteins.
The Nature article focuses on the structure of the dopamine transporter, which helps regulate dopamine levels in the brain. Dopamine is an essential neurotransmitter for the human body’s central nervous system; abnormal levels of dopamine are present in a range of neurological disorders, including Parkinson’s disease, drug addiction, depression and schizophrenia. Along with dopamine, the neurotransmitters noradrenaline and serotonin are transported by related transporters, which can be studied with greater accuracy based on the dopamine transporter structure.
The Gouaux lab’s more detailed view of the dopamine transporter structure better reveals how antidepressants act on the transporters and thus do their work.
The more detailed view could help scientists and pharmaceutical companies develop drugs that do a much better job of targeting what they’re trying to target — and not create side effects caused by a broader blast at the brain proteins.
"By learning as much as possible about the structure of the transporter and its complexes with antidepressants, we have laid the foundation for the design of new molecules with better therapeutic profiles and, hopefully, with fewer deleterious side effects," said Gouaux.
Gouaux’s latest dopamine transporter research is also important because it was done using the molecule from fruit flies, a dopamine transporter that is much more similar to those in humans than the bacteria models that previous studies had used.
The dopamine transporter article was one of two articles Gouaux had published in today’s edition of Nature. The other article also dealt with a modified amino acid transporter that mimics the mammalian neurotransmitter transporter proteins targeted by antidepressants. It gives new insights into the pharmacology of four different classes of widely used antidepressants that act on certain transporter proteins, including transporters for dopamine, serotonin and noradrenaline. The second paper in part was validated by findings of the first paper — in how an antidepressant bound itself to a specific transporter.
"What we ended up finding with this research was complementary and mutually reinforcing with the other work — so that was really important," Gouaux said. "And it told us a great deal about how these transporters work and how they interact with the antidepressant molecules."
(Source: ohsu.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.”