Posts tagged science
Posts tagged science
Diseases of the central nervous system are a big burden to society. According to estimates, they cost €800 billion per year in Europe. And for most of them, there is no definitive cure. This is true, for example, for Parkinson disease. Although good treatments exist to manage its symptoms, they become more and more ineffective as the disease progresses. Now, the EU-funded REPLACES project, completed in 2013, which associated scientists with clinicians, has shed light on the abnormal working of a particular brain circuitry related to Parkinson’s disease. The results of the project suggest that these same circuits are implicated in different forms of pathologies. And this gives important insights into the possible common links between neurodegenerative diseases such as Parkinson and intellective disabilities or autism.
Existing treatments for Parkinson are very effective at the beginning. When the disease progresses, however, drugs, such as levodopa and so-called dopamine agonists, produce side effects that are sometimes even worse than the initial symptoms of the condition. In particular, they cause a complication called dyskinesia, characterised by abnormal involuntary movements. Therapies are therefore sought that allow better management of symptoms.
The project focused on the study of a highly plastic brain circuitry, which connects regions of the cerebral cortex with the basal ganglia. It is involved in very important functions such as learning and memory. “This system, based onglutamate as a mean of signalling between neurons, has also been discovered to be damaged in Parkinson disease,” says Monica Di Luca, professor of neuropharmacology at the University of Milan, Italy, and the project coordinator. She adds: “Parkinson’s more well-known and characteristic trait is the selective loss of cells producers of neurotransmitter dopamine.”
Researchers involved into the project studied the function and plasticity of this circuit in different animal models of Parkinson disease, from mice to non-human primates. They found that exactly the same alterations were present and conserved. This makes it an interesting and alternative target for trying to re-establish the correct functioning and reverse the symptoms of the disease.
One expert agrees with the need to target alternative target systems. “What researchers are trying to do is to intervene to modulate other systems that do not involve dopamine and obtain a better symptoms management,” explains Erwan Bezard, a researcher at the Neurodenerative Diseases Institute at the University of Bordeaux, in France. He also works on alternative targets in Parkinson disease. In monkeys, compounds that target glutamate receptors, used in combination with traditional drugs, have previously shown to improve some deficits in voluntary motor control.
But the research has also shed some light into apparently unrelated diseases. It is becoming more and more obvious that the same alterations in the working of the communication systems among neurons are shared among different diseases. “This is why we speak about ‘synaptopathies’: there are common players among Parkinson disease, autism and other forms of intellectual disabilities and even schizophrenia. Several of the mutated genes are the same, and affect the signalling systems through common molecules,” says Claudia Bagni, who works on synaptic plasticity in the context of intellectual disabilities at the University of Leuven, in Belgium and University of Rome Tor Vergata, in Italy. “For example, the glutamatergic system is also affected in the X-fragile syndrome, the most common form of inherited intellectual disability.”
Progress is in sight thanks to a much better understanding of the working of the abnormal synapses in Parkinson disease, and experiments performed in monkeys showing encouraging results. Indeed, “the team studied human primates, the model system closest to humans, and therefore their findings are relevant to human health.” says Bagni. Project researchers hope the door is now opened for the first clinical trials in humans. “We have identified a potential new target for treatment, and tested a couple of molecules in animals,” says Di Luca, the “next step would be to find a partnership with pharmaceutical industries interested in pursuing this research.”
Harvard neuroscientists have made a discovery that turns 160 years of neuroanatomy on its head.
Myelin, the electrical insulating material in the body long known to be essential for the fast transmission of impulses along the axons of nerve cells, is not as ubiquitous as thought, according to new work led by Professor Paola Arlotta of the Harvard Stem Cell Institute (HSCI) and the University’s Department of Stem Cell and Regenerative Biology, in collaboration with Professor Jeff Lichtman of Harvard’s Department of Molecular and Cellular Biology.
“Myelin is a relatively recent invention during evolution,” says Arlotta. “It’s thought that myelin allowed the brain to communicate really fast to the far reaches of the body, and that it has endowed the brain with the capacity to compute higher-level functions.”
In fact, loss of myelin is a feature in a number of devastating diseases, including multiple sclerosis and schizophrenia.
But the new research shows that despite myelin’s essential roles in the brain, “some of the most evolved, most complex neurons of the nervous system have less myelin than older, more ancestral ones,” said Arlotta, co-director of the HSCI neuroscience program.
What this means, she said, is that the higher one looks in the cerebral cortex — closer to the top of the brain, which is its most evolved part — the less myelin one finds. Not only that, but “neurons in this part of the brain display a brand-new way of positioning myelin along their axons that has not been previously seen. They have ‘intermittent myelin’ with long axon tracts that lack myelin interspersed among myelin-rich segments.”
“Contrary to the common assumptions that neurons use a universal profile of myelin distribution on their axons, the work indicates that different neurons choose to myelinate their axons differently,” Arlotta said. “In classic neurobiology textbooks, myelin is represented on axons as a sequence of myelinated segments separated by very short nodes that lack myelin. This distribution of myelin was tacitly assumed to be always the same, on every neuron, from the beginning to the end of the axon. This new work finds this not to be the case.”
The results of the research by Arlotta and postdoctoral fellow Giulio Srubek Tomassy, the first author on the report, are published in the latest edition of the journal Science.
The paper is accompanied by a “perspective” by R. Douglas Fields of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, who said that Arlotta and Tomassy’s findings raise important questions about the purpose of myelin, and “are likely to spark new concepts about how information is transmitted and integrated in the brain.”
Arlotta and Tomassy collaborated closely on the new work with postdoctoral fellow Daniel Berger of the Lichtman lab, which generated one of the two massive electron microscopy databases that made the work possible.
“The fact that it is the most evolved neurons, the ones that have expanded dramatically in humans, suggest that what we’re seeing might be the ‘future.’ As neuronal diversity increases and the brain needs to process more and more complex information, neurons change the way they use myelin to achieve more,” said Arlotta.
Tomassy said it is possible that these profiles of myelination “may be giving neurons an opportunity to branch out and ‘talk’ to neighboring neurons.” For example, because axons cannot make synaptic contacts when they are myelinated, one possibility is that these long myelin gaps may be needed to increase neuronal communication and synchronize responses across different neurons. He and Arlotta postulate that the intermittent myelin may be intended to fine-tune the electrical impulses traveling along the axons, in order to allow the emergence of highly complex neuronal behaviors.
Older people who have apathy but not depression may have smaller brain volumes than those without apathy, according to a new study published in the April 16, 2014, online issue of Neurology®, the medical journal of the American Academy of Neurology. Apathy is a lack of interest or emotion.
“Just as signs of memory loss may signal brain changes related to brain disease, apathy may indicate underlying changes,” said Lenore J. Launer, PhD, with the National Institute on Aging at the National Institutes of Health (NIH) in Bethesda, MD, and a member of the American Academy of Neurology. “Apathy symptoms are common in older people without dementia. And the fact that participants in our study had apathy without depression should turn our attention to how apathy alone could indicate brain disease.”
Launer’s team used brain volume as a measure of accelerated brain aging. Brain volume losses occur during normal aging, but in this study, larger amounts of brain volume loss could indicate brain diseases.
For the study, 4,354 people without dementia and with an average age of 76 underwent an MRI scan. They were also asked questions that measure apathy symptoms, which include lack of interest, lack of emotion, dropping activities and interests, preferring to stay at home and having a lack of energy.
The study found that people with two or more apathy symptoms had 1.4 percent smaller gray matter volume and 1.6 percent less white matter volume compared to those who had less than two symptoms of apathy. Excluding people with depression symptoms did not change the results.
Gray matter is where learning takes place and memories are stored in the brain. White matter acts as the communication cables that connect different parts of the brain.
“If these findings are confirmed, identifying people with apathy earlier may be one way to target an at-risk group,” Launer said.
A new study points to a conceptually novel therapeutic strategy for treating depression. Instead of dampening neuron firing found with stress-induced depression, researchers demonstrated for the first time that further activating these neurons opens a new avenue to mimic and promote natural resilience. The findings were so surprising that the research team thinks it may lead to novel targets for naturally acting antidepressants. Results from the study are published online April 18 in the journal Science.
Researchers from the Icahn School of Medicine at Mount Sinai point out that in mice resilient to social defeat stress (a source of constant stress brought about by losing a dispute or from a hostile interaction), their cation channel currents, which pass positive ions in dopamine neurons, are paradoxically elevated to a much greater extent than those of depressed mice and control mice. This led researchers to experimentally increase the current of cation channels with drugs in susceptible mice, those prone to depression, to see whether it would enhance coping and resilience. They found that such boosting of cation channels in dopamine neurons caused the mice to tolerate the increased stress without succumbing to depression-related symptoms, and unexpectedly the hyperactivity of the dopamine neurons was normalized.
Allyson K. Friedman, PhD, Postdoctoral Fellow in Pharmacology and Systems Therapeutics at the Icahn School of Medicine at Mount Sinai, and the study’s lead author said: “To achieve resiliency when under social stress, the brain must perform a complex balancing act in which negative stress-related changes in the brain actively trigger positive changes. But that can only happen once the negative changes reach a tipping point.”
The research team used optogenetics, a combination of laser optics and gene virus transfer, to control firing activity of the dopamine neurons. When light activation or the drug lamotrigine is given to these neurons, it drives the current and neuron firing higher. But at a certain point, it triggers compensatory mechanisms, normalizes neuron firing, and achieves a kind of homeostatic (or balanced) resilience.
"To our surprise, we found that resilient mice, instead of avoiding deleterious changes in the brain, experience further deleterious changes in response to stress, and use them beneficially," said Ming-Hu Han, PhD, at Icahn School of Medicine at Mount Sinai, who leads the study team as senior author.
Drs. Friedman and Han see this counterintuitive finding as stimulating research in a conceptually novel antidepressant strategy. If a drug could enhance coping and resilience by pushing depressed (or susceptible) individuals past the tipping point, it potentially might have fewer side effects, and work as a more naturally acting antidepressant.
Eric Nestler, MD, PhD, at the Icahn School of Medicine at Mount Sinai praised the study. “In this elegant study, Drs. Friedman and Han and their colleagues reveal a highly novel mechanism that controls an individual’s susceptibility or resilience to chronic social stress. The discoveries have important implications for the development of new treatments for depression and other stress-related disorders.”
A ground-breaking computer technology raises hope for people struck by ischemic stroke (缺乏血性中風), which is a very common kind of stroke accounting for over 80 per cent of overall stroke cases. Developed by research experts at The Hong Kong Polytechnic University (PolyU), this novel application that expertly analyses brain scans could save lives by helping doctors determine if a patient has the life-threatening condition.
The CAD stroke technology is capable of detecting signs of stroke from computed tomography (CT) scans. A CT scan uses X-rays to take pictures of the brain in slices. When blood flow to the brain is blocked, an area of the brain turns softer or decreases in density due to insufficient blood flow, pointing to an ischemic stroke.
As demonstrated by Dr Fuk-hay Tang from the Department of Health Technology and Informatics at PolyU, CT scans are fed into the CAD stroke computer, which will make sophisticated calculations and comparisons to locate areas suspected of insufficient blood flow. In 10 minutes, scans with highlighted areas of abnormality will come out for doctors’ review. Early changes including loss of insular ribbon, loss of sulcus and dense MCA signs can be identified, helping doctors determine if blood clots are present.
Ischemic stroke occurs when an artery to the brain is blocked, cutting off oxygen and essential nutrients being sent to the brain, and brain cells will die in just a few minutes. Clot-busting drugs are effective in minimising brain damage but they should be administered within 3 hours from the onset. Immediate diagnosis and treatment are therefore absolutely essential.
In that sense, a diagnostic tool that can expedite the process will be greatly helpful in saving lives. As Dr Tang shared with us, “The clock is ticking for stroke patients. Medications taken in three hours from the onset of stroke are deemed most effective. Chances of recovery decrease with every minute passing by. It usually takes half an hour for the ambulance to arrive at the hospital, at best. Then, another 45 minutes to 1 hour are needed for CT or MRI scans after the patient has been checked and dispatched for the test, which means some waiting and time will slip by. Afterwards, the brain scan will take another 10 to 15 minutes. If our tool can help doctors arrive at a diagnosis in 10 minutes, the shorter response time will make meeting the target more achievable.”
“It might come in handy for physicians with less experience in stroke,” added Dr Tang, “and patient care can be maintained in hospitals where human and other vital resources are already stretched to the limit.”
The life-saving application can also detect subtle and minute changes in the brain that would escape the eye of even an experienced specialist, slashing the chances of missed diagnosis. False-positive and false-negative cases, and other less serious conditions that mimic a stroke can also be ruled out, allowing a fully-informed decision to be made.
Furthermore, equipped with the built-in artificial intelligence feature, the CAD stroke technology would learn by experience. With every scan passing through, along with feedback from stroke specialists, the application will improve on its accuracy over time.
“It is important to identify stroke patients and help them get the urgent treatment they need,” said Dr Tang. “Prompt and accurate diagnosis is in the forefront of our minds when designing the medical application. Healthcare professionals should focus on what they do best and let us take care of the rest.”
By discovering a new mechanism that allows blood to enter the brain immediately after a stroke, researchers at UC Irvine and the Salk Institute have opened the door to new therapies that may limit or prevent stroke-induced brain damage.
A complex and devastating neurological condition, stroke is the fourth-leading cause of death and primary reason for disability in the U.S. The blood-brain barrier is severely damaged in a stroke and lets blood-borne material into the brain, causing the permanent deficits in movement and cognition seen in stroke patients.
Dritan Agalliu, assistant professor of developmental & cell biology at UC Irvine, and Axel Nimmerjahn of the Salk Institute for Biological Studies developed a novel transgenic mouse strain in which they use a fluorescent tag to see the tight, barrier-forming junctions between the cells that make up blood vessels in the central nervous system. This allows them to perceive dynamic changes in the barrier during and after strokes in living animals.
While observing that barrier function is rapidly impaired after a stroke (within six hours), they unexpectedly found that this early barrier failure is not due to the breakdown of tight junctions between blood vessel cells, as had previously been suspected. In fact, junction deterioration did not occur until two days after the event.
Instead, the scientists reported dramatic increases in carrier proteins called serum albumin flowing directly into brain tissue. These proteins travel through the cells composing blood vessels – endothelial cells – via a specialized transport system that normally operates only in non-brain vessels or immature vessels within the central nervous system. The researchers’ work indicates that this transport system underlies the initial failure of the barrier, permitting entry of blood material into the brain immediately after a stroke (within six hours).
“These findings suggest new therapeutic directions aimed at regulating flow through endothelial cells in the barrier after a stroke occurs,” Agalliu said, “and any such therapies have the potential to reduce or prevent stroke-induced damage in the brain.”
His team is currently using genetic techniques to block degradation of the tight junctions between endothelial cells in mice and examining the effect on stroke progression. Early post-stroke control of this specialized transport system identified by the Agalliu and Nimmerjahn labs may spur the discovery of imaging methods or biomarkers in humans to detect strokes as early as possible and thereby minimize damage.
What’s one of your worst memories? How did it make you feel? According to psychologists, remembering the emotions felt during a negative personal experience, such as how sad you were or how embarrassed you felt, can lead to emotional distress, especially when you can’t stop thinking about it.
When these negative memories creep up, thinking about the context of the memories, rather than how you felt, is a relatively easy and effective way to alleviate the negative effects of these memories, a new study suggests.
Researchers at the Beckman Institute at the University of Illinois, led by psychology professor Florin Dolcos of the Cognitive Neuroscience Group, studied the behavioral and neural mechanisms of focusing away from emotion during recollection of personal emotional memories, and found that thinking about the contextual elements of the memories significantly reduced their emotional impact.
“Sometimes we dwell on how sad, embarrassed, or hurt we felt during an event, and that makes us feel worse and worse. This is what happens in clinical depression—ruminating on the negative aspects of a memory,” Dolcos said. “But we found that instead of thinking about your emotions during a negative memory, looking away from the worst emotions and thinking about the context, like a friend who was there, what the weather was like, or anything else non-emotional that was part of the memory, will rather effortlessly take your mind away from the unwanted emotions associated with that memory. Once you immerse yourself in other details, your mind will wander to something else entirely, and you won’t be focused on the negative emotions as much.”
This simple strategy, the study suggests, is a promising alternative to other emotion-regulation strategies, like suppression or reappraisal.
“Suppression is bottling up your emotions, trying to put them away in a box. This is a strategy that can be effective in the short term, but in the long run, it increases anxiety and depression,” explains Sanda Dolcos, co-author on the study and postdoctoral research associate at the Beckman Institute and in the Department of Psychology.
“Another otherwise effective emotion regulation strategy, reappraisal, or looking at the situation differently to see the glass half full, can be cognitively demanding. The strategy of focusing on non-emotional contextual details of a memory, on the other hand, is as simple as shifting the focus in the mental movie of your memories and then letting your mind wander.”
Not only does this strategy allow for effective short-term emotion regulation, but it has the possibility of lessening the severity of a negative memory with prolonged use.
In the study, participants were asked to share their most emotional negative and positive memories, such as the birth of a child, winning an award, or failing an exam, explained Sanda Dolcos. Several weeks later participants were given cues that would trigger their memories while their brains were being scanned using magnetic resonance imaging (MRI). Before each memory cue, the participants were asked to remember each event by focusing on either the emotion surrounding the event or the context. For example, if the cue triggered a memory of a close friend’s funeral, thinking about the emotional context could consist of remembering your grief during the event. If you were asked to remember contextual elements, you might instead remember what outfit you wore or what you ate that day.
“Neurologically, we wanted to know what happened in the brain when people were using this simple emotion-regulation strategy to deal with negative memories or enhance the impact of positive memories,” explained Ekaterina Denkova, first author of the report. “One thing we found is that when participants were focused on the context of the event, brain regions involved in basic emotion processing were working together with emotion control regions in order to, in the end, reduce the emotional impact of these memories.”
Using this strategy promotes healthy functioning not only by reducing the negative impact of remembering unwanted memories, but also by increasing the positive impact of cherished memories, Florin Dolcos said.
In the future, the researchers hope to determine if this strategy is effective in lessening the severity of negative memories over the long term. They also hope to work with clinically depressed or anxious participants to see if this strategy is effective in alleviating these psychiatric conditions.
These results were published in Social Cognitive and Affective Neuroscience.
A major challenge of systems biology is understanding how phenomena at the cellular scale correlate with activity at the organism level. A concerted effort has been made especially in the brain, as scientists are aiming to clarify how neural activity is translated into consciousness and other complex brain activities. One example of the technologies needed is whole-brain imaging at single-cell resolution. This imaging normally involves preparing a highly transparent sample that minimizes light scattering and then imaging neurons tagged with fluorescent probes at different slices to produce a 3D representation. However, limitations in current methods prevent comprehensive study of the relationship. A new high-throughput method, CUBIC (Clear, Unobstructed Brain Imaging Cocktails and Computational Analysis), published in Cell, is a great leap forward, as it offers unprecedented rapid whole-brain imaging at single cell resolution and a simple protocol to clear and transparentize the brain sample based on the use of aminoalcohols.
In combination with light sheet fluorescence microscopy, CUBIC was tested for rapid imaging of a number of mammalian systems, such as mouse and primate, showing its scalability for brains of different size. Additionally, it was used to acquire new spatial-temporal details of gene expression patterns in the hypothalamic circadian rhythm center. Moreover, by combining images taken from opposite directions, CUBIC enables whole brain imaging and direct comparison of brains in different environmental conditions.
CUBIC overcomes a number of obstacles compared with previous methods. One is the clearing and transparency protocol, which involves serially immersing fixed tissues into just two reagents for a relatively short time. Second, CUBIC is compatible with many fluorescent probes because of low quenching, which allows for probes with longer wavelengths and reduces concern for scattering when whole brain imaging while at the same time inviting multi-color imaging. Finally, it is highly reproducible and scalable. While other methods have achieved some of these qualities, CUBIC is the first to realize all.
CUBIC provides information on previously unattainable 3D gene expression profiles and neural networks at the systems level. Because of its rapid and high-throughput imaging, CUBIC offers extraordinary opportunity to analyze localized effects of genomic editing. It also is expected to identify neural connections at the whole brain level. In fact, last author Hiroki Ueda is optimistic about further application to even larger mammalian systems. “In the near future, we would like to apply CUBIC technology to whole-body imaging at single cell resolution.”
As reported in a paper published online today in the journal Nature, Caltech biologist David J. Anderson and his colleagues have genetically identified neurons that control aggressive behavior in the mouse hypothalamus, a structure that lies deep in the brain (orange circle in the image). Researchers have long known that innate social behaviors like mating and aggression are closely related, but the specific neurons in the brain that control these behaviors had not been identified until now.
The interdisciplinary team of graduate students and postdocs, led by Caltech senior research fellow Hyosang Lee, found that if these neurons are strongly activated by pulses of light, using a method called optogenetics, a male mouse will attack another male or even a female. However, weaker activation of the same neurons will trigger sniffing and mounting: mating behaviors. In fact, the researchers could switch the behavior of a single animal from mounting to attack by gradually increasing the strength of neuronal stimulation during a social encounter (inhibiting the neurons, in contrast, stops these behaviors dead in their tracks).
These results suggest that the level of activity within the population of neurons may control the decision between mating and fighting.
The neurons initially were identified because they express a protein receptor for the hormone estrogen, reinforcing the view that estrogen plays an important role in the control of male aggression, contrary to popular opinion. Because the human brain contains a hypothalamus that is structurally similar to that in the mouse, these results may be relevant to human behavior as well.
Fruit flies are pretty predictable when it comes to scheduling their days, with peaks of activity at dawn and dusk and rest times in between. Now, researchers reporting in the Cell Press journal Cell Reports on April 17th have found that the clusters of brain cells responsible for each of those activity peaks—known as the morning and evening oscillators, respectively—don’t work alone. For flies’ internal clocks to follow the sun, cooperation is key.
"Without proper synchronization, circadian clocks are useless or can even be deleterious to organisms," said Patrick Emery from the University of Massachusetts Medical School. "In addition, most organisms have to detect changes in day length to adapt their rhythms to seasons.
"Our work clearly shows that light is detected by individual neurons that then communicate with each other to properly define the phase of circadian behavior," he added. "This emphasizes the importance of neural interaction in the generation of properly phased circadian rhythms."
In the brains of Drosophila fruit flies, there are approximately 150 circadian neurons, explained Emery and coauthor Yong Zhang, including a small group of morning oscillators that promote activity early in the day and another group of evening oscillators that promote activity later. Morning oscillators also set the pace of molecular rhythms in other parts of the brain, and hence the phase of circadian behavior. Scientists had thought they did this by relying heavily on their own sensitivity to light—what Emery calls “cell-autonomous photoreception.” Indeed, these cells do express fruit flies’ dedicated photoreceptor Cryptochrome (CRY). But recent evidence suggested that something was missing from that simple view.
In the new study, the researchers manipulated CRY’s ability to function through another clock component, known as JET (short for Jetlag), in different circadian neurons and watched what happened. The studies show that light detection by the morning oscillators isn’t enough to keep flies going about their business in a timely way. They need those evening oscillators too.
JET’s role is bigger than expected as well. In addition to enabling cell-autonomous light sensing, the protein also allows distinct circadian neurons to talk to each other in rapid fashion after light exposure, although the researchers don’t yet know how.
The new model also suggests that flies and mammals have more similarities than had been appreciated when it comes to synchronizing their activities to the sun, the researchers say. In mammals, specific neurons of the circadian pacemaker of the brain (known as the Suprachiasmatic Nucleus or SCN) receive light input from the retina. Those cells then communicate with pacemaker neurons, which resets the circadian network as a whole.