Splice this: End-to-end annealing demonstrated in neuronal neurofilaments
While popularly publicized neuroscience research focuses on structural and functional connectomes, timing patterns of axonal spikes, neural plasticity, and other areas of inquiry, the intraneuronal environment also receives a great deal of investigative attention.
One example is the study of cytoskeletal polymers called neurofilaments –intermediate filaments of nerve cells that and a major component of the neuronal cytoskeleton believed to provide the axon with structural support. Neurofilaments are transported into axons where they accumulate during development, causing the axons to expand in girth. This is important because the cross-sectional area of an axon influences the rate of propagation of the nerve impulse. The space-filling properties of these polymers are maximized by spoke-like projection domains called side-arms that function to space the polymers apart. Once in the axons these polymers (which are barely 10 nm in diameter) can grow to reach remarkably long lengths – 100,000 nm (0.1 mm) or more – but how they attain such lengths and how their length is regulated is not known. Recently, scientists at The Ohio State University – who previously showed that neurofilaments and vimentin filaments expressed in nonneuronal cell lines can lengthen by joining ends in a process known as end-to-end annealing – demonstrated robust and efficient end-to-end annealing of neurofilaments in nerve cells. In additions, the researchers reported evidence for a neurofilament-severing mechanism.
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Filed under neurofilaments nerve cells nerve impulse axons neuroscience science
Impaired visual signals might contribute to schizophrenia symptoms
By observing the eye movements of schizophrenia patients while playing a simple video game, a University of British Columbia researcher has discovered a potential explanation for some of their symptoms, including difficulty with everyday tasks.
The research, published in a recent issue of the Journal of Neuroscience, shows that, compared to healthy controls, schizophrenia patients had a harder time tracking a moving dot on the computer monitor with their eyes and predicting its trajectory. But the impairment of their eye movements was not severe enough to explain the difference in their predictive performance, suggesting a breakdown in their ability to interpret what they saw.
Lead author Miriam Spering, an assistant professor of ophthalmology and visual sciences, says the patients were having trouble generating or using an “efference copy” – a signal sent from the eye movement system in the brain indicating how much, and in what direction, their eyes have moved. The efference copy helps validate visual information from the eyes.
"An impaired ability to generate or interpret efference copies means the brain cannot correct an incomplete perception," says Spering, who conducted the dot-tracking experiments as a postdoctoral fellow at New York University, and is now conducting similar studies at UBC. The brain might fill in the blanks by extrapolating from prior experience, contributing to psychotic symptoms, such as hallucinations.
My vision would be a mobile device that patients could use to practice that skill, so they could more easily do common tasks that involve motion perception, such as walking along a crowded sidewalk.
"But just as a person might, through practice, improve their ability to predict the trajectory of a moving dot, a person might be able to improve their ability to generate or use that efference copy," Spering says. "My vision would be a mobile device that patients could use to practice that skill, so they could more easily do common tasks that involve motion perception, such as walking along a crowded sidewalk."
Filed under schizophrenia eye movements motion perception neuroscience science
It happens to all of us at least once each winter in Montreal. You’re walking on the sidewalk and before you know it you are slipping on a patch of ice hidden under a dusting of snow. Sometimes you fall. Surprisingly often you manage to recover your balance and walk away unscathed. McGill researchers now understand what’s going on in the brain when you manage to recover your balance in these situations. And it is not just a matter of good luck.
Prof. Kathleen Cullen and her PhD student Jess Brooks of the Dept of Physiology have been able to identify a distinct and surprisingly small cluster of cells deep within the brain that react within milliseconds to readjust our movements when something unexpected happens, whether it is slipping on ice or hitting a rock when skiing. What is astounding is that each individual neuron in this tiny region that is smaller than a pin’s head displays the ability to predict and selectively respond to unexpected motion.
This finding both overturns current theories about how we learn to maintain our balance as we move through the world, and also has significant implications for understanding the neural basis of motion sickness.
Scientists have theorized for some time that we fine-tune our movements and maintain our balance, thanks to a neural library of expected motions that we gain through “sensory conflicts” and errors. “Sensory conflicts” occur when there is a mismatch between what we think will happen as we move through the world and the sometimes contradictory information that our senses provide to us about our movements.
This kind of “sensory conflict” may occur when our bodies detect motion that our eyes cannot see (such as during plane, ocean or car travel), or when our eyes perceive motion that our bodies cannot detect (such as during an IMAX film, when the camera swoops at high speed over the edge of steep cliffs and deep into gorges and valleys while our bodies remain sitting still). These “sensory conflicts” are also responsible for the feelings of vertigo and nausea that are associated with motion sickness.
But while the areas of the brain involved in estimating spatial orientation have been identified for some time, until now, no one has been able to either show that distinct neurons signaling “sensory conflicts” existed, nor demonstrate exactly how they work. “We’ve known for some time that the cerebellum is the part of the brain that takes in sensory information and then causes us to move or react in appropriate ways,” says Prof. Cullen. “But what’s really exciting is that for the first time we show very clearly how the cerebellum selectively encodes unexpected motion, to then send our body messages that help us maintain our balance. That it is such a very exact neural calculation is exciting and unexpected.”
By demonstrating that these “sensory conflict” neurons both exist and function by making choices “on the fly” about which sensory information to respond to, Cullen and her team have made a significant advance in our understanding of how the brain works to keep our bodies in balance as we move about.
The research was done by recording brain activity in macaque monkeys who were engaged in performing specific tasks while at the same time being unexpectedly moved around by flight-simulator style equipment.
(Source: eurekalert.org)
Filed under motion sickness balance neurons cerebellum motor activity motion neuroscience science
A neural code for navigation
Neurons in the rat brain use a preexisting set of firing sequences to encode future navigational experiences
Specialized neurons called place cells, located in the hippocampus region of the brain, fire when an animal is in a particular location in its environment, and it is the linear sequence of their firing that encodes in the brain movement trajectories from one location to another. Building on previous work, George Dragoi and Susumu Tonegawa from the RIKEN–MIT Center for Neural Circuit Genetics have now shown that place cells have a preexisting inventory of firing sequences that they can use to encode multiple novel routes of exploration.
Specific sequences of place cells are known to encode spatial experiences, but it has been debated whether such sequences are formed during a new experience or preformed and adapted to specific experiences when required. Dragoi and Tonegawa recently showed that ‘future’ place cells fire in sequence while the animal is asleep, prior to experiencing a novel environment, and that animals use this preexisting neuronal firing pattern to rapidly learn how to navigate their surroundings.
To confirm and investigate this mechanism further, the researchers first recorded the neuronal activity of place cells in rats during one hour of sleep. Next, they monitored this activity during movement along a track that the rat had not previously explored, and later recorded it during movement along the same track with two additional lengths separated by right-angle turns. They then correlated the temporal pattern of place cell activity recorded during sleep with the spatial pattern of activity recorded while the animals were freely exploring the longer track.
The researchers found that the sequences of place cell activity were unique for each of the three lengths of the track and matched those recorded during sleep. “We had observed the same sequences as independent clusters of correlated temporal sequences during the preceding sleep period,” explains Dragoi.
The results suggest that rapid encoding of particular trajectories within novel environments is achieved during exploration by selecting from a set of preexisting temporal sequences that fired during sleep. In other words, hippocampal place cells appear to be prearranged into sets of sequential firing cells that can be adapted rapidly to encode for multiple spatial trajectories that the animal could undertake in its surroundings. Based on their data, Dragoi and Tonegawa predict that the sets of hippocampal place cells could encode for at least 15 unique future spatial experiences. In addition, their findings could explain the role that the hippocampus plays in humans in imagining future encounters within our own complex environment.
Filed under neuronal activity navigation place cells animal model hippocampus neuroscience science
A small percentage of people diagnosed with a mysterious neurological condition may only experience psychiatric changes - such as delusional thinking, hallucinations, and aggressive behavior - according to a new study by researchers in the Perelman School of Medicine at the University of Pennsylvania. In addition, people who had previously been diagnosed with this disease, called anti-NMDA receptor (anti-NMDAR) encephalitis, had relapses that only involved psychiatric behavior. In an article published Online First in JAMA Neurology, researchers suggest that, while isolated psychiatric episodes are rare in anti-NMDAR encephalitis cases, abnormal test findings or subtle neurological symptoms should prompt screening for the condition, as it is treatable with immunotherapies.
Within a large group of 571 patients with confirmed Anti-NMDAR Encephalitis, only 23 patients (4 percent) had isolated psychiatric episodes. Of the 23, 5 patients experienced the onset of behavior changes as their only symptoms, without neurological changes, while 18 patients had psychiatric symptoms emerge at the outset of a relapse of Anti-NMDAR Encephalitis in which no neurological changes were identified. After being treated for the condition, 83 percent of these patients recovered substantially or completely.
"While many patients with Anti-NMDAR Encephalitis present with isolated psychiatric symptoms, most of these patients subsequently develop, in a matter of days, additional neurological symptoms which help to make the diagnosis of the disease. In the current study, we find out that a small percentage of patients do not develop neurological symptoms, or sometimes these are very subtle and transitory. Studies using brain MRI and analysis of the cerebrospinal fluid may help to demonstrate signs of inflammation," said Josep Dalmau, MD, PhD, adjunct professor of Neurology. "For patients who have been previously diagnosed with Anti-NMDAR Encephalitis and are in remission, any behavior change may present a relapse and should be tested quickly and treated aggressively."
Anti-NMDAR Encephalitis is one of the most common forms of autoimmune encephalitis, and symptoms can include psychiatric symptoms, memory issues, speech disorders, seizures, involuntary movements, and loss of consciousness. In an earlier Penn Medicine study, 38 percent of all patients (and 46 percent of females with the condition) were found to have a tumor, most commonly it was an ovarian tumor. When correctly diagnosed and treated early, Anti-NMDAR Encephalitis can be effectively treated.
"For patients with new psychotic symptoms that are evaluated in centers where an MRI, EEG or spinal fluid test may not have been administered, there is a chance that Anti-NMDAR Encephalitis may be missed,” said lead author Matthew Kayser, MD, PhD, postdoctoral fellow and attending physician in Psychiatry at Penn. "However, the likelihood of pure or isolated new-onset psychosis to be anti-NMDAR encephalitis gradually decreases if no other symptoms emerge during the first 4 weeks of psychosis."
Anti-NMDAR Encephalitis was first characterized by Penn’s Josep Dalmau, MD, PhD, adjunct professor of Neurology, and David R. Lynch, MD, PhD, associate professor of Neurology and Pediatrics, in 2007. One year later, the same investigators, in collaboration with Rita Balice-Gordon, PhD, professor of Neuroscience, characterized the main syndrome and provided preliminary evidence that the antibodies have a pathogenic effect on the NR1 subunit of the NMDA receptor in the Lancet Neurology in December 2008. The disease can be diagnosed using a test developed at the University of Pennsylvania and currently available worldwide. With appropriate treatment, approximately 81 percent of patients significantly improve and, with a recovery process that takes an average of 2 years, can fully recover.
(Source: uphs.upenn.edu)
Filed under anti-NMDA receptor encephalitis psychiatric episodes immunotherapy neuroscience science
Researchers Uncover Cellular Mechanisms for Attention in the Brain
The ability to pay attention to relevant information while ignoring distractions is a core brain function. Without the ability to focus and filter out “noise,” we could not effectively interact with our environment. Despite much study of attention in the brain, the cellular mechanisms responsible for the effects of attention have remained a mystery… until now.
In a study appearing in the journal Nature, researchers from Dartmouth’s Geisel School of Medicine and the University of California Davis studied communications between synaptically connected neurons under conditions where subjects shifted their attention toward or away from visual stimuli that activated the recorded neurons. Using this highly sensitive measure of attention’s influence on neuron-to-neuron communication, they were able to demonstrate that attention operates at the level of the synapse to improve sensitivity to incoming signals, sharpen the precision of these signals, and selectively boost the transmission of attention-grabbing information while reducing the level of noisy or attention-disrupting information.
The results point to a novel mechanism by which attention shapes perception by selectively altering presynaptic weights to highlight sensory features among all the noisy sensory input.
"While our findings are consistent with other reported changes in neuronal firing rates with attention, they go far beyond such descriptions, revealing never-before tested mechanisms at the synaptic level," said study co-author Farran Briggs, PhD, assistant professor of Physiology and Neurobiology at the Geisel School of Medicine.
In addition to expanding our understanding of brain, this study could help people with attention deficits resulting from brain injury or disease, possibly leading to improved screening and new treatments.
Filed under attention attention deficit neurons neuronal communication perception neuroscience science
Princeton University researchers have created “souped up” versions of the calcium-sensitive proteins that for the past decade or so have given scientists an unparalleled view and understanding of brain-cell communication.
Reported July 18 in the journal Nature Communications, the enhanced proteins developed at Princeton respond more quickly to changes in neuron activity, and can be customized to react to different, faster rates of neuron activity. Together, these characteristics would give scientists a more precise and comprehensive view of neuron activity.
The researchers sought to improve the function of proteins known as green fluorescent protein/calmodulin protein (GCaMP) sensors, an amalgam of various natural proteins that are a popular form of sensor proteins known as genetically encoded calcium indicators, or GECIs. Once introduced into the brain via the bloodstream, GCaMPs react to the various calcium ions involved in cell activity by glowing fluorescent green. Scientists use this fluorescence to trace the path of neural signals throughout the brain as they happen.
GCaMPs and other GECIs have been invaluable to neuroscience, said corresponding author Samuel Wang, a Princeton associate professor of molecular biology and the Princeton Neuroscience Institute. Scientists have used the sensors to observe brain signals in real time, and to delve into previously obscure neural networks such as those in the cerebellum. GECIs are necessary for the BRAIN Initiative President Barack Obama announced in April, Wang said. The estimated $3 billion project to map the activity of every neuron in the human brain cannot be done with traditional methods, such as probes that attach to the surface of the brain. “There is no possible way to complete that project with electrodes, so you have to do it with other tools — GECIs are those tools,” he said.
Despite their value, however, the proteins are still limited when it comes to keeping up with the fast-paced, high-voltage ways of brain cells, and various research groups have attempted to address these limitations over the years, Wang said.
“GCaMPs have made significant contributions to neuroscience so far, but there have been some limits and researchers are running up against those limits,” Wang said.
One shortcoming is that GCaMPs are about one-tenth of a second slower than neurons, which can fire hundreds of times per second, Wang said. The proteins activate after neural signals begin, and mark the end of a signal when brain cells have (by neuronal terms) long since moved on to something else, Wang said. A second current limitation is that GCaMPs can only bind to four calcium ions at a time. Higher rates of cell activity cannot be fully explored because GCaMPs fill up quickly on the accompanying rush of calcium.
The Princeton GCaMPs respond more quickly to changes in calcium so that changes in neural activity are seen more immediately, Wang said. By making the sensors a bit more sensitive and fragile — the proteins bond more quickly with calcium and come apart more readily to stop glowing when calcium is removed — the researchers whittled down the roughly 20 millisecond response time of existing GCaMPs to about 10 milliseconds, Wang said.
The researchers also tweaked certain GCaMPs to be sensitive to different types of calcium ion concentrations, meaning that high rates of neural activity can be better explored. “Each probe is sensitive to one range or another, but when we put them together they make a nice choir,” Wang said.
The researchers’ work also revealed the location of a “bottleneck” in GCaMPs that occurs when calcium concentration is high, which poses a third limitation of the existing sensors, Wang said. “Now that we know where that bottle neck is, we think we can design the next generation of proteins to get around it,” Wang said. “We think if we open up that bottleneck, we can get a probe that responds to neuronal signals in one millisecond.”
The faster protein that the Princeton researchers developed could pair with work in other laboratories to improve other areas of GCaMP function, Wang said. For instance, a research group out of the Howard Hughes Medical Institute reported in Nature July 17 that it developed a GCaMP with a brighter fluorescence. Such improvements on existing sensors gradually open up more of the brain to exploration and understanding, said Wang, adding that the Princeton researchers will soon introduce their sensor into fly and mammalian brains.
“At some level, what we’ve done is like taking apart an engine, lubing up the parts and putting it back together. We took what was the best version of the protein at the time and made changes to the letter code of the protein,” Wang said. “We want to watch the whole symphony of thousands of neurons do their thing, and we think this variant of GCaMPs will help us do that better than anyone else has.”
(Source: blogs.princeton.edu)
Filed under neural activity proteins GCaMP calcium ions neuroscience science
Analysis of 26 networked autism genes suggests functional role in the cerebellum
A team of scientists has obtained intriguing insights into two groups of autism candidate genes in the mammalian brain that new evidence suggests are functionally and spatially related. The newly published analysis identifies two networked groupings from 26 genes associated with autism that are overexpressed in the cerebellar cortex, in areas dominated by neurons called granule cells.
The team, composed of neuroscientists and computational biologists, worked from a database providing expression levels of individual genes throughout the mouse brain, as complied in the open-source Allen Mouse Brain Atlas. To promote reproducibility, the scientists surveyed expression data of over 3000 genes, about three-fourths of all the genes listed in the Atlas for which two independent sets of data have been complied.
The work was led by Professor Partha Mitra of Cold Spring Harbor Laboratory (CSHL) and scientists from MindSpec, a nonprofit research organization, founded by Dr. Sharmila Banerjee-Basu.
Despite obvious genetic and neuroanatomical differences between mouse and human, the team explains, mouse models are extremely effective in dissecting out the role of specific genes, pathways, neuronal subtypes and brain regions in specific abnormal behaviors manifested in both mice and people.
Based on years of studies in both species, scientists now know of mutations affecting more than 300 genes whose occurrence correlates with autism susceptibility; more are certain to be identified. Some of these candidate genes are more strongly correlated with the illness than others, although correlation is not the same thing as direct evidence of causation.
Nevertheless, “the key question as yet unanswered,” notes Dr. Mitra, “concerns the way or ways in which particular mutations, singly or in combination, cause pathologies that result in the complex combination of symptoms that characterizes autism in children.” It is assumed that autism pathologies are the result of insults — genetic, environmental, or most likely both — sustained at the time of conception and early in development.
Dr. Idan Menashe, now of Ben-Gurion University of the Negev in Israel, and Dr. Pascal Grange, a postdoctoral researcher in the Mitra lab, demonstrated that co-expression of 26 autism genes was “significantly higher” than would occur by chance. “This suggests that these 26 genes have common neuro-functional properties,” says Dr. Menashe.
The team found two co-expressed networks or “cliques” of genes that are significantly enriched with autism genes. They then asked where in the mouse brain these cliques are expressed. Notably, genes in both groups showed significant overexpression in the cerebellar cortex, and particularly in regions in which granule cells predominate. “This result supports prior studies pointing to involvement of the cerebellum in autism,” says Dr. Grange. Specifically, a recent neuroimaging study highlighted functional subregions in the cerebellum as playing a role in both motor and cognitive tasks. Other genes associated with autism have been shown in other studies to play a role in the development of this brain region.
“Our study provides insights into co-expression properties of genes associated with autism and suggests specific brain regions implicated in pathology. Complementing these findings with additional genomic and neuroimaging analyses from both mouse and human brains will help in obtaining a broader picture of the autistic brain,” the team concludes.
Filed under autism ASD genes cerebellar cortex animal model granule cells mouse brain neuroscience science
A class of drug, called ACE inhibitors, which are used to lower blood pressure, slow the rate of cognitive decline typical of dementia, suggests research published in the online journal BMJ Open.
Furthermore, these drugs may even boost brain power, the research indicates.
The researchers compared the rates of cognitive decline in 361 patients who had either been diagnosed with Alzheimer’s disease, vascular dementia, or a mix of both.
Eighty five of the patients were already taking ACE inhibitors; the rest were not.
The researchers also assessed the impact of ACE inhibitors on the brain power of 30 patients newly prescribed these drugs, during their first six months of treatment. The average age of all the participants was 77.
Between 1999 and 2010, the cognitive decline of each patient was assessed using either the Standardised Mini Mental State Examination (SMMSE) or the Quick Mild Cognitive Impairment (Qmci) screen on two separate occasions, six months apart.
Compared with those not taking ACE inhibitors, those on these drugs experienced marginally slower rates of cognitive decline.
In those whose brain power had been assessed by Qmci, which is a more sensitive screen than the SMMSE, the difference was small, but significant.
And the brain power of those patients newly prescribed ACE inhibitors actually improved over the six month period, compared with those already taking them, and those not taking them at all.
This might be because these patients stuck to their medication regimen better, or it might be a by-product of better blood pressure control, or improved blood flow to the brain, suggest the authors.
But it is the first time that there has been any evidence to suggest that blood pressure lowering drugs may not only halt cognitive decline, but may actually improve brain power.
“This [study] supports the growing body of evidence for the use of ACE inhibitors and other [blood pressure lowering] agents in the management of dementia,” write the authors.
“Although the differences were small and of uncertain clinical significance, if sustained over years, the compounding effects may well have significant clinical benefits,” they add.
They caution, however, that recent evidence indicates that ACE inhibitors may be harmful in some cases, so if larger studies confirm that they work well in dementia, it may be only certain groups of patients with the condition who stand to benefit.
(Source: group.bmj.com)
Filed under ACE inhibitors dementia cognitive decline neuroscience science
Scientists ID compounds that target amyloid fibrils in Alzheimer’s, other brain diseases
UCLA chemists and molecular biologists have for the first time used a “structure-based” approach to drug design to identify compounds with the potential to delay or treat Alzheimer’s disease, and possibly Parkinson’s, Lou Gehrig’s disease and other degenerative disorders.
All of these diseases are marked by harmful, elongated, rope-like structures known as amyloid fibrils, linked protein molecules that form in the brains of patients.
Structure-based drug design, in which the physical structure of a targeted protein is used to help identify compounds that will interact with it, has already been used to generate therapeutic agents for a number of infectious and metabolic diseases.
The UCLA researchers, led by David Eisenberg, director of the UCLA–Department of Energy Institute of Genomics and Proteomics and a Howard Hughes Medical Institute investigator, report the first application of this technique in the search for molecular compounds that bind to and inhibit the activity of the amyloid-beta protein responsible for forming dangerous plaques in the brain of patients with Alzheimer’s and other degenerative diseases.
In addition to Eisenberg, who is also a professor of chemistry, biochemistry and biological chemistry and a member of UCLA’s California NanoSystems Institute, the team included lead author Lin Jiang, a UCLA postdoctoral scholar in Eisenberg’s laboratory and Howard Hughes Medical Institute researcher, and other UCLA faculty.
The research was published July 16 in eLife, a new open-access science journal backed by the Howard Hughes Medical Institute, the Max Planck Society and the Wellcome Trust.
A number of non-structure-based screening attempts have been made to identify natural and synthetic compounds that might prevent the aggregation and toxicity of amyloid fibrils. Such studies have revealed that polyphenols, naturally occurring compounds found in green tea and in the spice turmeric, can inhibit the formation of amyloid fibrils. In addition, several dyes have been found to reduce amyloid’s toxic effects, although significant side effects prevent them from being used as drugs.
Armed with a precise knowledge of the atomic structure of the amyloid-beta protein, Jiang, Eisenberg and colleagues conducted a computational screening of 18,000 compounds in search of those most likely to bind tightly and effectively to the protein.
Those compounds that showed the strongest potential for binding were then tested for their efficacy in blocking the aggregation of amyloid-beta and for their ability to protect mammalian cells grown in culture from the protein’s toxic effects, which in the past has proved very difficult. Ultimately, the researchers identified eight compounds and three compound derivatives that had a significant effect.
While these compounds did not reduce the amount of protein aggregates, they were found to reduce the protein’s toxicity and to increase the stability of amyloid fibrils — a finding that lends further evidence to the theory that smaller assemblies of amyloid-beta known as oligomers, and not the fibrils themselves, are the toxic agents responsible for Alzheimer’s symptoms.
The researchers hypothesize that by binding snugly to the protein, the compounds they identified may be preventing these smaller oligomers from breaking free of the amyloid-beta fibrils, thus keeping toxicity in check.
An estimated 5 million patients in the U.S. suffer from Alzheimer’s disease, the most common form of dementia. Alzheimer’s health care costs in have been estimated at $178 billion per year, including the value of unpaid care for patients provided by nearly 10 million family members and friends.
In addition to uncovering compounds with therapeutic potential for Alzheimer’s disease, this research presents a new approach for identifying proteins that bind to amyloid fibrils — an approach that could have broad applications for treating many diseases.
Filed under neurodegenerative diseases amyloid fibrils amyloid beta alzheimer's disease oligomers neuroscience science
