Posts tagged science
Articles and news from the latest research reports.
Stress hormone receptors localized in sweet taste cells
According to new research from the Monell Center, receptors for stress-activated hormones have been localized in oral taste cells responsible for detection of sweet, umami, and bitter. The findings suggest that these hormones, known as glucocorticoids, may act directly on taste receptor cells under conditions of stress to affect how these cells respond to sugars and certain other taste stimuli.
"Sweet taste may be particularly affected by stress," said lead author M. Rockwell Parker, PhD, a chemical ecologist at Monell. "Our results may provide a molecular mechanism to help explain why some people eat more sugary foods when they are experiencing intense stress."
Glucocorticoid (GC) hormones affect the body by activating specialized GC receptors located inside of cells. Knowing that stress can have major effects on metabolism and food choice, the researchers used a mouse model to ask whether taste receptor cells contain these GC receptors.
The findings, published online ahead of print in the journal Neuroscience Letters, revealed that GC receptors are present on the tongue, where they are specifically localized to the cells that contain receptors for sweet, umami and bitter taste. The highest concentrations of GC receptors were found in Tas1r3 taste cells, which are sensitive to sweet and umami taste.
GC hormones act on cells via a multi-step process. After GCs bind to their receptors within target cells, the activated receptor complex moves, or translocates, to the cell nucleus, where it then influences gene expression and protein assembly.
To explore whether GC receptors in taste tissue are activated by stress, the researchers compared the proportion of taste cells with translocated receptors in stressed and non-stressed mice. Compared to controls, the stressed mice had a 77 percent increase of GC receptors within taste cell nuclei.
Together, the results suggest that sweet taste perception and intake, which are known to be altered by stress, may be specifically affected via secretion of GCs and subsequent activation of GC receptors in taste cells.
"Taste provides one of our initial evaluations of potential foods. If this sense can be directly affected by stress-related hormonal changes, our food interaction will likewise be altered," said Parker.
Parker noted that although stress is known to affect intake of salty foods, GC receptors were not found in cells thought to be responsible for detecting sally and sour taste. One explanation, he said, is that stress may influence salt taste processing in the brain.
Implications of the findings extend beyond the oral taste system. Noting that taste receptors are found throughout the body, senior author and Monell molecular neurobiologist Robert Margolskee, MD, PhD, said, “Taste receptors in the gut and pancreas might also be influenced by stress, potentially impacting metabolism of sugars and other nutrients and affecting appetite.”
Future studies will continue to explore how stress hormones act to affect the taste system.
(Source: eurekalert.org)
Complex Neural Circuitry Keeps You From Biting Your Tongue
Eating, like breathing and sleeping, seems to be a rather basic biological task. Yet chewing requires a complex interplay between the tongue and jaw, with the tongue positioning food between the teeth and then moving out of the way every time the jaw clamps down to grind it up.
If the act weren’t coordinated precisely, the unlucky chewer would end up biting more tongue than burrito.
Duke University researchers have used a sophisticated tracing technique in mice to map the underlying brain circuitry that keeps mealtime relatively painless. The study, which appears June 3 in eLife, could lend insight into a variety of human behaviors, from nighttime teeth grinding to smiling or complex vocalizations.
"Chewing is an activity that you can consciously control, but if you stop paying attention these interconnected neurons in the brain actually do it all for you," said Edward Stanek IV, lead study author and graduate student at Duke University School of Medicine. "We were interested in understanding how this all works, and the first step was figuring out where these neurons reside."
Previous mapping attempts have produced a relatively blurry picture of this chewing control center. Researchers know that the movement of the muscles in the jaw and tongue are governed by special neurons called motoneurons and that these are in turn controlled by another set of neurons called premotor neurons. But the exact nature of these connections — which premotor neurons connect to which motoneurons — has not been defined.
Senior study author Fan Wang, Ph.D., associate professor of neurobiology and a member of the Duke Institute for Brain Sciences, has been mapping neural circuits in mice for many years. Under her guidance, Stanek used a special form of the rabies virus to trace the origins of chewing movements.
The rabies virus works naturally by jumping backwards across neurons until it has infected the entire brain of its victim. For this study, Stanek used a genetically disabled version of rabies that could only jump from the muscles to the motoneurons, and then back to the premotor neurons. The virus also contained a green or red fluorescent tag, which enabled the researchers to see where it landed after it was done jumping.
Stanek injected these fluorescently labeled viruses into two muscles, the tongue-protruding genioglossus muscle and the jaw-closing masseter muscle. He found that a group of premotor neurons simultaneously connect to the motoneurons that regulate jaw opening and those that trigger tongue protrusion. Similarly, he found another group that connects to both motoneurons that regulate jaw closing and those responsible for tongue retraction. The results suggest a simple method for coordinating the movement of the tongue and jaw that usually keeps the tongue safe from injury.
"Using shared premotor neurons to control multiple muscles may be a general feature of the motor system," said Stanek. "For other studies on the rest of the brain, it is important to keep in mind that individual neurons can have effects in multiple downstream areas."
The researchers are interested in using their technique to jump even further back in the mouse brain, eventually mapping the circuitry all the way up to the cortex. But first they plan to delve deeper into the connections between the premotor and motoneurons.
"This is just a small step in understanding the control of these orofacial movements," Stanek said. "We only looked at two muscles and there are at least 10 other muscles active during chewing, drinking, and speech. There is still a lot of work to look at these other muscles, and only then can we get a complete picture of how these all work as a unit to coordinate this behavior," said Stanek.
New Amyloid-Reducing Compound Could Be a Preventive Measure Against Alzheimer’s
Scientists at NYU Langone Medical Center have identified a compound, called 2-PMAP, in animal studies that reduced by more than half levels of amyloid proteins in the brain associated with Alzheimer’s disease. The researchers hope that someday a treatment based on the molecule could be used to ward off the neurodegenerative disease since it may be safe enough to be taken daily over many years.
“What we want in an Alzheimer’s preventive is a drug that modestly lowers amyloid beta and is also safe for long term use,” says Martin J. Sadowski, MD, PhD, associate professor of neurology, psychiatry, and biochemistry and molecular pharmacology, who led the research to be published online June 3 in the journal Annals of Neurology. “Statin drugs that lower cholesterol appear to have those properties and have made a big impact in preventing coronary artery disease. That’s essentially what many of us envision for the future of Alzheimer’s medicine.”
The 2-PMAP molecule that Dr. Sadowski’s team identified is non-toxic in mice, gets easily into the brain, and lowers the production of amyloid beta and associated amyloid deposits.
The prime target for Alzheimer’s prevention is amyloid beta. Decades before dementia begins, this small protein accumulates in clumps in the brain. Modestly lowering the production of amyloid beta in late middle age, and thus removing some of the burden from the brain’s natural clearance mechanisms, is believed to be a good prevention strategy. Researchers two years ago reported that something like this happens naturally in about 0.5 percent of Icelanders, due to a mutation they carry that approximately halves amyloid beta production throughout life. These fortunate people show a slower cognitive decline in old age, live longer, and almost never get Alzheimer’s.
Prevention of Alzheimer’s dementia is now considered more feasible than stopping it after it has begun, when brain damage is already severe. Every prospective Alzheimer’s drug in clinical trials has failed even to slow the disease process at that late stage. “The key is to prevent the disease process from going that far,” Dr. Sadowski says.
Dr. Sadowski and colleagues screened a library of compounds and found that 2-PMAP reduced the production of amyloid beta’s mother protein, known as amyloid precursor protein (APP). The APP protein normally is cut by enzymes in a way that leaves amyloid beta as one of the fragments. Dr. Sadowski’s team found that 2-PMAP, even at low, non-toxic concentrations, significantly reduced APP production in test cells, lowering amyloid beta levels by 50 percent or more.
The scientists subsequently found that 2-PMAP had essentially the same impact on APP and amyloid beta in the brains of living mice. The mice were engineered to have the same genetic mutations found in Alzheimer’s patients with a hereditary form of the disease, causing overproduction of APP and Alzheimer’s-like amyloid deposits. A five-day treatment with 2-PMAP lowered brain levels of APP and, even more so, levels of amyloid beta. Four months of treatment sharply reduced the amyloid deposits and prevented the cognitive deficits that are normally seen in these transgenic mice as they get older.
Dr. Sadowski and his laboratory are now working to make chemical modifications to the compound to improve its effectiveness. But 2-PMAP already seems to have advantages over other amyloid-lowering compounds, he says. One is that it can cross efficiently from the bloodstream to the brain, and thus doesn’t require complex modifications that might compromise its effects on APP.
The compound also appears to have a highly selective effect on APP production, by interfering with the translation of APP’s gene transcript into the APP protein itself. The best known candidates for Alzheimer’s preventives lower amyloid by inhibiting the secretase enzymes that cleave amyloid beta from APP, tending to cause unwanted side-effects via their off target interference with the processing of other client proteins cleaved by these enzymes. A clinical trial of one secretase inhibitor was halted in 2010 after it was found to worsen dementia and cause a higher incidence of skin cancer.
Alzheimer’s disease, the most common form of dementia, currently afflicts more than five million Americans, according to the Alzheimer’s Association. Unless preventive drugs or treatments are developed, the prevalence of Alzheimer’s is expected to triple by 2050.
(Source: communications.med.nyu.edu)
Molecular ‘scaffold’ could hold key to new dementia treatments
Researchers at King’s College London have discovered how a molecular ‘scaffold’ which allows key parts of cells to interact, comes apart in dementia and motor neuron disease, revealing a potential new target for drug discovery.
The study, published today in Nature Communications, was funded by the UK Medical Research Council, Wellcome Trust, Alzheimer’s Research UK and the Motor Neurone Disease Association.
Researchers looked at two components of cells: mitochondria, the cell ‘power houses’ which produce energy for the cell;and the endoplasmic reticulum (ER) which makes proteins and stores calcium for signalling processes in the cell. ER and mitochondria form close associations and these interactions enable a number of important cell functions. However the mechanism by which ER and mitochondria become linked has not, until now, been fully understood.
Professor Chris Miller, from the Department of Neuroscience at the Institute of Psychiatry at King’s and lead author of the paper, says: “At the molecular level, many processes go wrong in dementia and motor neuron disease,and one of the puzzles we’re faced with is whether there is a common pathway connecting these different processes. Our study suggests that the loosening of this ‘scaffold’ between the mitochondria and ER in the cell may be a key process in neurodegenerative diseases such as dementia or motor neuron disease.”
By studying cells in a dish, the researchers discovered that an ER protein called VAPB binds to a mitochondrial protein called PTPIP51, to form a ‘scaffold’ enabling ER and mitochondria to form close associations. In fact, by increasing the levels of VAPB and PTPIP51, mitochondria and ER re-organised themselves to form tighter bonds.
Many of the cell’s functions that are controlled by ER-mitochondria associations are disrupted in neurodegenerative diseases, so the researchers studied how the strength of this ‘scaffold’ was affected in these diseases. TDP-43 is a protein which is strongly linked to Amyotrophic Lateral Sclerosis (ALS, a form of motor neuron disease) and Fronto-Temporal Dementia (FTD, the second most common form of dementia), but exactly how the protein causes neurodegeneration is not properly understood.
The researchers studied how TDP-43 affected mouse cells in a dish. They found that higher levels of TDP-43 resulted in a loosening of the scaffold which reduced ER-mitochondria bonds,affecting some important cellular functions that are linked to ALS and FTD.
Professor Miller concludes: “Our findings are important in terms of advancing our understanding of basic biology, but may also provide a potential new target for developing new treatments for these devastating disorders.”
(Source: kcl.ac.uk)
Hypnosis extends restorative slow-wave sleep
Deep sleep promotes our well-being, improves our memory and strengthens the body’s defences. Zurich and Fribourg researchers demonstrate how restorative SWS can also be increased without medication – using hypnosis.
Sleeping well is a crucial factor contributing to our physical and mental restoration. SWS in particular has a positive impact for instance on memory and the functioning of the immune system. During periods of SWS, growth hormones are secreted, cell repair is promoted and the defence system is stimulated. If you feel sick or have had a hard working day, you often simply want to get some good, deep sleep. A wish that you can’t influence through your own will – so the widely held preconception.
Sleep researchers from the Universities of Zurich and Fribourg now prove the opposite. In a study that has now been published in the scientific journal “Sleep”, they have demonstrated that hypnosis has a positive impact on the quality of sleep, to a surprising extent. “It opens up new, promising opportunities for improving the quality of sleep without drugs”, says biopsychologist Björn Rasch who heads the study at the Psychological Institute of the University of Zurich in conjunction with the “Sleep and Learning” project*.
Brain waves – an indicator of sleep quality
Hypnosis is a method that can influence processes which are very difficult to control voluntarily. Patients with sleep disturbances can indeed be successfully treated with hypnotherapy. However, up to now it hadn’t been proven that this can lead to an objectively measurable change in sleep. To objectively measure sleep, electrical brain activity is recorded using an electroencephalogram (EEG). The characteristic feature of slow-wave sleep, which is deemed to have high restorative capacity, is a very even and slow oscillation in electrical brain activity.
70 healthy young women took part in the UZH study. They came to the sleep laboratory for a 90-minute midday nap. Before falling asleep they listened to a special 13-minute slow-wave sleep hypnosis tape over loudspeakers, developed by hypnotherapist Professor Angelika Schlarb, a sleep specialist, or to a neutral spoken text. At the beginning of the experiment the subjects were divided into highly suggestible and low suggestible groups using a standard procedure (Harvard Group Scale of Hypnotic Susceptibility). Around half of the population is moderately suggestible. With this method women achieve on average higher values for hypnotic susceptibility than men. Nevertheless, the researchers expect the same positive effects on sleep for highly suggestible men.
Slow-wave sleep increased by 80 percent
In their study, sleep researchers Maren Cordi and Björn Rasch were able to prove that highly suggestible women experienced 80 percent more slow-wave sleep after listening to the hypnosis tape compared with sleep after listening to the neutral text. In parallel, time spent awake was reduced by around one-third. In contrast to highly suggestible women, low suggestible female participants did not benefit as much from hypnosis. With additional control experiments the psychologists confirmed that the beneficial impact of hypnosis on slow-wave sleep could be attributed to the hypnotic suggestion to “sleep deeper” and could not be reduced to mere expectancy effects.
According to psychologist Maren Cordi “the results may be of major importance for patients with sleep problems and for older adults. In contrast to many sleep-inducing drugs, hypnosis has no adverse side effects”. Basically, everyone who responds to hypnosis could benefit from improved sleep through hypnosis.
* The project “Sleep and Learning” is headed by Professor Björn Rasch from the University of Fribourg and conducted at the Universities of Zurich and Fribourg. The project is financed by the Swiss National Fund and the University of Zurich (main area of clinical research “Sleep and Health”). The goal of the project is to identify psychological and neurophysiological mechanisms underlying the positive role of sleep for our memory and mental health.
(Source: mediadesk.uzh.ch)
Left-handed fetuses could show effects of maternal stress on unborn babies
Fetuses are more likely to show left-handed movements in the womb when their mothers are stressed, according to new research.
Researchers at Durham and Lancaster universities say their findings are an indicator that maternal stress could have a temporary effect on unborn babies, adding that their research highlights the importance of reducing stress during pregnancy.
However, the researchers emphasised that their study was not evidence that maternal stress led to fixed left-handedness in infants after birth. They said that some people might be genetically predisposed to being left-handed and that there are examples where right and left-handedness can switch throughout a person’s life.
Using 4d ultrasound scans, the researchers observed 57 scans of 15 healthy fetuses, recording 342 facial touches.
The fetuses were scanned at four different stages between 24 and 36 weeks of pregnancy. Researchers also asked the mothers of these babies how much stress they had experienced in the four weeks between each of the scans.
The researchers found that the more stress mothers reported, the more frequently fetuses touched their faces with their left hands. They added that a significant number of touches by the fetuses of stressed mothers were done with their left, rather than right hands - therefore fetal touches of their own faces, indicated a left-handed tendency.
As right-handedness is more common in the general population, the researchers had expected to see more of a bias towards right-handed movements in the fetuses as they grew older. The high percentage of left-handed behaviour, observed only when mothers reported being stressed, led them to conclude that maternal stress has an effect on the lateral behaviour of the babies they scanned.
The findings are published in the journal Laterality: Asymmetries of Body, Brain and Cognition.
Lead author Dr Nadja Reissland, in Durham University’s Department of Psychology, said: “Our research suggests that stressed mothers have fetuses who touch their face relatively more with their left hand.
“This suggests maternal stress could be having on effect on the child’s behaviour in the womb and highlights the importance of reducing maternal stress in pregnancy.
“Such measures may include increased emphasis on stopping stressful work early, the inclusion of relaxation classes in pre-natal care and involvement of the whole family in the pre-natal period.
“While we observed a higher degree of left-handed behaviour in the fetuses of stressed mothers than had been expected, we are not saying that maternal stress leads to a child becoming left-handed after birth, as there could be a number of reasons for this.
“The research does suggest, however, that a fetus can detect when a mother is stressed and that it responds to this stress.”
Professor Brian Francis, of Lancaster University, emphasised that the study also showed that overall preference for left or right hand varied considerably from scan to scan within each fetus, though fetuses showed more left-hand movements when mothers reported that they had experienced stress. He said: “Overall, there was no consistent handedness preference being shown by the fetuses, with most fetuses switching in preference at least once over the four scans.”
The researchers added that while mothers were asked to report their stress levels in the four weeks between scans, in practice some might have reported the stress they were experiencing at the time of being surveyed.
Previous research has shown that maternal stress in pregnancy leads to increased levels of cortisol – a hormone produced in response to stress - in mothers that could lead to an altered preference for left-sided or right-sided behaviour in fetuses.
The current study did not assess the stress levels of fetuses and Dr Reissland said that future research could examine cortisol levels in fetuses to further determine the effect of stress on lateral behaviour.
Dr Reissland added that further research was also needed to look at whether or not maternal prenatal stress had longer-term effects on the development of infants and children after birth.
(Source: dur.ac.uk)
MRI-Guided Laser Procedure Provides Alternative to Epilepsy Surgery
For patients with mesial temporal lobe epilepsy (MTLE) that can’t be controlled by medications, a minimally invasive laser procedure performed under MRI guidance provides a safe and effective alternative to surgery, suggests a study in the June issue of Neurosurgery, official journal of the Congress of Neurological Surgeons. The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.
"Real-time magnetic resonance-guided stereotactic laser amygdalohippocampotomy (SLAH) is a technically novel, safe and effective alternative to open surgery," according to the new research by Dr. Robert E. Gross of Emory University School of Medicine, Atlanta, and colleagues.
MRI Guides Precise Laser Destruction of Area Causing Epilepsy…
The researchers report their experience with MRI-guided SLAH in 13 adult patients with epilepsy mapped to a part of the brain called the mesial temporal lobe. The patients, median age 24 years, had “intractable” seizures despite treatment with antiepileptic drugs.
In the SLAH procedure, a saline-cooled fiberoptic laser probe was precisely targeted to the area of the brain—the “amygdalohippocampal complex”—responsible for the procedures. Using real-time MRI guidance, the neurosurgeon was able to pinpoint the area of the brain responsible for seizure activity and destroy (ablate) by computer-controlled laser energy, without harming neighboring brain tissue.
The technical aspects of the procedure were successfully carried out in all patients. Using thermal imaging and MRI guidance, the surgeons were able to see the area of laser ablation as treatment proceeded. The average laser exposure time was just under ten minutes.
On average, 60 percent of the amygdalohippocampal complex was destroyed in the SLAH procedure; the average length of the ablated area was 2.5 centimeters. Median time spent in the hospital was just one day—compared to a typical two to five-day stay after conventional temporal lobe surgery, and SLAH patients did not have to be admitted to the intensive care unit.
…With Good Control of Seizures at Follow-Up
Most important, the procedure was effective in reducing or eliminating seizures in patients with MTLE. At a median of 14 months after SLAH, ten out of thirteen patients achieved meaningful seizure reductions, while seven were free of “disabling seizures.” This included six out of nine patients whose epilepsy was caused by an abnormality called mesial temporal sclerosis.
Although some complications occurred, none were directly caused by laser application. Two patients had an additional SLAH procedure to control seizures, and another patient underwent standard open surgery.
Open brain surgery is the standard treatment for patients with intractable MTLE. Surgery has a high success rate, but carries a significant risk of neurological and cognitive (intellectual) impairment. Minimally invasive approaches like the new MRI-guided laser ablation technique might produce similar seizure control with lower risks than surgery.
The new study shows “technical feasibility and encouraging results” with the minimally invasive MRI-guided SLAH technique for patients with MTLE. Effectiveness in relieving or eliminating seizures approaches that of surgery—perhaps especially among patients whose seizures are caused by mesial temporal sclerosis. “These are promising results considering that this reflects our initial experience, and results may improve with greater experience with this novel technique,” notes Dr. Gross.
"Such minimally invasive techniques may be more desirable to patients and result in increased use of epilepsy surgery among the large number of medically intractable epilepsy patients," Dr. Gross and colleagues conclude. They note that a larger, longer-term study of SLAH is underway, including assessment of the effects on cognitive function as well as seizures.
Marijuana shows potential in treating autoimmune disease
A team of University of South Carolina researchers led by Mitzi Nagarkatti, Prakash Nagarkatti and Xiaoming Yang have discovered a novel pathway through which marijuana can suppress the body’s immune functions. Their research has been published online in the Journal of Biological Chemistry.
Marijuana is the most frequently used illicit drug in the United States, but as more states legalize the drug for medical and even recreational purposes, research studies like this one are discovering new and innovative potential health applications for the federal Schedule I drug.
Marijuana is now regularly and successfully used to alleviate the nausea and vomiting many cancer patients experience as side effects to chemotherapy, combat the wasting syndrome that causes some AIDS patients to lose significant amounts of weight and muscle mass and ease chronic pain that is unresponsive to opioids, among other applications.
The university study has uncovered yet another potential application for marijuana, in the suppression of immune response to treat autoimmune diseases. The work builds on recent scientific discoveries that the environment in which humans live can actually trigger changes that occur outside of human DNA, but nevertheless can cause alterations to the function of genes controlled by DNA. These outside molecules that have the ability to alter DNA function are known collectively as the epigenome. In this study, the investigators wanted to find out if the tetrahydrocannabinol found in marijuana has the capacity to affect DNA expression through epigenetic pathways outside of the DNA itself.
The recent findings show that marijuana THC can change critical molecules of epigenome called histones, leading to suppression of inflammation. These results suggest that one potential negative impact of marijuana smoking could be suppression of beneficial inflammation in the body. But they also suggest that, because of its epigenetic influence toward inflammation suppression, marijuana use could be efficacious in the treatment of autoimmune diseases such as arthritis, lupus, colitis, multiple sclerosis and the like, in which chronic inflammation plays a central role.
(Source: eurekalert.org)
Why inflammation leads to a leaky blood-brain barrier: MicroRNA-155
Until now, scientists have not known exactly how inflammation weakens the Blood-Brain Barrier, allowing toxins and other molecules access to the brain. A new research report appearing in the June 2014 issue of The FASEB Journal solves this mystery by showing that a molecule, called “microRNA-155,” is responsible for cleaving epithelial cells to create microscopic gaps that let material through. Not only does this discovery help explain the molecular underpinnings of diseases like multiple sclerosis, but it also opens an entirely new avenue for developing therapies that can help penetrate the Blood-Brain Barrier to deliver lifesaving drugs.
According to Ignacio A, Romero, Ph.D., “We are beginning to understand the mechanisms by which the barrier between the blood and the brain becomes leaky in inflammatory conditions. Based on these and other findings, drugs that reduce the leakiness of the barrier have the potential to improve symptoms in many neurological conditions.” Romero is one of the researchers involved in the work from the Department of Life, Health and Chemical Sciences of the Biomedical Research Network at The Open University in the United Kingdom.
To make this discovery, Romero and colleagues first measured microRNA-155 (miR-155) levels in cultured human cells and compared them to cells under inflammatory conditions. Researchers then measured levels in the blood vessels of inflamed brain areas of patients with multiple sclerosis (MS) and compared them to non-inflamed areas. In both cases, miR-155 was elevated in inflammation. Then, in mice, normal mice were compared with mice that were genetically altered to lose miR-155. When an inflammatory reaction was induced in these two groups of mice, the mice that could not express miR-155 had a much reduced increase in “leakiness” of the Blood-Brain Barrier than normal mice. Finally, scientists investigated in cultured human cells the mechanism by which miR-155 levels cause leakiness of the barrier and concluded that miR-155 affects the organization of the complex structures that form the tight connections between endothelial cells.
"This study has the potential to be a game-changer in terms of how we treat neurological conditions and how we deliver drugs to the brain," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “Since it was first discovered, the Blood-Brain Barrier has always been a touch elusive. Now, after careful analysis, we are learning exactly how our bodies keep our brains safe and that microRNA-155 is a key player.”
(Source: eurekalert.org)
(Image caption: In this artist’s representation of the adult subependymal neurogenic niche (viewed from underneath the ependyma), electrical signals generated by the ChAT+ neuron give rise to newborn migrating neuroblasts, seen moving over the underside of ependymal cells. Credit: Illustration by O’Reilly Science Art.)
Neuron Tells Stem Cells to Grow New Neurons
Duke researchers have found a new type of neuron in the adult brain that is capable of telling stem cells to make more new neurons. Though the experiments are in their early stages, the finding opens the tantalizing possibility that the brain may be able to repair itself from within.
Neuroscientists have suspected for some time that the brain has some capacity to direct the manufacturing of new neurons, but it was difficult to determine where these instructions are coming from, explains Chay Kuo, M.D. Ph.D., an assistant professor of cell biology, neurobiology and pediatrics.
In a study with mice, his team found a previously unknown population of neurons within the subventricular zone (SVZ) neurogenic niche of the adult brain, adjacent to the striatum. These neurons expressed the choline acetyltransferase (ChAT) enzyme, which is required to make the neurotransmitter acetylcholine. With optogenetic tools that allowed the team to tune the firing frequency of these ChAT+ neurons up and down with laser light, they were able to see clear changes in neural stem cell proliferation in the brain.
The findings appeared as an advance online publication June 1 in the journal Nature Neuroscience.
The mature ChAT+ neuron population is just one part of an undescribed neural circuit that apparently talks to stem cells and tells them to increase new neuron production, Kuo said. Researchers don’t know all the parts of the circuit yet, nor the code it’s using, but by controlling ChAT+ neurons’ signals Kuo and his Duke colleagues have established that these neurons are necessary and sufficient to control the production of new neurons from the SVZ niche.
"We have been working to determine how neurogenesis is sustained in the adult brain. It is very unexpected and exciting to uncover this hidden gateway, a neural circuit that can directly instruct the stem cells to make more immature neurons," said Kuo, who is also the George W. Brumley, Jr. M.D. assistant professor of developmental biology and a member of the Duke Institute for Brain Sciences. "It has been this fascinating treasure hunt that appeared to dead-end on multiple occasions!"
Kuo said this project was initiated more than five years ago when lead author Patricia Paez-Gonzalez, a postdoctoral fellow, came across neuronal processes contacting neural stem cells while studying how the SVZ niche was assembled.
The young neurons produced by these signals were destined for the olfactory bulb in rodents, as the mouse has a large amount of its brain devoted to process the sense of smell and needs these new neurons to support learning. But in humans, with a much less impressive olfactory bulb, Kuo said it’s possible new neurons are produced for other brain regions. One such region may be the striatum, which mediates motor and cognitive controls between the cortex and the complex basal ganglia.
"The brain gives up prime real estate around the lateral ventricles for the SVZ niche housing these stem cells," Kuo said. "Is it some kind of factory taking orders?" Postdoctoral fellow Brent Asrican made a key observation that orders from the novel ChAT+ neurons were heard clearly by SVZ stem cells.
Studies of stroke injury in rodents have noted SVZ cells apparently migrating into the neighboring striatum. And just last month in the journal Cell, a Swedish team observed newly made control neurons called interneurons in the human striatum for the first time. They reported that interestingly in Huntington’s disease patients, this area seems to lack the newborn interneurons.
"This is a very important and relevant cell population that is controlling those stem cells," said Sally Temple, director of the Neural Stem Cell Institute of Rensselaer, NY, who was not involved in this research. "It’s really interesting to see how innervations are coming into play now in the subventricular zone."
Kuo’s team found this system by following cholinergic signaling, but other groups are arriving in the same niche by following dopaminergic and serotonergic signals, Temple said. “It’s a really hot area because it’s a beautiful stem cell niche to study. It’s this gorgeous niche where you can observe cell-to-cell interactions.”
These emerging threads have Kuo hopeful researchers will eventually be able to find the way to “engage certain circuits of the brain to lead to a hardware upgrade. Wouldn’t it be nice if you could upgrade the brain hardware to keep up with the new software?” He said perhaps there will be a way to combine behavioral therapy and stem cell treatments after a brain injury to rebuild some of the damage.
The questions ahead are both upstream from the new ChAT+ neurons and downstream, Kuo says. Upstream, what brain signals tell ChAT+ neurons to start asking the stem cells for more young neurons? Downstream, what’s the logic governing the response of the stem cells to different frequencies of ChAT+ electrical activity?
There’s also the big issue of somehow being able to introduce new components into an existing neuronal circuit, a practice that parts of the brain might normally resist. “I think that some neural circuits welcome new members, and some don’t,” Kuo said.