Posts tagged neuroscience
Articles and news from the latest research reports.
First Non-Study Site to Implant Device for Stopping Uncontrolled Seizures
NYU Langone Medical Center last month became the first hospital outside of a clinical trial site to implant a pacemaker-like device in the brain that may be a game-changer for patients with epilepsy.
The device, called the RNS System, was implanted April 17, 2014 in a patient with seizures that previously could not be controlled with medication, or intractable epilepsy, by Werner Doyle, MD, an associate professor in the Department of Neurosurgery at NYU Langone. The patient has recovered completely from the surgery.
The first-of-its-kind device is similar to an implantable cardioverter-defibrillator (ICD), which delivers electrical pulses to the heart to prompt it to beat a normal rhythm and provides a new alternative treatment to vagus nerve stimulation and surgical removal of the focus site – parts in the brain where the seizures originate — for people with intractable epilepsy.
Prior to last month’s surgery, the only implants of the seizure-reducing medical device took place at U.S. medical centers that had previously researched the device’s effectiveness and safety, making NYU Langone the first non-study hospital in the U.S. and New York metropolitan area to offer the RNS System to patients.
"Medically intractable epilepsy is often a debilitating disorder that puts sufferers at risk from sudden loss of consciousness and uncontrolled movements. It stigmatizes patients and restricts their independence," said Dr. Doyle. "Epilepsy surgery is an important therapeutic option for patients, which can significantly or completely control their seizures and return their lives to normal. The RNS device improves our ability to control seizures with surgery and now offers patients who may not have been surgical candidates in the past a surgical option."
According to the Centers for Disease Control and Prevention, about 2.3 million Americans suffer from epilepsy, with about one in 26 people expected to be diagnosed in their lifetimes. Approximately one-third of patients do not respond to medications and face major challenges with daily living. Uncontrolled seizures may interfere with normal activities such as working, going to school and driving. Patients also face increased risk for anxiety, depression, injury, brain damage, and in rare cases, death.
The RNS System, manufactured by NeuroPace Inc. of Mountain View, Calif., is a responsive stimulation device that’s implanted in the skull along with brain electrodes to detect abnormal electrical activity in the brain associated with seizures. After two or more weeks of recording the activity, doctors program the device to specifically respond to these abnormal signals by delivering imperceptible electrical pulses to the brain that normalize the activity. The device essentially “reboots” the portion of the brain where the seizure is originating, thereby effectively interrupting the abnormal electrical activity before it spreads or causes its unwanted effects.
The RNS System received pre-market approval from the Food and Drug Administration in November 2013 to treat patients’ seizures that have not been controlled by two or more antiepileptic medications.
In clinical trials performed at medical centers across the U.S., including at Saint Barnabas Medical Center in New Jersey by Dr. Doyle and Orrin Devinsky, MD, director of the Comprehensive Epilepsy Center at NYU Langone, 55 percent of patients experienced a 50 percent or greater reduction in seizures two years post implantation.
"The RNS System represents one of the most important and innovative therapies to treat people with epilepsy," says Dr. Devinsky. "This new surgical therapy uses information to target and shut down points in the brain where seizures start without removing tissue, providing a novel option for patients with uncontrolled seizures."
For more information:
Neurology, Morrell et al, 2011.
Researchers identify pattern of cognitive risks in some children with cochlear implants
Children with profound deafness who receive a cochlear implant had as much as five times the risk of having delays in areas of working memory, controlled attention, planning and conceptual learning as children with normal hearing, according to Indiana University research published May 22 in the Journal of the American Medical Association Otolaryngology—Head and Neck Surgery.
The authors evaluated 73 children implanted before age 7 and 78 children with normal hearing to determine the risk of deficits in executive functioning behaviors in everyday life.
Executive functioning, a set of mental processes involved in regulating and directing thinking and behavior, is important for focusing and attaining goals in daily life. All children in the study had average to above-average IQ scores. The results, reported in “Neurocognitive Risk in Children With Cochlear Implants,” are the first from a large-scale study to compare real-world executive functioning behavior in children with cochlear implants and those with normal hearing.
A cochlear implant device consists of an external component that processes sound into electrical signals that are sent to an internal receiver and electrodes that stimulate the auditory nerve. Although the device restores the ability to perceive many sounds to children who are born deaf, some details and nuances of hearing are lost in the process.
First author William Kronenberger, Ph.D., professor of clinical psychology in psychiatry at the IU School of Medicine and a specialist in neurocognitive and executive function testing, said that delays in executive functioning have been commonly reported by parents and others who work with children with cochlear implants. Based on these observations, his group sought to evaluate whether elevated risks of delays in executive functioning in children with cochlear implants exist, and what components of executive functioning were affected.
"In this study, about one-third to one-half of children with cochlear implants were found to be at-risk for delays in areas of parent-rated executive functioning such as concept formation, memory, controlled attention and planning. This rate was 2 to 5 times greater than that seen in normal-hearing children," reported Dr. Kronenberger, who also is co-chief of the ADHD-Disruptive Behavior Disorders Clinic and directs the psychology testing clinic at Riley Hospital for Children at IU Health.
"This is really innovative work," said co-author David B. Pisoni, Ph.D., director of the Speech Research Laboratory in the IU Department of Psychological and Brain Sciences. "Almost no one has looked at these issues in these children. Most audiologists, neuro-otologists, surgeons and speech-language pathologists — the people who work in this field — focus on the hearing deficit as a medical condition and have been less focused on the important discoveries in developmental science and cognitive neuroscience." Dr. Pisoni also is a Chancellors’ Professor of Psychological and Brain Sciences at IU Bloomington.
Richard Miyamoto, M.D., chair of the IU School of Medicine Department of Otolaryngology-Head and Neck Surgery and a pioneer in the field of cochlear implantation in children and adults, said this finding augments other research on interventions to help children with cochlear implants perform at a level similar to children without hearing deficits.
"The ultimate goal of our department’s research with cochlear implants has always been to influence higher-level neurocognitive functioning," Dr. Miyamoto said. "Much of the success we have seen to date clearly relates to the brain’s ability to process an incomplete signal. The current research will further assist in identifying gaps in our knowledge."
One possible answer may lie in earlier implantation, Dr. Miyamoto said. The age at which children are implanted has been steadily decreasing, which has produced significant improvement in spoken language outcomes. Research shows the early implantation is related to better outcomes in speech and understanding, and it is reasonable to believe that there may be less of a deficit in executive functioning with earlier implantation, said Dr. Miyamoto, who is the Arilla Spence DeVault Professor of Otolaryngology-Head and Neck Surgery and medical director of audiology and speech language pathology at the IU School of Medicine.
Preschoolers in the IU study were implanted at an average age of 18 months, and they had fewer executive function delays than school-age children who were implanted 10 months later, at an average age of 28 months.
Children in the study were divided into two age groups: preschool (3 to 5 years) and school-age (7 to17 years). Using an established rating scale, parents rated executive function in everyday life for children with cochlear implants and for the control group with normal hearing.
"We compared parent ratings and looked at the percentage of children in each group who scored above a cut-off value that indicates at least a mild delay in executive functioning," Dr. Kronenberger said. "In the critical areas of controlled attention, working memory, planning and solving new problems, about 30 to 45 percent of the children with cochlear implants scored above the cut-off value, compared to about 15 percent or less of the children in the normal-hearing sample."
Dr. Kronenberger said the research also shows that many children develop average or better executive functioning skills after cochlear implantation.
"These results show that half or more of our group with cochlear implants did not have significant delays in executive functioning," Dr. Kronenberger said. "Cochlear implants produce remarkable gains in spoken language and other neurocognitive skills, but there is a certain amount of learning and catch-up that needs to take place with children who have experienced a hearing loss prior to cochlear implantation. So far, most of the interventions to help with this learning have focused on speech and language. Our findings show a need to identify and help some children in certain domains of executive functioning as well."
"We are now looking for early markers in children who are at risk before they get implants," Dr. Pisoni said. "It will be beneficial to identify as early as possible which children might be at risk for poor outcomes, and we need to understand the variability in the outcome and what can be done about it."
(Source: news.medicine.iu.edu)
One third of all brain aneurysms rupture: the size is not a significant risk factor
Approximately one third of all brain aneurysms rupture during a patient’s lifetime, resulting in a brain haemorrhage. A recent Finnish study demonstrates that, unlike what was previously assumed, the size of the aneurysm does not significantly impact the risk of rupture.
(Image credit: Miikka Korja)
The new Finnish study established that approximately one third of all aneurysms and up to one fourth of small aneurysms will rupture during a patient’s lifetime. The lifetime risk for rupture of a brain aneurysm depends heavily on the patient’s overall load of risk factors.
The risk of rupture is particularly high for female smokers with brain aneurysms of seven millimetres or more in diameter.
What surprised the researchers most was that the size of an aneurysm had little impact on its risk for rupture, particularly for men, despite a previously presumed correlation. In addition, the risk of rupture among non-smoking men was exceptionally low.
This is not to say that aneurysms in non-smoking men never rupture, but that the risk is much lower than we previously thought. This means treating every unruptured aneurysm may be unnecessary if one is discovered in a non-smoking man with low blood pressure, says Docent Seppo Juvela, University of Helsinki.
The study, published in Stroke 22nd May, is unique in that it monitored aneurysm patients over their entire lifetimes, whereas typical follow-up studies last only between one and five years in duration. The study is also exceptionally broad in scope.
It is unlikely that another similar, non-selected lifetime follow-up study on aneurysm patients will ever be conducted again, Juvela states.
Current care practices are based largely on the results of previous, shorter studies. Such studies have shown that the size of the aneurysm is the most significant factor predicting its risk for rupture. Consequently, small aneurysms have often been left untreated.
It is difficult to conduct reliable epidemiological research in brain aneurysms. The past 10–15 years have seen a distortion in the field due to a very limited group of researchers determining the direction for research. Now the situation is clearly changing, and clinically reasonable, population-based studies using non-selected data are on the rise again, states Docent Miikka Korja of the HUCS neurosurgery clinic.
(Source: uutiset.helsinki.fi)
Fruit flies ‘think’ before they act
Oxford University neuroscientists have shown that fruit flies take longer to make more difficult decisions.
In experiments asking fruit flies to distinguish between ever closer concentrations of an odour, the researchers found that the flies don’t act instinctively or impulsively. Instead they appear to accumulate information before committing to a choice.
Gathering information before making a decision has been considered a sign of higher intelligence, like that shown by primates and humans.
'Freedom of action from automatic impulses is considered a hallmark of cognition or intelligence,' says Professor Gero Miesenböck, in whose laboratory the new research was performed. 'What our findings show is that fruit flies have a surprising mental capacity that has previously been unrecognised.'
The researchers also showed that the gene FoxP, active in a small set of around 200 neurons, is involved in the decision-making process in the fruit fly brain.
The team reports its findings in the journal Science. The group was funded by the Wellcome Trust, the Gatsby Charitable Foundation, the US National Institutes of Health and the Oxford Martin School.
The researchers observed Drosophila fruit flies make a choice between two concentrations of an odour presented to them from opposite ends of a narrow chamber, having been trained to avoid one concentration.
When the odour concentrations were very different and easy to tell apart, the flies made quick decisions and almost always moved to the correct end of the chamber.
When the odour concentrations were very close and difficult to distinguish, the flies took much longer to make a decision, and they made more mistakes.
The researchers found that mathematical models developed to describe the mechanisms of decision making in humans and primates also matched the behaviour of the fruit flies.
The scientists discovered that fruit flies with mutations in a gene called FoxP took longer than normal flies to make decisions when odours were difficult to distinguish – they became indecisive.
The researchers tracked down the activity of the FoxP gene to a small cluster of around 200 neurons out of the 200,000 neurons in the brain of a fruit fly. This implicates these neurons in the evidence-accumulation process the flies use before committing to a decision.
Dr Shamik DasGupta, the lead author of the study, explains: ‘Before a decision is made, brain circuits collect information like a bucket collects water. Once the accumulated information has risen to a certain level, the decision is triggered. When FoxP is defective, either the flow of information into the bucket is reduced to a trickle, or the bucket has sprung a leak.’
Fruit flies have one FoxP gene, while humans have four related FoxP genes. Human FoxP1 and FoxP2 have previously been associated with language and cognitive development. The genes have also been linked to the ability to learn fine movement sequences, such as playing the piano.
'We don't know why this gene pops up in such diverse mental processes as language, decision-making and motor learning,' says Professor Miesenböck. However, he speculates: 'One feature common to all of these processes is that they unfold over time. FoxP may be important for wiring the capacity to produce and process temporal sequences in the brain.'
Professor Miesenböck adds: ‘FoxP is not a “language gene”, a “decision-making gene”, even a “temporal-processing” or “intelligence” gene. Any such description would in all likelihood be wrong. What FoxP does give us is a tool to understand the brain circuits involved in these processes. It has already led us to a site in the brain that is important in decision-making.’
Training brain patterns of empathy using functional brain imaging
An unprecedented research conducted by a group of neuroscientists has demonstrated for the first time that it is possible to train brain patterns associated with empathic feelings – more specifically, tenderness. The research showed that volunteers who received neurofeedback about their own brain activity patterns whilst being scanned inside a functional magnetic resonance (fMRI) machine were able to change brain network function of areas related to tenderness and affection felt toward loved ones. These significant findings could open new possibilities for treatment of clinical situations, such as antisocial personality disorder and postpartum depression.
In Ridley Scott’s film “Blade Runner”, based on the science fiction book ‘Do androids dream of electric sheep?’ by Philip K. Dick, empathy-detection devices are employed to measure tenderness or affection emotions felt toward others (called “affiliative” emotions). Despite recent advances in neurobiology and neurotechnology, it is unknown whether brain signatures of affiliative emotions can be decoded and voluntarily modulated.
The article entitled “Voluntary enhancement of neural signatures of affiliative emotion using fMRI neurofeedback” published in PLOS ONE is the first study to demonstrate through a neurotechnology tool, real-time neurofeedback using functional Magnetic Resonance Imaging (fMRI), the possibility to help the induction of empathic brain states.
The authors conducted this research at the D’Or Institute for Research and Education where a sophisticated computational tool was designed and used to allow the participants to modulate their own brain activity related to affiliative emotions and enhance this activity. This method employed pattern-detection algorithms, called “support vector machines” to classify complex activity patterns arising simultaneously from tenths of thousands of voxels (the 3-D equivalent of pixels) inside the participants’ brains.
Volunteers who received real time information of their ongoing neural activity could change brain network function among connected areas related to tenderness and affection felt toward loved ones, while the control group who performed the same fMRI task without neurofeedback did not show such improvement.
Thus, it was demonstrated that those who received a “real” feedback were able to “train” specific brain areas related to the experience of affiliative emotions that are key for empathy. These findings can lead the way to new opportunities to investigate the use of neurofeedback in conditions associated with reduced empathy and affiliative feelings, such as antisocial personality disorders and post-partum depression.
The authors point out that this study may represent a step towards the construction of the ‘empathy box’, an empathy-enhancing machine described by Philip K. Dick’s novel.
(Image caption: These are mature nerve cells generated from human cells using enhanced transcription factors. Credit: Fahad Ali)
Functional nerve cells from skin cells
A new method of generating mature nerve cells from skin cells could greatly enhance understanding of neurodegenerative diseases, and could accelerate the development of new drugs and stem cell-based regenerative medicine.
The nerve cells generated by this new method show the same functional characteristics as the mature cells found in the body, making them much better models for the study of age-related diseases such as Parkinson’s and Alzheimer’s, and for the testing of new drugs.
Eventually, the technique could also be used to generate mature nerve cells for transplantation into patients with a range of neurodegenerative diseases.
By studying how nerves form in developing tadpoles, researchers from the University of Cambridge were able to identify ways to speed up the cellular processes by which human nerve cells mature. The findings are reported in the May 27th edition of the journal Development.
Stem cells are our master cells, which can develop into almost any cell type within the body. Within a stem cell, there are mechanisms that tell it when to divide, and when to stop dividing and transform into another cell type, a process known as cell differentiation. Several years ago, researchers determined that a group of proteins known as transcription factors, which are found in many tissues throughout the body, regulate both mechanisms.
More recently, it was found that by adding these proteins to skin cells, they can be reprogrammed to form other cell types, including nerve cells. These cells are known as induced neurons, or iN cells. However, this method generates a low number of cells, and those that are produced are not fully functional, which is a requirement in order to be useful models of disease: for example, cortical neurons for stroke, or motor neurons for motor neuron disease.
In addition, for age-related diseases such as Parkinson’s and Alzheimer’s, both of which affect millions worldwide, mature nerve cells which show the same characteristics as those found in the body are crucial in order to enhance understanding of the disease and ultimately determine the best way to treat it.
"When you reprogramme cells, you’re essentially converting them from one form to another but often the cells you end up with look like they come from embryos rather than looking and acting like more mature adult cells," said Dr Anna Philpott of the Department of Oncology, who led the research. "In order to increase our understanding of diseases like Alzheimer’s, we need to be able to work with cells that look and behave like those you would see in older individuals who have developed the disease, so producing more ‘adult’ cells after reprogramming is really important."
By manipulating the signals which transcription factors send to the cells, Dr Philpott and her collaborators were able to promote cell differentiation and maturation, even in the presence of conflicting signals that were directing the cell to continue dividing.
When cells are dividing, transcription factors are modified by the addition of phosphate molecules, a process known as phosphorylation, but this can limit how well cells can convert to mature nerves. However, by engineering proteins which cannot be modified by phosphate and adding them to human cells, the researchers found they could produce nerve cells that were significantly more mature, and therefore more useful as models for disease such as Alzheimer’s.
Additionally, very similar protein control mechanisms are at work to mature important cells in other tissues such as pancreatic islets, the cell type that fails to function effectively in type 2 diabetes. As well as making more mature nerves, Dr Philpott’s lab is now using similar methods to improve the function of insulin-producing pancreas cells for future therapeutic applications.
"We’ve found that not only do you have to think about how you start the process of cell differentiation in stem cells, but you also have to think about what you need to do to make differentiation complete - we can learn a lot from how cells in developing embryos manage this," said Dr Philpott.
Blocking pain receptors extends lifespan, boosts metabolism in mice
Blocking a pain receptor in mice not only extends their lifespan, it also gives them a more youthful metabolism, including an improved insulin response that allows them to deal better with high blood sugar.
"We think that blocking this pain receptor and pathway could be very, very useful not only for relieving pain, but for improving lifespan and metabolic health, and in particular for treating diabetes and obesity in humans," said Andrew Dillin, a professor of molecular and cell biology at the University of California, Berkeley, and senior author of a new paper describing these results. "As humans age they report a higher incidence of pain, suggesting that pain might drive the aging process."
The “hot” compound in chili peppers, capsaicin, is already known to activate this pain receptor, called TRPV1 (transient receptor potential cation channel subfamily V member 1). In fact, TRPV1 is often called the capsaicin receptor. Constant activation of the receptor on a nerve cell results in death of the neuron, mimicking loss of TRPV1, which could explain why diets rich in capsaicin have been linked to a lower incidence of diabetes and metabolic problems in humans.
More relevant therapeutically, however, is an anti-migraine drug already on the market that inhibits a protein called CGRP that is triggered by TRPV1, producing an effect similar to that caused by blocking TRPV1. Dillin showed that giving this drug to older mice restored their metabolic health to that of younger mice.
"Our findings suggest that pharmacological manipulation of TRPV1 and CGRP may improve metabolic health and longevity," said Dillin, who is a Howard Hughes Medical Institute investigator and the Thomas and Stacey Siebel Distinguished Chair in Stem Cell Research. "Alternatively, chronic ingestion of compounds that affect TRPV1 might help prevent metabolic decline with age and lead to increased longevity in humans."
Dillin and his colleagues at UC Berkeley and The Salk Institute for Biological Studies in La Jolla, Calif., will publish their results in the May 22 issue of the journal Cell.
Pain and obesity
TRPV1 is a receptor found in the skin, nerves and joints that reacts to extremely high temperatures and other painful stimuli. The receptor is also found in nerve fibers that contact the pancreas, where it stimulates the release of substances that cause inflammation or, like CGRP (calcitonin gene-related peptide), prevent insulin release. Insulin promotes the uptake of sugar from the blood and storage in the body’s tissue, including fat.
Past research has shown that mice lacking TRPV1 are protected against diet-induced obesity, suggesting that this receptor plays a role in metabolism. Disrupting sensory perception also increases longevity in worms and flies. But until now, it was not known whether sensory perception also affects aging in mammals.
Dillin and his team have now found that mice genetically manipulated to lack TRPV1 receptors lived, on average, nearly four months – or about 14 percent – longer than normal mice. The TRPV1-deficient mice also showed signs of a youthful metabolism late in life, due to low levels of CGRP — a molecule that blocks insulin release resulting in increased blood glucose levels and thus could contribute to the development of type 2 diabetes. Throughout aging, these mice showed improved ability to quickly clear sugar from the blood as well as signs that they could burn more calories without increasing exercise levels.
Moreover, old mice treated with the anti-migraine drug, which inhibits the activity of CGRP receptors, showed a more youthful metabolic profile than untreated old mice.
UC Berkeley and The Salk Institute filed a patent May 16 on the technology described in the Cell paper. Dillin plans to continue his studies of the effects of TRPV1 and CGRP blockers on mice and, if possible, humans.
(Source: eurekalert.org)
Genes discovered linking circadian clock with eating schedule
For most people, the urge to eat a meal or snack comes at a few, predictable times during the waking part of the day. But for those with a rare syndrome, hunger comes at unwanted hours, interrupts sleep and causes overeating.
Now, Salk scientists have discovered a pair of genes that normally keeps eating schedules in sync with daily sleep rhythms, and, when mutated, may play a role in so-called night eating syndrome. In mice with mutations in one of the genes, eating patterns are shifted, leading to unusual mealtimes and weight gain. The results were published in Cell Reports today.
"We really never expected that we would be able to decouple the sleep-wake cycle and the eating cycle, especially with a simple mutation," says senior study author Satchidananda Panda, an associate professor in Salk’s Regulatory Biology Laboratory. "It opens up a whole lot of future questions about how these cycles are regulated."
More than a decade ago, researchers discovered that individuals with an inherited sleep disorder often carry a particular mutation in a protein called PER2. The mutation is in an area of the protein that can be phosphorylated—the ability to bond with a phosphate chemical that changes the protein’s function. Humans have three PER, or period, genes, all thought to play a role in the daily circadian clock and all containing the same phosphorylation spot.
The Salk scientists joined forces with a Chinese team led by Ying Xu of Nanjing University to test whether mutations in the equivalent area of PER1 would have the same effect as those in PER2 that caused the sleep disorder. So they bred mice to lack the mouse period genes, and added in a human PER1 or PER2 with a mutation in the phosphorylation site. As expected, mice with a mutated PER2 had sleep defects, dozing off earlier than usual. The same wasn’t true for PER1 mutations though.
"In the mice without PER1, there was no obvious defect in their sleep-wake cycles," says Panda. "Instead, when we looked at their metabolism, we suddenly saw drastic changes."
Mice with the PER1 phosphorylation defects ate earlier than other mice—causing them to wake up and snack before their sleep cycle was over—and ate more food throughout their normal waking period. When the researchers looked at the molecular details of the PER1 protein, they found that the mutated PER1 led to lower protein levels during the sleeping period, higher levels during the waking period, and a faster degradation of protein whenever it was produced by cells.
Panda and his colleagues hypothesize that normally, PER1 and PER2 are kept synchronized since they have identical phosphorylation sites—they are turned on and off at the same times, keeping sleep and eating cycles aligned. But a mutation in one of the genes could break this link, and cause off-cycle eating or sleeping.
"For a long time, people discounted night eating syndrome as not real," says Panda. "These results in mice suggest that it could actually be a genetic basis for the syndrome." The researchers haven’t yet tested, however, whether any humans with night eating syndrome have mutations in PER1.
When Panda and Xu’s team restricted access to food, providing it only at the mice’s normal meal times, they found that even with a genetic mutation in PER1, mice could maintain a normal weight. Over a 10-week follow-up, these mice—with a PER1 mutation but timed access to food—showed no differences to control animals. This tells the researchers that the weight gain caused by PER1 is entirely caused by meal mistiming, not other metabolic defects.
Next, they hope to study exactly how PER1 controls appetite and eating behavior—whether its molecular actions work through the liver, fat cells, brain or other organs.
Releasing the brakes for learning
Learning can only occur if certain neuronal “brakes” are released. As the group led by Andreas Lüthi at the Friedrich Miescher Institute for Biomedical Research has now discovered, learning processes in the brain are dynamically regulated by various types of interneurons. The new connections essential for learning can only be established if inhibitory inputs from interneurons are reduced at the right moment. These findings have now been published in Nature.
Image caption: Example of a dendrite of a principal neuron (white) and synaptic contacts (yellow arrowheads) from SOM1 interneurons.
For some years, most neurobiologists studying learning processes have assumed that the new connections required for learning can only be established and ultimately reinforced if certain neuronal “brakes” are released – a process known as disinhibition. It has also been supposed for some time that various types of interneurons could be involved in disinhibition. Interneurons are nerve cells that surround and – via their connections – inhibit the activity of principal neurons. It has not been clear, however, whether these cell types actually play a role in disinhibition and how they control learning.
Andreas Lüthi and his group at the Friedrich Miescher Institute for Biomedical Research have now demonstrated for the first time how a learning process is dynamically regulated by specific types of interneurons.
In Lüthi’s experiments, mice were trained to associate a sound with an unpleasant stimulus, so that the animals subsequently knew what would happen when they heard the auditory cue. The researchers showed that, during the learning process, the sound stimulus released a brake in some of the principal neurons. More precisely, it induced the activation of parvalbumin-positive (PV+) interneurons, leading indirectly – via somatostatin-positive (SOM+) interneurons – to disinhibition of the principal neurons. The latter thus became receptive to further sensory inputs. If this was immediately followed by the unpleasant stimulus, then another brake was released. Once again, PV+ interneurons were involved, but this time the principal neurons were directly disinhibited. Steffen Wolff, a postdoc in Lüthi’s group and first author of the publication, explains: “The principal neurons temporarily reached a level of activation enabling neuronal connections to be reinforced in such a way that the animal could learn the association between the sound and the unpleasant stimulus.”
Lüthi comments: “This is the first time we’ve been able to identify so clearly the function of defined interneurons in a learning process, and to show how successive disinhibition can enable this process. We assume that interneurons disinhibit the principal neurons in a highly dynamic manner. They integrate, as it were, the state of numerous different neural networks, activated for example by sensory input, earlier experiences or emotional states, and thus permit or prevent learning. I think these findings are also of interest in the context of conditions where learning processes are impaired or dysfunctional, as in the case of anxiety disorders.”
(Source: fmi.ch)
One Molecule To Block Both Pain And Itch
Duke University researchers have found an antibody that simultaneously blocks the sensations of pain and itching in studies with mice.
The new antibody works by targeting the voltage-sensitive sodium channels in the cell membrane of neurons. The results appear online on May 22 in Cell.
Voltage-sensitive sodium channels control the flow of sodium ions through the neuron’s membrane. These channels open and close by responding to the electric current or action potential of the cells. One particular type of sodium channel, called the Nav1.7 subtype, is responsible for sensing pain.
Mutations in the human gene encoding the Nav1.7 sodium channel can lead to either the inability to sense pain or pain hypersensitivity. Interestingly, these mutations do not affect other sensations such as touch or temperature. Hence, the Nav1.7 sodium channel might be a very specific target for treating pain disorders without perturbing the patients’ ability to feel other sensations.
"Originally, I was interested in isolating these sodium channels from cells to study their structure," said Seok-Yong Lee, assistant professor of biochemistry in the Duke University Medical School and principal investigator of the study. He designed antibodies that would capture the sodium channels so that he could study them. "But then I thought, what if I could make an antibody that interferes with the channel function?"
The team first tested the antibody in cultured cells engineered to express the Nav1.7 sodium channel. They found that the antibody can bind to the channel and stabilize its closed state.
"The channel is off when it is closed," Lee explained. "Since the antibody stabilizes the closed state, the channel becomes less sensitive to pain." If this held true in live animals, then the animals would also be less sensitive to pain.
To test this idea, Lee sought the help of Ru-Rong Ji, professor of anesthesiology and neurobiology, who is an expert in the study of pain and itch sensation. Using laboratory mouse models of inflammatory and neuropathic pain, they showed that the antibody can target the Nav1.7 channel and reduce the pain sensation in these mice. More importantly, mice receiving the treatment did not show signs of physical dependence or enhanced tolerance toward the antibody.
"Pain and itch are distinct sensations, and pain is often known to suppress itch", said Ji.
The team found that the antibody can also relieve acute and chronic itch in mouse models, making them the first to discover the role of Nav1.7 in transmitting the itch sensation.
"Now we have a compound that can potentially treat both pain and itch at the same time," said Lee. Both of these symptoms are common in allergic contact dermatitis, which affects more than 10 million patients a year in the United States alone.
The team is pursuing a patent for the antibody.
"We hope our discovery will garner interest from pharmaceutical companies that can help us expand our studies into clinical trials," Lee said. Their goal is to develop a safer treatment for pain and itch as an alternative to opioids, which often cause addiction and other detrimental side effects.
(Source: today.duke.edu)