Posts tagged nerve cells
Articles and news from the latest research reports.
Why Our Backs Can’t Read Braille: Scientists map sensory nerves in mouse skin
Johns Hopkins scientists have created stunning images of the branching patterns of individual sensory nerve cells. Their report, published online in the journal eLife on Dec. 18, details the arrangement of these branches in skin from the backs of mice. The branching patterns define ten distinct groups that, the researchers say, likely correspond to differences in what the nerves do and could hold clues for pain management and other areas of neurological study.
Each type of nerve cell that the team studied was connected at one end to the spinal cord through a thin, wire-like projection called an axon. On the other side of the cell’s “body” was another axon that led to the skin. The axons branched in specific patterns, depending on the cell type, to reach their targets within the skin. “The complexity and precision of these branching patterns is breath-taking,” says Jeremy Nathans, M.D., Ph.D., a Howard Hughes researcher and professor of molecular biology and genetics at the Institute for Basic Biomedical Sciences at the Johns Hopkins School of Medicine.
Brake on nerve cell activity after seizures discovered
Given that epilepsy impacts more than 2 million Americans, there is a pressing need for new therapies to prevent this disabling neurological disorder. New findings from the neuroscience laboratory of Mark S. Shapiro, Ph.D., at The University of Texas Health Science Center at San Antonio, published Dec. 20 in the high-impact scientific journal, Neuron, may provide hope.
“A large fraction of epilepsy sufferers cannot take drugs for their disorder or the existing drugs do not manage it,” said Dr. Shapiro, professor of physiology in the School of Medicine. “As a result, many opt for surgery to remove the hippocampus, a part of the brain where memories are stored but also where seizures are often localized. The heart-wrenching choice is between their memories and the epilepsy.”
Genes go into action
A major finding of the study is that selected genes get switched on during and after a seizure, sending swarms of signals to reduce uncontrolled firing of nerve cells. A medication that amplifies this response after a person’s initial seizure could thus prevent recurrent seizures and the onset of devastating epilepsy.
Uncontrolled electrical activity by specialized electricity-producing proteins in the brain called “ion channels” triggers epileptic seizures. One in 10 people have a lifetime risk of suffering a seizure, which can occur for a variety of reasons including traumatic brain injury, stroke or drug overdoses.
A powerful brake
Although not all seizures lead to epilepsy, some trigger changes in the brain that heighten the risk of the disorder. Dr. Shapiro’s research sheds light on why most isolated seizures do not lead to full-blown epilepsy, whereas others do. An ion channel called the “M-channel” acts as a powerful “brake” on hyper-excitability in the brain. Another organizational protein, called AKAP79, acting much like an air-traffic controller, calls in more M channels as part of neuroprotective response machinery.
Pharmacological therapy to enhance M-channel gene expression or AKAP79 function “could jump-start this neuroprotective mechanism to prevent a seizure from turning into epilepsy,” Dr. Shapiro said. “Administering it right after a traumatic brain injury could be very effective.”
It was not known that electrical activity could regulate M-channel genes, Dr. Shapiro said. Nor was it known that the AKAP79 organizer protein, which coordinates many aspects of M-channel function, could turn on their genes in a person’s DNA. By increasing M-channel expression in the brain, uncontrolled electrical firing of nerve cells in the brain is sharply controlled.
Mouse experiments
The Shapiro lab team records electrical currents and performs imaging in living nerve cells to measure M-channel activity. This study included inducing seizures in healthy mice. After a seizure, gene expression of M-channels in the hippocampus increased more than 10-fold within 24 hours, Dr. Shapiro said. This protective effect was completely absent in mice lacking the mouse version of the AKAP79 gene.
“Because excessive firing of nerve cells is also involved in chronic pains, such as migraines, mood disorders and hypertension, increasing M-channel signals to reduce nerve-cell firing could also likely be effective in treating those conditions,” Dr. Shapiro said.
Working with mice, Johns Hopkins scientists have discovered that a particular protein helps nerve cells extend themselves along the spinal cord during mammalian development. Their results shed light on the subset of muscular dystrophies that result from mutations in the gene that holds the code for the protein, called dystroglycan, and also show how the nerve and muscle failings of the degenerative diseases are related.
As mammals like mice and humans develop, nerve cells in the brain and spinal cord must form connections with themselves and with muscles to assure proper control of movement. Nerve cells sometimes extend the whole length of the spinal cord to connect sensory nerves bearing information, for example, from the legs to the brain. To do so, nerve cells anchor their “headquarters,” or cell bodies, in one location, and then extend a long, thin projection all the way to their target locations. These projections, or axons, can be 10,000 times longer than the cell body.
In a report published in the journal Neuron on Dec. 6, the authors suggest that, during fetal development, axons extend themselves along specific pathways created by dystroglycan.
Hypertension traced to source in brain
When the heart works too hard, the brain may be to blame, says new Cornell research that is changing how scientists look at high blood pressure (hypertension). The study, published in the Journal of Clinical Investigation in November, traces hypertension to a newfound cellular source in the brain and shows that treatments targeting this area can reverse the disease.
In what peer reviewers are calling “a new paradigm” for tackling the worldwide hypertension epidemic, this insight into its roots could give hope to the billion people it currently afflicts. Hypertension occurs when the force of blood against vessel walls grows strong enough to potentially cause such problems as heart attack, stroke and heart or kidney disease. The heart pumps harder, and often the hormone angiotensin-II (AngII) gets the pressure cooking by triggering nerve cells that constrict blood vessels.
"We knew the central nervous system orchestrates this process, and now we’ve found the conductor," said Robin Davisson, the Andrew Dickson White Professor of Molecular Physiology with a joint appointment at Cornell’s College of Veterinary Medicine and Weill Cornell Medical College.
Two-thirds of Americans have hypertension, which is the leading cause of North America’s No. 1 killer: heart disease, according to the Centers for Disease Control and Prevention.
Davisson’s lab traced neurochemical signals back to endoplasmic reticulum (ER), the protein factory and stress-management control center in every cell. If something goes wrong in a cell, the ER activates processes to adapt to the stress. Long-term ER stress can cause chronic disease, and several stressors that ER responds to have been connected to hypertension. Davisson’s lab found that high levels of AngII put stress on the ER, which responds by triggering the cascade of neural and hormonal signals that start hypertension.
But not just any cell’s ER can conduct this complex orchestra. Those that can trigger the signal cascade are clustered near the bottom of the brain in a gatelike structure called the subfornical organ (SFO). Unlike most of the brain, the SFO hangs outside a protective barrier that keeps most circulating particles from entering the brain. The SFO can interact with particles like AngII that are too big to cross through and can also communicate with the brain’s inner chambers.
This is good news for developing therapies—because the SFO sits outside the barrier, it can be reached through such normal treatment routes as pills or injections rather than riskier brain procedures. Davisson’s lab showed that treatments that inhibit ER stress in the SFO can completely stop AngII-based hypertension and lower blood pressure to normal levels.
"Our work provides the first evidence that higher levels of AngII cause ER stress in the SFO, that this causes hypertension, and that we can do something about it," said Davisson. "This finding may also suggest a role for ER stress in hypertension types that don’t involve AngII, like some spontaneous or genetic forms."
Inspired by the paradigm shift that this study has sparked, the editors of the Journal of Clinical Investigation published a commentary concluding that this discovery “opens new avenues for investigation and may lead to new therapeutic approaches for this disease.”
Countering brain chemical could prevent suicides
Researchers have found the first proof that a chemical in the brain called glutamate is linked to suicidal behavior, offering new hope for efforts to prevent people from taking their own lives.
Writing in the journal Neuropsychopharmacology, Michigan State University’s Lena Brundin and an international team of co-investigators present the first evidence that glutamate is more active in the brains of people who attempt suicide. Glutamate is an amino acid that sends signals between nerve cells and has long been a suspect in the search for chemical causes of depression.
“The findings are important because they show a mechanism of disease in patients,” said Brundin, associate professor of translational science and molecular medicine in MSU’s College of Human Medicine. “There’s been a lot of focus on another neurotransmitter called serotonin for about 40 years now. The conclusion from our paper is that we need to turn some of that focus to glutamate.”
Brundin and colleagues examined glutamate activity by measuring quinolinic acid – which flips a chemical switch that makes glutamate send more signals to nearby cells – in the spinal fluid of 100 patients in Sweden. About two-thirds of the participants were admitted to a hospital after attempting suicide and the rest were healthy.
They found that suicide attempters had more than twice as much quinolinic acid in their spinal fluid as the healthy people, which indicated increased glutamate signaling between nerve cells. Those who reported the strongest desire to kill themselves also had the highest levels of the acid.
The results also showed decreased quinolinic acid levels among a subset of patients who came back six months later, when their suicidal behavior had ended.
The findings explain why earlier research has pointed to inflammation in the brain as a risk factor for suicide. The body produces quinolinic acid as part of the immune response that creates inflammation.
Brundin said anti-glutamate drugs are still in development, but could soon offer a promising tool for preventing suicide. In fact, recent clinical studies have shown the anesthetic ketamine – which inhibits glutamate signaling – to be extremely effective in fighting depression, though its side effects prevent it from being used widely today.
In the meantime, Brundin said physicians should be aware of inflammation as a likely trigger for suicidal behavior. She is partnering with doctors in Grand Rapids, Mich., to design clinical trials using anti-inflammatory drugs.
“In the future, it’s likely that blood samples from suicidal and depressive patients will be screened for inflammation,” Brundin said. “It is important that primary health care physicians and psychiatrists work closely together on this.”
Does the Brain Become Unglued in Autism?
A new study published in Biological Psychiatry suggests that autism is associated with reductions in the level of cellular adhesion molecules in the blood, where they play a role in immune function.
Cell adhesion molecules are the glue that binds cells together in the body. Deficits in adhesion molecules would be expected to compromise processes at the interfaces between cells, influencing tissue integrity and cell-to-cell signaling. In the brain, deficits in adhesion molecules could compromise brain development and communication between nerve cells.
Over the years, deficits in neural cell adhesion molecules have been implicated in schizophrenia and other psychiatric disorders. One adhesion molecule, neurexin, is strongly implicated in the heritable risk for autism.
Cell adhesion molecules also play a crucial role in regulating immune cell access to the central nervous system. Prior research provided evidence of immune system dysfunction in individuals diagnosed with autism spectrum disorder (ASD). This led scientists from the University of California, Davis to examine whether adhesion molecules are altered in children with ASD.
"For the first time, we show that levels of soluble sPECAM-1 and sP-selectin, two molecules that mediate leukocyte migration, are significantly decreased in young children with ASD compared with typically developing controls of the same age," explained the authors. "This finding is consistent with previous reports of decreased levels of both sPECAM-1 and sP-selectin in adults with high-functioning autism."
They also found that repetitive behavior scores and sPECAM-1 levels were associated in children with ASD. Repetitive, stereotyped behaviors are a typical feature of ASD and these data suggest a potential relationship between molecule levels and the severity of repetitive behaviors.
Finally, they also discovered that head circumference was associated with increased sPECAM-1 levels in the typically developing children, but not in the children with ASD. This indicates that perhaps sPECAM-1 plays a role in normal brain growth, as larger head circumference is a known feature of individuals with autism.
(Image courtesy of Cord Blood Registry)
How Different Nerve Cells Develop in the Eye
Neurobiologists from Heidelberg University’s Centre for Organismal Studies (COS) have gained new insights into how different types of nerve cells are formed in the developing animal. Through specialised microscopes, they were able to follow the development of the neural retina in the eye of living zebrafish embryos. Using high-resolution three-dimensional time-lapse images the researchers simultaneously observed the division of retinal nerve cells and changes in gene expression. This enabled them to gain insights into the way in which the two processes are linked during eye development and how the number and proportion of different cell types are regulated.
A central question in developmental and regenerative neurobiology concerns the growth processes in animal organisms: How does a growing animal control the generation of the right number of each type and subtype of nerve cell in the brain and what is the relationship between these cells? The retina consists of many different kinds of nerve cells, which are well characterised and common to all vertebrates. Thus, the retina is a particularly good model for studying neuronal development. The researchers studied such retinal developmental processes in living organisms using zebrafish embryos, which are completely transparent and grow rapidly outside their mother.
All retinal cells, which are either excitatory or inhibitory, arise from a relatively small number of apparently homogeneous progenitor cells. These progenitors are able to generate all the different retinal cell types. “It is a challenge to understand how each progenitor cell contributes to the correct number and subtype of nerve cells that compose the final retinal network. Our work contributes to the understanding of how different genes orchestrate neuronal diversity along a progenitor cell lineage, that is the number of cell divisions and types of neurons generated”, says Heidelberg researcher Dr. Lucia Poggi.
To tackle this challenge, Dr. Poggi’s team used different lines of transgenic zebrafish, in which fluorescent reporter proteins highlight the expression of different genes in dividing cells. Working in close cooperation with Dr. Patricia Jusuf of the Australian Regenerative Medicine Institute at Monash University, the researchers found that some particular kinds of excitatory and inhibitory nerve cells tend to be lineally related, i.e. they derive from a common progenitor cell. For the first time, 4D recordings permitted an in vivo analysis of how the generation of particular inhibitory cells is regulated through coordination of cell division mode and gene expression within individual retinal progenitors of excitatory nerve cells.
This study has established a model of how cell lineage influences neuronal subtype specification and neuronal circuitry formation in the native environment of the vertebrate brain. The results were published in the Journal of Neuroscience.
(Source: uni-heidelberg.de)
In an article published online this week in the journal Nature, the UCSF team has identified the exact subset of nerve cells responsible for communicating gentle touch to the brains of Drosophila larvae—called class III neurons. They also uncovered a particular protein called NOMPC, which is found abundantly at the spiky ends of the nerves and appears to be critical for sensing gentle touch in flies.Without this key molecule, the team discovered, flies are insensitive to any amount of eyelash stroking, and if NOMPC is inserted into neurons that cannot sense gentle touch, those neurons gain the ability to do so.
“NOMPC is sufficient to confer sensitivity to gentle touch,” said Yuh Nung Jan, PhD, a professor of physiology, biochemistry and biophysics and a Howard Hughes Medical Institute investigator at UCSF. Jan led the study with his wife Lily Jan, PhD, who is also a UCSF professor and a Howard Hughes Medical Institute investigator.
The work sheds light on a poorly understood yet fundamental sense through which humans experience the world and derive pleasure and comfort.
Why is Touch Still Such a Mystery?
Scientists generally feel that, like those other senses, the sense of touch is governed by peripheral nerve fibers stretching from the spine to nerve endings all over the body. Special molecules in these nerve endings detect the mechanical movement of the skin surrounding them when it is touched, and they respond by opening and allowing ions to rush in. The nerve cell registers this response, and if the signal is strong enough, it will fire, signaling the gentle touch to the brain.
What has been missing from the picture, however, are the details of this process. The new finding is a milestone in that it defines the exact nerves and uncovers the identity of the NOMPC channel, one of the major molecular players involved—at least in flies.
Jan and his colleagues made this discovery through an unusual route. They were looking at the basic physiology of the developing fruit fly, examining how class III neurons develop in larvae. They noticed that when these cells developed in the insects, their nerve endings would always become branches into spiky “dendrites.”
Wanting to know what these neurons are responsible for, they examined them closely and found the protein NOMPC was abundant at the spiky ends. They then examined a fly genetically engineered to have a non-functioning form of NOMPC and showed that it was insensitive to gentle touch. They also showed that they could induce touch sensitivity in neurons that do not normally respond to gentle touch by inserting copies of the NOMPC protein into them.
(Image: Dietrich Meyer)
Scientists Identify Two Genes Essential for Breathing
A team of researchers at the New York University’s Langone Medical Center has discovered that two genes, called Hoxa5 and Hoxc5, play a critical role in establishing the neuronal circuits required for breathing. The discovery could help advance treatments for spinal cord injuries and neurodegenerative diseases.
The three-year study published in the journal Nature Neuroscience identifies a molecular code that distinguishes a group of muscle-controlling nerve cells collectively known as the phrenic motor column (PMC).
“These cells lie about halfway up the back of the neck, just above the fourth cervical vertebra, and are probably the most important motor neurons in your body,” explained senior author Prof Jeremy Dasen of the Howard Hughes Medical Institute.
Harming the part of the spinal cord where the PMC resides can instantly shut down breathing. But relatively little is known about what distinguishes PMC neurons from neighboring neurons, and how PMC neurons develop and wire themselves to the diaphragm in the fetus. The PMC cells relay a constant flow of electrochemical signals down their bundled axons and onto the diaphragm muscles, allowing the lungs to expand and relax in the natural rhythm of breathing.
“We now have a set of molecular markers that distinguish those cells from other populations of motor neurons, so that we can study them in detail and look for ways to selectively enhance their survival,” Prof Dasen said.
A new promising approach in the therapy of pain
The treatment of inflammatory pain can be improved by endogenous opioid peptides acting directly in injured tissue. Scientists at the Charité – Universitätsmedizin Berlin and the Université Paris Descartes showed that pain can be successfully treated by targeting immune and nerve cells outside the brain or spinal cord. The study is published in the current issue of The FASEB Journal.
Inflammatory pain is the most common form of painful diseases. Examples are acute pain after surgery, and chronic pain as in the case of rheumatoid arthritis. However, the treatment of inflammatory pain is often difficult because it rarely responds to conventional therapies. Furthermore, opiates, such as morphine, produce serious side effects including addiction mediated in the brain, while drugs, such as ibuprofen, may cause stomach ulcers, internal bleeding, and cardiovascular complications. The activation of opiate receptors in nerve cells outside the brain or spinal cord can alleviate pain without serious side effects. This can be achieved by synthetic opiates or endogenous opioid peptides, e.g. enkephalins and endorphins. However, these peptides are rapidly inactivated by two major enzymes, aminopeptidase N (APN) and neutral endopeptidase (NEP), which limit their analgesic effects.
The aim of the research group of Prof. Halina Machelska-Stein from the Klinik für Anästhesiologie at Campus Benjamin Franklin was to prevent the breakdown of endogenous opioid peptides directly in the inflamed tissue. In an animal model, the group has shown that inflammatory pain can be alleviated if the two enzymes (APN and NEP), responsible for the inactivation of the opioid peptides, were blocked by the selective inhibitors. In preparations from immune or nerve cells, which express these enzymes, the opioid peptides were quickly broken down. This was prevented by the enzyme inhibitors, bestatin, thiorpan and P8B. As a result, the sensation of pain was either markedly reduced or completely disappeared. “Targeting of endogenous opioid peptides directly in injured tissues might be a promising strategy to treat inflammatory pain without serious side effects,” states Prof. Machelska-Stein, explaining the results of the investigation. Furthermore, blocking pain at the site of its origin may prevent excitatory mechanisms in the nervous system, which lead to the development of chronic pain.
(Source: charite.de)