Posts tagged science
Articles and news from the latest research reports.
Hitting the perfect tennis serve requires hours and hours of practice, but for scientists who study complex motor behaviors, there always has been a large unanswered question — what is the brain learning from those hours spent on the court? Is it simply the timing required to hit the perfect serve, or is it the precise path along which to move the hand?
The answer, Harvard researchers say, is both — but in separate circuits.
Bence Ölveczky, the John L. Loeb Associate Professor of the Natural Sciences, has found that the brain uses two largely independent neural circuits to learn the temporal and spatial aspects of a motor skill. The study is described in a Sept. 26 paper in Neuron.
“What we’re studying is the structure of motor-skill learning,” Ölveczky said. “What we were able to show is that the brain divides something that’s complex into modules — in this case for timing and for motor implementation — as a way to take advantage of the hierarchical structure of the motor system, and it imprints learning at the different levels independently.”
To tease out how those independent circuits operate, Ölveczky and his colleagues turned to a creature well-known for its ability to learn — the zebra finch. The tiny birds are regularly used in studies of learning because each male learns to sing a unique song from its father.
In a series of experiments, Ölveczky’s team used traditional conditioning techniques to change the timing of a bird’s song by speeding up or slowing down certain “syllables” in the song. They could also change which vocal muscles were activated and have the bird sing at a higher or lower pitch.
“But when you change the pitch of a syllable, the duration doesn’t change, and when you change the duration the pitch doesn’t change,” Ölveczky said. “It appears the neural circuits for the two features are separate.”
Additional evidence that the circuits for learning motor implementation and timing are distinct came when researchers lesioned the basal ganglia of the birds — the region of the brain long thought to play a critical role in song learning.
“The thinking had been that there was one circuit for song-learning in general,” Ölveczky said. “We found that if we lesioned the basal ganglia and repeated the pitch-shift experiment, the bird could no longer use the information it got from our feedback to change its behavior — in other words, it couldn’t learn.”
Experiments aimed at changing the birds’ timing, however, were just as effective, suggesting two separate learning circuits — with only one involving the basal ganglia.
Such independence and modularity is critical, Ölveczky said, because it allows different features of a behavior to be modified independently if circumstances change. Parallel learning of different features can also speed up the learning process and enable the flexibility we see in birdsong and many human motor skills.
“If you learn something — it could be your tennis serve, or it could be any behavior — and you need to slow it down or speed it up to fit some new contingency, you don’t have to completely re-learn the whole thing, you can just change the timing, and everything else will remain exactly the same.
“In fact, ‘slow practice,’ a technique used by many piano and dance teachers, makes good use of this modularity,” Ölveczky said. “Students are first taught to perform the movements of a piece slowly. Once they have learned it, all they need to do is get the timing right. The technique works because the two processes — motor implementation and timing — do not interfere with each other.”
The hope among researchers, Ölveczky said, is that a better understanding of how birds learn complex motor tasks such as singing unique songs will help shed new light on the neural underpinnings of learning in humans.
“For us, this is inspiration to look at similar types of questions in mammals,” he said. “The flexibility with which we can alter the spatial and temporal structure of our motor output is similar to songbirds, but our understanding of how the mammalian brain implements the underlying learning process is not anywhere near as advanced as for songbirds. The intriguing parallels in both circuitry and behavior, however, suggest a general principle of how the brain parses the motor skill learning process.”
Musicians have sharper minds are able to pick up mistakes and fix them quicker than the rest of us, according to new research.
The study, by researchers at the University of St Andrews, suggests that musical activity could protect against decline in mental abilities through age or illness.
The work, published in the journal Neuropsychologia, extends previous findings that mental abilities are positively related to musical skills. The researchers say that the latest findings demonstrate the potential for ‘far reaching benefits’ of musical activity on mental and physical well-being.
The study was led by St Andrews psychologist Dr Ines Jentzsch, who compared the cognitive ability of amateur musicians versus non-musicians in performing simple mental tasks.
The most striking difference she found lay in the musicians’ ability to recognise and correct mistakes. Not only that, but they responded faster than those with little or no musical training, with no loss in accuracy. This is perhaps not surprising since musicians learn to be constantly aware of their performance, but to not be overly affected by mistakes.
Dr Jentzsch, a Reader in the University’s School of Psychology and Neuroscience, commented, “Our study shows that even moderate levels of musical activity can benefit brain functioning.
“Our findings could have important implications as the processes involved are amongst the first to be affected by aging, as well as a number of mental illnesses such as depression. The research suggests that musical activity could be used as an effective intervention to slow, stop or even reverse age- or illness-related decline in mental functioning.”
The study compared groups of amateur musicians with varying levels of time they had spent in practicing their instrument to a non-musician control group. They then measured each group’s behavioural and brain responses to simple mental tests.
The results showed that playing a musical instrument, even at moderate levels, improves the ability to monitor our behavior for errors and adjust subsequent responses more effectively when needed.
Dr Jentzsch, herself a keen pianist, continued, “Musical activity cannot only immensely enrich our lives but the associated benefits for our physical and mental functioning could be even more far-reaching than proposed in our and previous research.
“Music plays an important role in virtually all societies. Nevertheless, in times of economic hardship, funds for music education are often amongst the first to be cut.
“We strongly encourage political decision makers to reconsider funding cuts for arts education and to increase public spending for music tuition.
“In addition, adults who have never played an instrument or felt too old to learn should be encouraged to take up music - it’s never too late.”
Sheep’s mucosa shows the way to more effective medicine for severe neurological diseases
New Danish/Italian research shows how medicine for the brain can be absorbed through the nose. This paves the way to more effective treatment of neurological diseases like Alzheimer’s and tumors in the brain.
A big challenge in medical science is to get medicine into the brain when treating patients with neurological diseases. The brain will do everything to keep foreign substances out and therefore the brains of neurological patients fight a constant, daily battle to throw out the medicine prescribed to help the patients.
The problem is the so-called blood-brain barrier, which prevents the active substances in medicine from travelling from the blood into the brain.
"The barrier is created because there is extremely little space between the cells in the brain’s capillar walls. Only very small molecules can enter through these openings and become active in the brain. And for the substances which finally get in, a new problem arises: The brain will do anything to throw them out again", explains assistant professor, Massimiliano di Cagno from in the Department of Physics, Chemistry and Pharmacy.
On this background science is looking for alternative pathways to the brain - and the nose is a candidate receiving much attention. From cocaine abusers it is well known that a substance can be absorbed through the nose and reach the brain extremely effective.
"It is very interesting to investigate if medical drugs can do the same", says di Cagno.
In recent years research has shown that it can be a very good idea to send medicine to the brain via the nose. The medicine can be sprayed into the nose and absorbed through the olfactory bulb, which is positioned at the front of the underside of the brain. Once the medicine passes the olfactory bulb there is direct access to the brain.
But there are many challenges to be solved before patients can be prescribed medication to be taken nasally.
"One of the biggest challenges is getting the olfactory bulb to absorb the substances aimed for the brain", explains di Cagno.
Together with Barbara Luppi from the University of Bologna in Italy he therefore investigated how to improve access to the olfactory bulb.
"It’s all done at nano-level, and the challenge is to find the vehicles that can transport the required medicine to the brain. In our attempts to come up with efficient vehicles we now point at some special liposomes and polymers that can bring an active substance to the olfactory bulb more than 2-3 times more efficiently than when using the standard techniques", explains di Cagno.
Liposomes are small spheres of fat, which is often used to protect active substance and carry them into the body. Polymers are long molecules that can be attached to the liposomes so that they can be made to look like water and thus not be rejected by the body’s immune system.
The improved efficiency is very important for the development of future medicines for neurological diseases. Today a pill has to contain millions of times more active ingredients than the brain needs to fight the disease. But because the blood-brain barrier is so effective and the brain so good at throwing foreign substances out, you have to send an extreme amount of active substances towards the brain.
"In a pill patients receive extremely more medicine than they need, and when we talk about medicines with severe and unpleasant side effects, it is not good. It is therefore very important that we get better at delivering exactly the amount of active substances needed - and no more", says di Cagno.
The new liposomes and polymers from his and Barbara Luppi’s work can not only carry the active ingredients efficiently through the slimy mucosa of a nose, so that they can reach the olfactory bulb. They can also do it over a longer time.
"We want to develop a vehicle that can release the active ingredients over a long time, over many hours, so the patients do not have to spray their nose too many times a day. In our experiments we still saw active substances being released after three hours, and we are very happy with that. One must remember that the nasal mucosa is constantly working to remove foreign objects and substances", says di Cagno.
The researchers performed their tests on the mucous membranes (mucosa) of sheep. Sheep and human mucosa and the mucinous secretions it produces in the nose are very similar. The sheep’s mucosa were cleaned, distributed on a tissue and then stretched over a container. In the container the researchers placed an active substance, hydrocortisone, that had been put inside different kinds of vehicles. After this the researchers observed how effectively and for how long time the various vehicles transported the hydrocortisone through the mucosa.
(Source: sdu.dk)
Malignant brain tumours can be transformed into benign forms
Cells of malignant brain tumours deceive our immune system so effectively that it starts working for them. But who lives by the sword, dies by the sword. Researchers from the Nencki Institute in Warsaw show how to deceive brain tumours and change malignant gliomas into benign forms.
The research team of Prof. Bożena Kamińska from the Nencki Institute of Experimental Biology of the Polish Academy of Sciences in Warsaw developed – so far only in animal model – a method of converting malignant gliomas (brain tumours) into benign forms. Since the cells of benign gliomas are subdued and sometimes even eliminated by the host’s immune system, the prospects for survival of sick animals significantly increase. This novel research was funded by the Polish National Science Centre.
The nervous system, including the brain, is inhabited, besides neurons and glial cells, by microglial cells. They support the nervous cells but also have important protective functions, patrolling the surroundings with their extenses and eliminating damaged or unnecessary cells. As macrophages of our immune system they also fight foreign bacteria, viruses and tumorous cells. Unfortunately, sometimes the glia cells themselves become cancerous. This is how brain tumours called gliomas form. However, they are not uniform entity and could differ significantly with respect to their behaviour and degree of malignancy. In benign variants the survival prospects for patients are quite high, while in the case of malignant gliomas few patients are expected to live longer than a year.
In 2007 the group of Prof. Kamińska showed that malignant gliomas can “re-program” the brain immune cells (microglia) to support tumour development instead of fighting it. Similarly the tumour even changed the protective immune cells recruited to the brain from blood and bone marrow (peripheral macrophages). The research to understand how the tumour deceives the host’s immune system and forces the microglial cells to support and foster its growth has taken several years.
The results of other research groups showed that in the case of breast cancer the factor responsible for changing the behaviour of tumour-infiltrating macrophages is the CSF1 protein, controlling the maturation of macrophages. Researchers from the Nencki Institute asked, whether a similar substance is not produces by the cells of the malignant gliomas.
Studies conducted by Prof. Kamińska’s group has shown that gliomas do not produce larger amounts of the CSF1 protein and this protein does not significantly impact tumour development. They were however lucky to discover the production of a different protein from the same family, the CSF2 protein. In benign tumours this protein was present in small amounts, while in malignant gliomas large amounts of it were discovered. Researchers from the Nencki Institute decided to investigate, whether this protein really influences tumour invasiveness. With the help of self-developed tools they turned off the gene responsible for the production of the CSF2 protein in glioma cells.
“We have observed that after turning off a single gene – the gene producing the CSF2 protein – the tumour cells stopped attracting the microglia and were not capable of converting these cells to support the tumour’s development. As a result the immune system started working as expected and the malignant tumour was transformed into a benign form. It did not disappear, but stopped growing”, says a PhD candidate Małgorzata Sielska from the Nencki Institute.
The protein responsible for “re-programming” the anti-tumour response and for high invasiveness of gliomas is present only in cancerous cells and is practically absent from healthy brain. Therefore researchers from the Nencki Institute suspect that when the gene responsible for its production is turned off in the brain, it would affect only the tumour.
Research on taming malignant brain tumours and converting them into benign forms has been conducted on mouse glioma cells growing in the brains of experimental animals, and published in the Journal of Pathology. Presently the group of Prof. Kamińska is checking the effectiveness of this method in the cells of human malignant gliomas. Preliminary results confirm that silencing one gene in human glioma cells growing in mouse brains also stops the growth of the tumour. Developing tools to turn off this gene’s expression, following the creation of appropriate carriers, will in the future open new possibilities for gene therapy in humans.
The findings has helped Nencki researchers develop small molecules (short peptides) which interfere with binding the CSF2 protein (expressed by tumorous cells) to the appropriate receptors on microglial cells. This way the signal coming from tumorous cells gets blocked and the microglia is prevented from “re-programming” itself. The developed molecules, together with relevant genetic tools, are covered by an international patent. Presently researchers work towards starting preclinical and clinical trials of this method.
The proposed solution holds great potential for therapies using small molecules – short peptides or in the case of gene therapy, short RNA silencing gene expression. Will this method really work? This will be confirmed by further experiments and tests. For Nencki researchers it is important that the patented molecules target only one fragment of the signalling pathway which functions between the cells of the malignant tumour and the microglia, thus guaranteeing that no other functions of the organism are affected. Moreover discovery of such an important signalling pathway encourages scientists to search for ways of blocking it in other places, which could be technically more feasible.
“Our research is investigative in nature and above all aims to explain why and how tumours develop. We conducted our research mostly on experimental models, mouse glioma cells or human glioma cells growing in mice. Therefore the road to develop drugs and therapies limiting the invasiveness of gliomas in human is still very long. Luckily we already discovered the molecule that is worth targeting”, sums up Prof. Kamińska.
Aphasia and bilingualism: Using one language to relearn another
In the era of globalization, bilingualism is becoming more and more frequent, and it is considered a plus. However, can this skill turn into a disadvantage, when someone acquires aphasia? More precisely, if a bilingual person suffers brain damage (i.e. stroke, head trauma, dementia) and this results in a language impairment called aphasia, then the two languages can be disrupted, thus increasing the challenge of language rehabilitation. According to Dr. Ana Inés Ansaldo, researcher at the Research Centre of the Institut universitaire de gériatrie de Montréal (IUGM), and a professor at the School of Speech Therapy and Audiology at Université de Montréal, research evidence suggests that bilingualism can be a lever—and not an obstacle—to aphasia recovery. A recent critical literature review conducted by Ana Inés Ansaldo and Ladan Ghazi Saidi -Ph.D student- points to three interventional avenues to promote cross-linguistic effects of language therapy (the natural transfer effects that relearning one language has on the other language).
It is important for speech-language pathologists to clearly identify a patient’s mastery of either language before and after aphasia onset, in order to decide which language to stimulate to achieve better results. Overall, the studies reviewed show that training the less proficient language (before or after aphasia onset)—and not the dominant language—results in bigger transfer effects on the untreated language.
Moreover, similarities between the two languages, at the levels of syntax, phonology, vocabulary, and meaning, will also facilitate language transfer. Specifically, working on “cognates,” or similar words in both languages, facilitates cross-linguistic transfer of therapy effects. For example, stimulating the word “table” in French will also help the retrieval of the word “table” in English, as these words have the same meaning and similar sounds in French and English. However, training “non-cognates” (words that sound alike, but do not share the same meanings) can be confusing for the bilingual person with aphasia.
In general, semantic therapy approaches, based on stimulating word meanings, facilitate transfer of therapy effects from the treated language to the untreated one. In other words, drilling based on the word’s semantic properties can help recovering both the target word and its cross-linguistic equivalent. For example, when the speech-language pathologist cues the patient to associate the word “dog” to the ideas of “pet,” “four legs” and “bark,”, the French word “chien”is as well activated, and will be more easily retrieved than by simply repeating the word “dog”.
“In the past, therapists would ask patients to repress or stifle one of their two languages, and focus on the target language. Today, we have a better understanding of how to use both languages, as one can support the other. This is a more complex approach, but it gives better results and respects the inherent abilities of bilingual people. Considering that bilinguals may soon represent the majority of our clients, this is definitely a therapeutic avenue we need to pursue,” explained Ana Inés Ansaldo, who herself is quadrilingual.
(Source: nouvelles.umontreal.ca)
Research attributes high rates of smoking among mentally ill to addiction vulnerability
People with mental illness smoke at much higher rates than the overall population. But the popular belief that they are self-medicating is most likely wrong, according to researchers at the Indiana University School of Medicine. Instead, they report, research indicates that psychiatric disease makes the brain more susceptible to addiction.
As smoking rates in the general population have fallen below 25 percent, smoking among the mentally ill has remained pervasive, encompassing an estimated half of all cigarettes sold. Despite the well-known health dangers of tobacco consumption, smoking among the mentally ill has long been widely viewed as “self-medication,” reducing the incentive among health care professionals to encourage such patients to quit.
"This is really a devastating problem for people with mental illness because of the broad health consequences of nicotine addiction," said R. Andrew Chambers, M.D., associate professor of psychiatry at the IU School of Medicine. "Nicotine addiction is the number one cause of premature illness and death in the United States, and most of that morbidity and mortality is concentrated in people with mental illness."
In a report published recently in the journal Addiction Biology, the research team lead by Dr. Chambers reported the results of experiments using an established animal model of schizophrenia in which rats display a neuropsychiatric syndrome that closely resembles the disease.
Both the schizophrenia-model rats and normal rats were given access to intravenous self-administration of nicotine.
"The mentally ill rats acquired nicotine use faster and consumed more nicotine," Dr. Chambers said. "Then when we cut them off from access to nicotine, they worked much harder to restore access to nicotine than did the normal ‘control’ rats."
In additional testing, the researchers found that administration of nicotine provided equal, but minimal, cognitive benefits to both groups of rats when performing a memory test. When the nicotine was withdrawn, however, both groups of rats were more cognitively impaired, so that any cognitive benefits to nicotine administration were “paid for” by cognitive impairments later.
“These results strongly suggest that what has changed in mental illness to cause smoking at such high rates results in a co-morbid addiction to which the mentally ill are highly biologically vulnerable. The evidence suggests that the vulnerability is an involuntary biological result of the way the brain is designed and how it develops after birth, rather than it being about a rational choice to use nicotine as a medicine,” Dr. Chambers said.
The data, he said, point to neuro-developmental mechanisms that increase the risk of addiction. Better understanding of those mechanisms could lead to better prevention and treatment strategies, especially among mentally ill smokers, Dr. Chambers said.
A video interview of Dr. Chambers discussing his research is available here.
(Source: news.medicine.iu.edu)
New research helps fight against motor neurone disease
New research from the University of Sheffield could offer solutions into slowing down the progression of motor neurone disease (MND).
Scientists from the University of Sheffield’s Institute for Translational Neuroscience (SITraN) conducted pioneering research assessing how the devastating debilitating disease affects individual patients.
MND is an incurable disease destroying the body’s cells which control movement causing progressive disability. Present treatment options for those with MND only have a modest effect in improving the patient’s quality of life.
Professor Pamela Shaw, Director of SITraN, and her research team worked in collaboration with a fellow world leading MND scientist Dr Caterina Bendotti and her group at the Mario Negri Institute for Pharmacological Research in Milan, Italy. Together they investigated why the progression of MND following onset of symptoms varies in speed, even in the presence of a known genetic cause of the condition.
The research, published in the scientific journal Brain, investigated two mouse models of MND caused by an alteration in the SOD1 gene, a known cause of MND in humans. One of the strains had a rapidly progressing disease course and the other a much slower change in the symptoms of MND. The teams from Sheffield and Milan looked at the factors which might explain the differences observed in speed and severity in the progression of the disease. They used a scientific technique known as gene expression profiling to identify factors within motor neurones that control vulnerability or resistance to MND in order to shed light on the factors important for the speed of motor neurone injury in human patients.
The study, funded by the Motor Neurone Disease Association, revealed new evidence, at the point of onset of the disease, before muscle weakness was observed, showing key differences in major molecular pathways and the way the protective systems of the body responded, between the profiles of the rapid progressing and slow progressing mouse models. In the case of the model with rapidly progressing MND the motor neurones showed reduced functioning of the cellular systems for energy production, disposal of waste proteins and neuroprotection. Motor neurones from the model with more slowly progressing MND showed an increase in protective inflammation and immune responses and increased function of the mechanisms that protect motor neurones from damage.
The research provides valuable clues about mechanisms that have the effect of slowing down the progression of disabling symptoms in MND.
Professor Shaw said that the state-of-the-art Functional Genomics laboratory in SITraN had enabled the research team to use a cutting edge technique called gene expression profiling.
“This enables us to ‘get inside’ the motor neurones in health and disease and understand better what is happening to cause motor neurone injury in MND,” she said.
“This project was a wonderful collaboration, supported by the MND Association, between research teams in Sheffield and Milan. We are very excited about the results which have given us some new ideas for treatment strategies which may help to slow disease progression in human MND.”
Dr Caterina Bendotti said: “MND is a clinically heterogenous disease with a high variability in its course which makes assessments of potential therapies difficult. Thanks to the recent evidence in our laboratory of a difference in the speed of symptom progression in two MND models carrying the same gene mutation and the successful collaboration with Professor Pamela Shaw and her team, we have identified some mechanisms that may help to predict the disease duration and eventually to slow it down.
“I strongly believe that the new hypotheses generated by this study and our ongoing collaboration are the prerequisites to be able to fight this disease.”
Brian Dickie from MND Association added: “These new and important findings in mice open up the possibility for new treatment approaches in man. It is heartening to see such a productive collaboration between two of the leading MND research labs in Europe, combining their unique specialist knowledge and technical expertise in the fight against this devastating disease.”
MND affects more than 6,000 sufferers in the UK with the majority of cases being sporadic but approximately five per cent of cases are familial or inherited with an identifiable genetic cause. Sufferers may lose their ability to walk, talk, eat and breathe.
(Source: sheffield.ac.uk)
Mouse studies reveal promising vitamin D-based treatment for MS
A diagnosis of multiple sclerosis (MS) is a hard lot. Patients typically get the diagnosis around age 30 after experiencing a series of neurological problems such as blurry vision, wobbly gait or a numb foot. From there, this neurodegenerative disease follows an unforgiving course.
Many people with MS start using some kind of mobility aid — cane, walker, scooter or wheelchair — by 45 or 50, and those with the most severe cases are typically bed-bound by 60. The medications that are currently available don’t do much to slow the relentless march of the disease.
In search of a better option for MS patients, a team of UW-Madison biochemists has discovered a promising vitamin D-based treatment that can halt — and even reverse — the course of the disease in a mouse model of MS. The treatment involves giving mice that exhibit MS symptoms a single dose of calcitriol, the active hormone form of vitamin D, followed by ongoing vitamin D supplements through the diet. The protocol is described in a scientific article that was published online in August in the Journal of Neuroimmunology.
"All of the animals just got better and better, and the longer we watched them, the more neurological function they regained," says biochemistry professor Colleen Hayes, who led the study.
MS afflicts around 400,000 people nationwide, with 200 new cases diagnosed each week. Early on, this debilitating autoimmune disease, in which the immune system attacks the myelin coating that protects the brain’s nerve cells, causes symptoms including weakness, loss of dexterity and balance, disturbances to vision, and difficulty thinking and remembering. As it progresses, people can lose the ability to walk, sit, see, eat, speak and think clearly.
Current FDA-approved treatments only work for some MS patients and, even among them, the benefits are modest. “And in the long term they don’t halt the disease process that relentlessly eats away at the neurons,” Hayes adds. “So there’s an unmet need for better treatments.”
While scientists don’t fully understand what triggers MS, some studies have linked low levels of vitamin D with a higher risk of developing the disease. Hayes has been studying this “vitamin D hypothesis” for the past 25 years with the long-term goal of uncovering novel preventive measures and treatments. Over the years, she and her researchers have revealed some of the molecular mechanisms involved in vitamin D’s protective actions, and also explained how vitamin D interactions with estrogen may influence MS disease risk and progression in women.
In the current study, which was funded by the National Multiple Sclerosis Society, Hayes’ team compared various vitamin D-based treatments to standard MS drugs. In each case, vitamin D-based treatments won out. Mice that received them showed fewer physical symptoms and cellular signs of disease.
First, Hayes’ team compared the effectiveness of a single dose of calcitriol to that of a comparable dose of a glucocorticoid, a drug now administered to MS patients who experience a bad neurological episode. Calcitriol came out ahead, inducing a nine-day remission in 92 percent of mice on average, versus a six-day remission in 58 percent for mice that received glucocorticoid.
"So, at least in the animal model, calcitriol is more effective than what’s being used in the clinic right now," says Hayes.
Next, Hayes’ team tried a weekly dose of calcitriol. They found that a weekly dose reversed the disease and sustained remission indefinitely.
But calcitriol can carry some strong side effects — it’s a “biological sledgehammer” that can raise blood calcium levels in people, Hayes says — so she tried a third regimen: a single dose of calcitriol, followed by ongoing vitamin D supplements in the diet. This one-two punch “was a runaway success,” she says. “One hundred percent of mice responded.”
Hayes believes that the calcitriol may cause the autoimmune cells attacking the nerve cells’ myelin coating to die, while the vitamin D prevents new autoimmune cells from taking their place.
While she is excited about the prospect of her research helping MS patients someday, Hayes is quick to point out that it’s based on a mouse model of disease, not the real thing. Also, while rodents are genetically homogeneous, people are genetically diverse.
"So it’s not certain we’ll be able to translate (this discovery to humans)," says Hayes. "But I think the chances are good because we have such a broad foundation of data showing protective effects of vitamin D in humans."
The next step is human clinical trials, a step that must be taken by a medical doctor, a neurologist. If the treatment works in people, patients with early symptoms of MS may never need to receive an official diagnosis.
"It’s my hope that one day doctors will be able to say, ‘We’re going to give you an oral calcitriol dose and ramp up the vitamin D in your diet, and then we’re going to follow you closely over the next few months. You’re just going to have this one neurological episode and that will be the end of it,’" says Hayes. "That’s my dream."
(Source: news.wisc.edu)
Made to Order at the Synapse: Dynamics of Protein Synthesis at Neuron Tip is Basis for Memory and Learning
Understanding RNA biology in dendrites may inform neurological and psychiatric illness therapeutics
Protein synthesis in the extensions of nerve cells, called dendrites, underlies long-term memory formation in the brain, among other functions. “Thousands of messenger RNAs reside in dendrites, yet the dynamics of how multiple dendrite messenger RNAs translate into their final proteins remain elusive,” says James Eberwine, PhD, professor of Pharmacology, Perelman School of Medicine at the University of Pennsylvania, and co-director of the Penn Genome Frontiers Institute.
Dendrites, which branch from the cell body of the neuron, play a key role in the communication between cells of the nervous system, allowing for many neurons to connect with each other. Dendrites detect the electrical and chemical signals transmitted to the neuron by the axons of other neurons. The synapse is the neuronal structure where this chemical connection is formed, and investigators surmise that it is here where learning and memory occur.
These structural and chemical changes – called synaptic plasticity — require rapid, new synthesis of proteins. Cells may use different rates of translation in different types of mRNA to produce the right amounts and ratios of required proteins.
Knowing how proteins are made to order – as it were - at the synapse can help researchers better understand how memories are made. Nevertheless, the role of this “local” environment in regulating which messenger RNAs are translated into proteins in a neuron’s periphery is still a mystery.
Eberwine, first author Tae Kyung Kim, PhD, a postdoc in the Eberwine lab, and colleagues including Jai Yoon Sul, PhD, assistant professor in Pharmacology, showed that protein translation of two dendrite mRNAs is complex in space and time, as reported online in Cell Reports this week.
“We needed to look at more than one RNA at the same time to get a better handle on real- world processes, and this is the first study to do that in a live neuron,” Eberwine explains.
At Home in the Hippocampus
“It’s not always one particular RNA that dominates at a translation hotspot versus another type of RNA,” says Eberwine. “Since there are 1,000 to 3,000 different mRNA types present in the dendrite overall, but not 1,000 to 3,000 different translational hot spots, do the mRNAs ‘take turns’ being translated in space and time at the ribosomes at the hotspots?”
The researchers engineered the glutamate receptor RNAs to contain different fluorescent proteins that are independently detectable, as well as a photo-switchable protein to determine when new proteins were being made. In the case of the photo-switchable protein studies, when an mRNA for the glutamate receptor protein is marked green, it means it has already been translated.
When a laser is passed over the green protein, it changes to red as a way of tagging when it has been been translated, and new proteins synthesized at that hotspot would be green, which is visible by the appearance of yellow fluorescence (green + red, as measured by light on the visible spectrum). These tricks of the light allow the team to keep track of newly made proteins over time and space.
“This is the first time this method of protein labeling has been used to measure the act of translation of multiple proteins over space and time in a quantitative way,” says Eberwine. “We call it quantitative functional genomics of live cell translation.”
“Our results suggest that the location of the translational hotspot is a regulator of the simultaneous translation of multiple messenger RNAs in nerve cell dendrites and therefore synaptic plasticity,” says Sul.
Laying the Groundwork
Almost 10 years ago, the Eberwine lab discovered that nerve-cell dendrites have the capacity to splice messenger RNA, a process once believed to take place only in the nucleus of cells. Here, a gene is copied into mRNA, which possesses both exons (mature mRNA regions that code for proteins) and introns (non-coding regions). mRNA splicing works by cutting out introns and merging the remaining exon pieces, resulting in an mRNA capable of being translated into a specific protein.
The vast array of proteins within the human body arises in part from the many ways that mRNAs can be spliced and reconnected. Specifically, splicing removes pieces of intron and exon regions from the RNA. The resulting spliced RNA is made into protein.
If the RNA has different exons spliced in and out of it, then different proteins can be made from this RNA. The Eberwine lab was successful in showing that splicing can occur in dendrites because they used sensitive technologies developed in their lab, which permits them to detect and quantify RNA splicing, as well as the translated protein in single isolated dendrites.
Understanding the dynamics of RNA biology and protein translation in dendrites promises to provide insight into regulatory mechanisms that may be modulated for therapeutic purposes in neurological and psychiatric illnesses. The directed development of therapeutics requires this detailed knowledge, says Eberwine.
Size matters: brain processes ‘big’ words faster than ‘small’ words
Bigger may not always be better, but when it comes to brain processing speed, it appears that size does matter.
A new study has revealed that words which refer to big things are processed more quickly by the brain than words for small things.
Researchers at the University of Glasgow had previously found that big concrete words – ‘ocean’, ‘dinosaur’, ‘cathedral’ – were read more quickly than small ones such as ‘apple’, ‘parasite’ and ‘cigarette’.
Now they have discovered that abstract words which are thought of as big – ‘greed’, ‘genius’, ‘paradise’ – are also processed faster than concepts considered to be small such as ‘haste’, ‘polite’ and ‘intimate’.
Dr Sara Sereno, a Reader in the Institute of Neuroscience and Psychology who led the study said: “It seems that size matters, even when it’s abstract and you can’t see it.”
The study, published in the online journal PLoS ONE, also involved researchers from Kent, Manchester and Oregon. Participants were presented with a series of real words referring to objects and concepts both big and small, as well as nonsense, made-up words, totalling nearly 500 items. The different word types were matched for length and frequency of use.
The 60 participants were asked to press one of two buttons to indicate whether each item was a real word or not. This decision took just over 500 milliseconds or around a half second per item. Results showed that words referring to larger objects or concepts were processed around 20 milliseconds faster than words referring to smaller objects or concepts.
“This might seem like a very short period of time,” said Dr Sereno, “but it’s significant and the effect size is typical for this task.”
Lead author Dr Bo Yao said: “It turned out that our big concrete and abstract words, like ‘shark’ and ‘panic’, tended to be more emotionally arousing than our small concrete and abstract words, like ‘acorn’ and ‘tight’. Our analysis showed that these emotional links played a greater role in the identification of abstract compared to concrete words.”
“Even though abstract words don’t refer to physical objects in the real world, we found that it’s actually quite easy to think of certain concepts in terms of their size,” said co-author Prof Paddy O’Donnell. “Everyone thinks that ‘devotion’ is something big and that ‘mischief’ is something small.”
Bigger things it seems, whether real or imagined, grab our attention more easily and our brains process them faster – even when they are represented by written words.