Posts tagged neurons
Articles and news from the latest research reports.
Researchers identify the neural circuits that modulate REM sleep
A team of scientists led by Dr. Antoine Adamantidis, a researcher at the Douglas Mental Health University Institute and an assistant professor at McGill University, has released the findings from their latest study, which will appear in the October issue of the prestigious scientific journal Nature Neuroscience.
(Image: iStockphoto)
Previous studies had established an association between the activity of certain types of neurons and the phase of sleep known as REM (rapid eye movement). Researchers on the team of Dr. Antoine Adamantidis identified, for the first time, a precise causal link between neuronal activity in the lateral hypothalamus (LH) and the state of REM sleep. Using optogenetics, they were able to induce REM sleep in mice and modulate the duration of this sleep phase by activating the neuronal network in this area of the brain.
This achievement is an important contribution to the understanding of sleep mechanisms in the brains of mammals, as well as the underlying neuronal network, which is still not well understood despite recent breakthroughs in neuroscience.
Better understanding how sleep is modulated to reduce sleep disorders
“These research findings could help us better grasp how the brain controls sleep and better understand the role of sleep in humans. These results could also lead to new therapeutic strategies to treat sleep disorders along with associated neuropsychiatric problems,” stated Dr. Antoine Adamantidis, who is also the Canada Research Chair in Neural Circuits and Optogenetics.
What is REM (rapid eye movement) sleep?
There are two types of sleep: REM and non-REM sleep. In humans, non-REM sleep has four stages. REM sleep, or deep sleep, is generally associated with dreaming and is a phase when the brain is very active, even though people are in a heavy sleep, their eyes move rapidly (hence the name), and their bodies have an almost total loss of muscle tonus.
Although our understanding of the mechanisms that control the wake and sleep cycle has progressed in recent years, many frontiers remain unexplored. However, we do know that a disruption in sleep can lead to adverse effects on physical and mental health in humans.
Optogenetics, a revolutionary technology
In 2010 in the journal Nature, optogenetics was recognized as one of the coming decade’s most promising techniques to better understand brain function. This new field of research and application integrates optics and genetics methodologies to modulate the activity of neural circuits. Optogenetics involves controlling neuronal activity with light. This technique is therefore used to manipulate a specific type of cell without affecting neighbouring cells. A researcher who uses optogenetics is therefore like a conductor who decides to change the sheet music for an instrument to observe the effects, however insignificant they may seem, on the orchestra’s entire performance.
(Source: douglas.qc.ca)
Decoding Sounds’ Source: Researchers Unravel Part of Mystery
As Baby Boomers age, many experience difficulty in hearing and understanding conversations in noisy environments such as restaurants. People who are hearing-impaired and who wear hearing aids or cochlear implants are even more severely impacted. Researchers know that the ability to locate the source of a sound with ease is vital to hear well in these types of situations, but much more information is needed to understand how hearing works to be able to design devices that work better in noisy environment.
Researchers from the Eaton-Peabody Laboratories of the Massachusetts Eye and Ear, Harvard Medical School, and Research Laboratory of Electronics, Massachusetts Institute of Technology have gained new insight into how localized hearing works in the brain. Their research is published in the Oct. 2, 2013 issue of the Journal of Neuroscience.
“Most people are able to locate the source of a sound with ease, for example, a snapping twig on the left, or a honking horn on the right. However this is actually a difficult problem for the brain to solve,” said Mitchell L. Day, Ph.D., investigator in the Eaton-Peabody Laboratories at Mass. Eye and Ear and instructor of Otology and Laryngology at Harvard Medical School “The higher levels of the brain that decide the direction a sound is coming from do not have access to the actual sound, but only the representation of that sound in the electrical activity of neurons at lower levels in the brain. How higher levels of the brain use information contained in the electrical activity of these lower-level neurons to create the perception of sound location is not known.”
In the experiment, researchers recorded the electrical activity of individual neurons in an essential lower-level auditory brain area called the inferior colliculus (IC) while an animal listened to sounds coming from different directions. They found that the location of a sound source could be accurately predicted from the pattern of activation across a population of less than 100 IC neurons – i.e., a particular pattern of IC activation indicated a particular location in space. Researchers further found that the pattern of IC activation could correctly distinguish whether there was a single sound source present or two sources coming from different directions – i.e., the pattern of IC activation could segregate concurrent sources.
“Our results show that higher levels of the brain may be able to accurately segregate and localize sound sources based on the detection of patterns in a relatively small population of IC neurons,” said Dr. Day. “We hope to learn more so that someday we can design devices that work better in noisy environments.”
(Source: masseyeandear.org)
When Cells ‘Eat’ Their Own Power Plants; Pitt Scientists Solve Mystery of Basic Cellular Process
A mix of serendipity and dogged laboratory work allowed a diverse team of University of Pittsburgh scientists to report in the Oct. 1 issue of Nature Cell Biology that they had solved the mystery of a basic biological function essential to cellular health.
By discovering a mechanism by which mitochondria – tiny structures inside cells often described as “power plants” – signal that they are damaged and need to be eliminated, the Pitt team has opened the door to potential research into cures for disorders such as Parkinson’s disease that are believed to be caused by dysfunctional mitochondria in neurons.
"It’s a survival process. Cells activate to get rid of bad mitochondria and consolidate good mitochondria. If this process succeeds, then the good ones can proliferate and the cells thrive," said Valerian Kagan, Ph.D., D.Sc., a senior author on the paper and professor and vice chair of the Pitt Graduate School of Public Health’s Department of Environmental and Occupational Health. "It’s a beautiful, efficient mechanism that we will seek to target and model in developing new drugs and treatments."
Dr. Kagan, who, as a recipient of a Fulbright Scholar grant, currently is serving as visiting research chair in science and the environment at McMaster University in Ontario, Canada, likened the process to cooking a Thanksgiving turkey.
"You put the turkey in the oven and the outside becomes golden, but you can’t just look at it to know it’s ready. So you put a thermometer in, and when it pops up, you know you can eat it," he said. "Mitochondria give out a similar ‘eat me’ signal to cells when they are done functioning properly."
Cardiolipins, named because they were first found in heart tissue, are a component on the inner membrane of mitochondria. When a mitochondrion is damaged, the cardiolipins move from its inner membrane to its outer membrane, where they encourage the cell to destroy the entire mitochondrion.
However, that is only part of the process, says Charleen T. Chu, M.D., Ph.D., professor and the A. Julio Martinez Chair in Neuropathology in the Pitt School of Medicine’s Department of Pathology, another senior author of the study. “It’s not just the turkey timer going off; it’s a question of who’s holding the hot mitt to bring it to the dining room?” That turns out to be a protein called LC3. One part of LC3 binds to cardiolipin, and LC3 causes a specialized structure to form around the mitochondrion to carry it to the digestive centers of the cell.
The research arose nearly a decade ago when Dr. Kagan had a conversation with Dr. Chu at a research conference. Dr. Chu, who studies autophagy, or “self-eating,” in Parkinson’s disease, was seeking a change on the mitochondrial surface that could signal to LC3 to bring in the damaged organelle for recycling. It turned out they were working on different sides of the same puzzle.
Together with Hülya Bayır, M.D., research director of pediatric critical care medicine, Children’s Hospital of Pittsburgh of UPMC and professor, Pitt’s Department of Critical Care Medicine, and a team of nearly two dozen scientists, the three senior authors worked out how the pieces of the mitochondria signaling problem fit together.
Now that they’ve worked out the basic mechanism, Dr. Chu indicates that many more research directions will likely follow.
"There are so many follow-up questions," she said. "What is the process that triggers the cardiolipin to move outside the mitochondria? How does this pathway fit in with other pathways that affect onset of diseases like Parkinson’s? Interestingly, two familial Parkinson’s disease genes also are linked to mitochondrial removal."
Dr. Bayir explained that while this process may happen in all cells with mitochondria, it is particularly important that it functions correctly in neuronal cells because these cells do not divide and regenerate as readily as cells in other parts of the body.
"I think these findings have huge implications for brain injury patients," she said. "The mitochondrial ‘eat me’ signaling process could be a therapeutic target in the sense that you need a certain level of clearance of damaged mitochondria. But, on the other hand, you don’t want the clearing process to go on unchecked. You must have a level of balance, which is something we could seek to achieve with medications or therapy if the body is not able to find that balance itself."
(Source: upmc.com)
Finding the place where the brain creates illusory shapes and surfaces
The logo of the 1984 Los Angeles Olympics includes red, white and blue stars, but the white star is not really there: It is an illusion. Similarly, the “S” in the USA Network logo is wholly illusory.
Both of these logos take advantage of a common perceptual illusion where the brain, when viewing a fragmented background, frequently sees shapes and surfaces that don’t really exist.
“It’s hallucinating without taking drugs,” said Alexander Maier, assistant professor of psychology at Vanderbilt University, who headed a team of neuroscientists who has pinpointed the area of the brain that is responsible for these “illusory contours.”
In the Sept. 30 online early edition of the Proceedings of the National Academy of Sciences, Maier’s team reported that they have discovered groups of neurons in a region of the visual cortex called V4 that fire when an individual is viewing a pattern that produces such an illusion and remain quiescent when viewing an almost identical pattern that doesn’t.
Studies have shown that a diverse range of species, including monkeys, cats, owls, goldfish and even honeybees perceive these illusory contours. This has led scientists to propose that they are the byproduct of methods that the brain has evolved to spot predators or prey hiding in the bushes, a capability with considerable survival value.
Although scientists discovered illusory contours more than a century ago, it is only in the last 30 years that they have begun studying them because they reveal the internal mechanisms that the brain uses to interpret sensory input.
The gold square marks the location in the V4 region of a macaque’s visual cortex, where the neurons respond to visual contours. (Alex Maier, Donna Pritchett / Vanderbilt)
In mammals, visual stimuli is processed in the back of the brain in an area called the visual cortex. Efforts to map this area have found that it is made up of five different regions at the back of brain (labeled V1 to V5.)
The primary visual cortex, V1, takes the stimuli coming from the eyes and sorts it by a variety of basic properties, including orientation, color and spatial variation. It also splits the information into two pathways, called the dorsal and ventral streams.
From V1, both streams are routed to the second major area of the visual cortex. V2 performs many of the same functions as V1 but adds some more complex processing, such as recognizing the disparities in the signals coming from the two eyes that produce binocular vision.
From V2, one pathway, sometimes called the “Where Pathway,” goes to V5 and is associated with object location and motion detection. The other pathway, sometimes called the “What Pathway,” goes to V4 and is associated with object representation and form recognition.
“Studies have shown that V4 is involved in both object recognition and visual attention, so we thought it might also be involved with illusory contours,” said Michele Cox, the Vanderbilt graduate student who is first author on the study.
A Kanizsa square (Courtesy of D. Alan Stubbs, University of Maine)
First, the researchers searched for the neurons in V4 that were associated with different locations in the retinas of macaque monkeys. Once these maps were complete, they rewarded the monkeys for staring at a screen containing an example of an illusory contour called a Kanizsa square. This consists of four “Pac-Man” figures with their “mouths” oriented to form the corners of a square. When black Pac-Men are placed on a white background, the brain creates a bright white square connecting them.
While the monkeys were looking at the Kanizsa square, the researchers discovered that the neurons that represented the area in the middle of the Pac-Men, the area covered by the illusory square, began firing. However, when the monkeys viewed the same four Pac-Men with their mouths facing outward – an orientation that doesn’t produce the illusion – these central neurons remained silent.
“Basically, the brain is acting like a detective,” said Maier. “It is responding to cues in the environment and making its best guesses about how they fit together. In the case of these illusions, however, it comes to an incorrect conclusion.”
Two graphs show the activity of neurons in V4 associated with the position of the illusory Kanizsa square. The percentage of neurons firing more than doubles when the monkey views pac-men with their mouths facing inward to produce the illusion (top) compared to their activity level when the monkey is viewing pac-men with their mouths facing outward (bottom). (Michelle Cox and Alex Maier / Vanderbilt)
(Source: news.vanderbilt.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.
Virginia Tech to Host Neuroscience Workshop in Switzerland
Neuroscientists will discuss cognition, computation, decisions
Nearly two dozen of the world’s leading neuroscientists will gather in Switzerland next month to share their latest findings on the mysteries of how the brain processes information and makes decisions.
The Virginia Tech Carilion Research Institute European–U.S. Workshop on the Neuroscience of Cognition, Computation, and Decisions will be held at Virginia Tech’s Center for European Studies and Architecture at Riva San Vitale in Ticino on Oct. 16 to Oct. 18.
“We have two principal goals for this intensive workshop,” said Michael Friedlander, associate provost for health sciences at Virginia Tech and executive director of the Virginia Tech Carilion Research Institute. “First, we want to identify new and powerful integrated approaches to bridge multiple levels of understanding brain function. We are also hoping to lay the foundations for pioneering innovative and disruptive approaches to transcending disciplines and technologies across teams of leading European brain researchers and Virginia Tech Carilion Research Institute neuroscientists.”
The workshop will convene 10 neuroscientists from the institute and 13 neuroscientists from prominent brain-research institutions in five European countries, includinbg the Centre National de la Recherche Scientifique and École Polytechnique in France; the Central Institute of Mental Health Mannheim, Freie Universität Berlin, the Max Planck Institute for Biological Cybernetics, the Max Planck Institute for Human Development, and the University of Heidelberg in Germany; the International School for Advanced Studies in Trieste, Italy; École Polytechnique Fédérale de Lausanne, ETH Zürich, and the University of Zurich in Switzerland; and University College London in the United Kingdom.
Workshop participants will address emerging views of how neuronal and synaptic networks in the brain assemble, process, store, and access information and how large-scale networks of interconnected neurons perform in humans and other mammals. The participants will also consider the functional architecture that underlies the brain’s decision-making capacity, the neural basis of social interactions, the effects of the environment on information processing, and the consequences of a range of disorders on the function of the human brain.
Participants will share their newest discoveries in multiple sessions of several speakers each, followed by in-depth discussions to identify congruent perspectives and converging insights from multiple disciplines.
The discoveries will represent a broad array of technological and conceptual approaches, including analysis of detailed structural and functional properties of individual neurons and synaptic networks obtained with powerful electrophysiological, genetic, and optical imaging methods; functional brain imaging and behavioral studies in individuals and groups of interacting humans; and computational analysis and modeling of brain function and behavior.
Additional experts will address economics and game theory applications to human brain function and behavior in health and in disease; analysis of development, aging, and educational interventions on brain function; and the modulation of brain function acutely and over time in health and in various disorders that affect behavior, neural information processing, and decision-making.
“This workshop is taking place at a confluence of important national and international milestones in brain research in both Europe and the United States,” Friedlander said. “The Blue Brain Project in Europe represents a major international coalition to support large-scale, detailed analysis of the circuitry of the brain, while in the United States, President Barack Obama’s BRAIN Initiative will support innovative new approaches to high-resolution, large-scale functional mapping of the brain. We’re hoping to harness the wisdom of experts on both continents to develop new approaches and better technologies for diagnosing and treating neurological and psychiatric disorders that affect people worldwide.”
A Brake in the Head: German researchers gain new insights into the working of the brain
Scientists of the Charité – Universitätsmedizin Berlin and the German Center for Neurodegenerative Diseases (DZNE) have managed to acquire new insights into the functioning of a region in the brain that normally is involved in spatial orientation, but is damaged by the Alzheimer’s disease. They investigated how nerve signals are suppressed inside the so-called entorhinal cortex. According to the researchers, this neuronal inhibition leads nerve cells to synchronize their activity. The results of this study are now published in Neuron.
The entorhinal cortex is a link between the brain’s memory centre, the hippocampus, and the other areas of the brain. It is, however, more than an interface that only transfers nervous impulses. The entorhinal cortex also has an independent role in learning and thinking processes. This is particularly applicable for spatial navigation. “We know precious little about how this happens,” says Prof. Dietmar Schmitz, a researcher at the Cluster of Excellence NeuroCure at the Charité – Universitätsmedizin Berlin and Site Speaker for the DZNE in Berlin. “This is why we are investigating in animal models how the nerve cells within the entorhinal cortex are connected with each other.“
Signals wander inside the brain as electrical impulses from nerve cell to nerve cell. In general, signals are not merely forwarded. Rather, operation of the brain critically depends on the fact that the nerve impulses in some situations are activated and in other cases suppressed. A correct balance between suppression and excitation is decisive for all brain processes. “Until now research has mainly concentrated on signal excitation within the entorhinal cortex. This is why we looked into inhibition and detected a gradient inside the entorhinal cortex,” explains Dr. Prateep Beed, lead author of the study. “This means that nerve signals are not suppressed equally. The blockage of the nerve signals is weaker in certain parts of the entorhinal cortex and stronger in others. The inhibition has, so to speak, a spatial profile.”
When the brain is busy, nerve cells often coordinate their operation. In an electroencephalogram (EEG) – a recording of the brain’s electrical activity – the synchronous rhythm of the nerve cells manifests as a periodic pattern. “It is a moot question as to how nerve cells synchronize their behavior and how they bring about such rhythms,” says Beed. As he explains, it is also unclear whether these oscillations are only just a side effect or whether they trigger other phenomena. “But it has been demonstrated that neuronal oscillations accompany learning processes and even happen during sleep. They are a typical feature of the brain’s activity,” describes the scientist. “In our opinion, the inhibitory gradient, which we detected, plays an important role in creating the synchronous rhythm of the nerve cells and the related oscillations.”
In the case of Alzheimer’s, the entorhinal cortex is among the regions of the brain that are the first to be affected. “In recent times, studies related to this brain structure have increased. Here, already in the early stages of Alzheimer’s, one finds the protein deposits that are typical of this disease,” explains Schmitz, who headed the research. “It is also known that patients affected by Alzheimer’s have a striking EEG. Our studies help us to understand how the nerve cells in the entorhinal cortex operate and how electrical activities might get interrupted in this area of the brain.”
![Stunted neuron branching restored in mice
In a new study in Neuron, Brown University researchers report that mutation of a gene associated with some autism forms in humans can hinder the proper growth and connectivity of brain cells in mice. They also show how that understanding allowed them to restore proper cell growth in the lab.
Brown University researchers have traced a genetic deficiency implicated in autism in humans to specific molecular and cellular consequences that cause clear deficits in mice in how well neurons can grow the intricate branches that allow them to connect to brain circuits. The researchers also show in their study (online Sep. 12, 2013, in Neuron) that they could restore proper neuronal growth by compensating for the errant molecular mechanisms they identified.
The study involves the gene that produces a protein called NHE6. Mutation of the gene is directly associated with a rare and severe autism-related condition known as Christianson syndrome. But scientists, including senior author Dr. Eric Morrow, have also associated the protein with more general autism.
“In generalized autism this protein is downregulated,” said Morrow, assistant professor of biology in the Department of Molecular Biology, Cellular Biology, and Biochemistry at Brown and a psychiatrist who sees autism patients at the Bradley Hospital in East Providence. “That meant to us that downregulation of NHE6 is relevant to a sizeable subset of autism.”
The NHE6 protein helps to regulate acidity in the endosomes of cells. These endosomes are responsible for transporting material around cells and for degrading proteins including ones that signal neurons to grow the elaborately branched axons and dendrites that form neural connections.
In their experiments the researchers measured acidity in the endosomes of brain cells of normal mice and in mice with mutations in the NHE6 gene. They found that the mutant mice had significantly higher endosome acidity. The mutant mice with the higher endosome acidity also had more degradation of a receptor protein, called TrkB, that responds a neurotrophic factor called BDNF. Together they signal axon and dendrite growth and branching.
Did the higher acidity and lower levels of TrkB signaling affect the neurons? Morrow and his colleagues were able to show directly in the mouse brain that the neuronal branching was diminished as were the number and maturity of connections between neurons, called synapses. Further still, working with co-author Julie Kauer, professor of medical science in the Department of Molecular Pharmacology, Physiology, and Biotechnology, they looked at synaptic and circuit function in the mice, and they found deficits corresponding to those anatomical findings.
“One of the overriding problems in disorders like autism, we think, is that it’s a problem of communication between different areas of the brain and neurons communicating with each other in networks,” said Morrow, who is affiliated with the Brown Institute for Brain Science.
Searching for a rescue
Having discovered a specific chain of events by which NHE6 mutations undermine neural branching and connectivity, Morrow and lead authors Qing Ouyang and Sofia Lizarraga sought to find out why and whether they could fix it.
Sometimes acidity in the endosome can activate protein-degrading enzymes called proteases. The team hypothesized that perhaps the acidity resulting from the absence of NHE6 was leading proteases to degrade TrkB, reducing its levels in mutant neurons compared to normal ones. When they treated mutant cells with a protease inhibitor called leupeptin, they found that the TrkB levels and signaling returned to levels close to those found in the normal cells.
Given that TrkB’s job is to bind with BDNF, the researchers also hypothesized that if the problem of NHE6 mutation was a reduction of TrkB, perhaps a suitable end-run around the problem would be to administer BDNF to cells directly. Indeed they found that NHE6 mutant cells, if given extra BDNF, produced axon and dendrite growth and branching that was more like normal neurons.
“In this paper we show that BDNF signaling is attenuated in the mutant mice, but it’s not blocked,” Morrow said. “You can rescue the [neuronal growth] by turning up the signaling.”
There are already drugs developed to deliver doses of chemicals that increase or mimic BDNF in the body, Morrow said, but many more tests beyond this study would have to be done before scientists and doctors could know whether a BDNF-related drug could have a therapeutic effect for patients with Christianson syndrome or any related form of autism.
“We don’t think that this is everything about the condition,” Morrow said. “But if we were able to treat this one mechanism by adding exogenous drug, would it repair enough or some element of it?”
Christianson syndrome and perhaps only a subset of autism appears to relate to deficits in neural branching. Some forms of autism, in fact, may result from too much branch growth. Moreover, doctors have no precise ways to tell whether a child diagnosed with autism has too much or too little neural branching.
But given the study results suggesting that NHE6 may play a role in some autism forms perhaps by hindering neural branching, the new research suggests a target for addressing it.](http://41.media.tumblr.com/e009fcc2c7849fe29ff87c8ca24f8f2e/tumblr_mt27q6gR1F1rog5d1o1_500.jpg)
Stunted neuron branching restored in mice
In a new study in Neuron, Brown University researchers report that mutation of a gene associated with some autism forms in humans can hinder the proper growth and connectivity of brain cells in mice. They also show how that understanding allowed them to restore proper cell growth in the lab.
Brown University researchers have traced a genetic deficiency implicated in autism in humans to specific molecular and cellular consequences that cause clear deficits in mice in how well neurons can grow the intricate branches that allow them to connect to brain circuits. The researchers also show in their study (online Sep. 12, 2013, in Neuron) that they could restore proper neuronal growth by compensating for the errant molecular mechanisms they identified.
The study involves the gene that produces a protein called NHE6. Mutation of the gene is directly associated with a rare and severe autism-related condition known as Christianson syndrome. But scientists, including senior author Dr. Eric Morrow, have also associated the protein with more general autism.
“In generalized autism this protein is downregulated,” said Morrow, assistant professor of biology in the Department of Molecular Biology, Cellular Biology, and Biochemistry at Brown and a psychiatrist who sees autism patients at the Bradley Hospital in East Providence. “That meant to us that downregulation of NHE6 is relevant to a sizeable subset of autism.”
The NHE6 protein helps to regulate acidity in the endosomes of cells. These endosomes are responsible for transporting material around cells and for degrading proteins including ones that signal neurons to grow the elaborately branched axons and dendrites that form neural connections.
In their experiments the researchers measured acidity in the endosomes of brain cells of normal mice and in mice with mutations in the NHE6 gene. They found that the mutant mice had significantly higher endosome acidity. The mutant mice with the higher endosome acidity also had more degradation of a receptor protein, called TrkB, that responds a neurotrophic factor called BDNF. Together they signal axon and dendrite growth and branching.
Did the higher acidity and lower levels of TrkB signaling affect the neurons? Morrow and his colleagues were able to show directly in the mouse brain that the neuronal branching was diminished as were the number and maturity of connections between neurons, called synapses. Further still, working with co-author Julie Kauer, professor of medical science in the Department of Molecular Pharmacology, Physiology, and Biotechnology, they looked at synaptic and circuit function in the mice, and they found deficits corresponding to those anatomical findings.
“One of the overriding problems in disorders like autism, we think, is that it’s a problem of communication between different areas of the brain and neurons communicating with each other in networks,” said Morrow, who is affiliated with the Brown Institute for Brain Science.
Searching for a rescue
Having discovered a specific chain of events by which NHE6 mutations undermine neural branching and connectivity, Morrow and lead authors Qing Ouyang and Sofia Lizarraga sought to find out why and whether they could fix it.
Sometimes acidity in the endosome can activate protein-degrading enzymes called proteases. The team hypothesized that perhaps the acidity resulting from the absence of NHE6 was leading proteases to degrade TrkB, reducing its levels in mutant neurons compared to normal ones. When they treated mutant cells with a protease inhibitor called leupeptin, they found that the TrkB levels and signaling returned to levels close to those found in the normal cells.
Given that TrkB’s job is to bind with BDNF, the researchers also hypothesized that if the problem of NHE6 mutation was a reduction of TrkB, perhaps a suitable end-run around the problem would be to administer BDNF to cells directly. Indeed they found that NHE6 mutant cells, if given extra BDNF, produced axon and dendrite growth and branching that was more like normal neurons.
“In this paper we show that BDNF signaling is attenuated in the mutant mice, but it’s not blocked,” Morrow said. “You can rescue the [neuronal growth] by turning up the signaling.”
There are already drugs developed to deliver doses of chemicals that increase or mimic BDNF in the body, Morrow said, but many more tests beyond this study would have to be done before scientists and doctors could know whether a BDNF-related drug could have a therapeutic effect for patients with Christianson syndrome or any related form of autism.
“We don’t think that this is everything about the condition,” Morrow said. “But if we were able to treat this one mechanism by adding exogenous drug, would it repair enough or some element of it?”
Christianson syndrome and perhaps only a subset of autism appears to relate to deficits in neural branching. Some forms of autism, in fact, may result from too much branch growth. Moreover, doctors have no precise ways to tell whether a child diagnosed with autism has too much or too little neural branching.
But given the study results suggesting that NHE6 may play a role in some autism forms perhaps by hindering neural branching, the new research suggests a target for addressing it.
"Brainbow" zebra fish.
Neurons are labeled in multiple colors with Brainbow fluorescence microscopy. Three fluorescent proteins (cyan, yellow and red) are randomly taken up by various neurons, offering a palette of dozens of colors to help scientists follow complex neural pathways. Shown here is a five-day-old zebra fish larva viewed from the dorsal side, captured using a 20X objective.
Image credit: Dr. Albert Pan, Harvard University, Cambridge, Mass., U.S.
(Source: scientificamerican.com)
Study creates new memories by directly changing the brain
Findings could prove helpful in understanding and resolving learning and memory disorders
By studying how memories are made, UC Irvine neurobiologists created new, specific memories by direct manipulation of the brain, which could prove key to understanding and potentially resolving learning and memory disorders.
Research led by senior author Norman M. Weinberger, a research professor of neurobiology & behavior at UC Irvine, and colleagues has shown that specific memories can be made by directly altering brain cells in the cerebral cortex, which produces the predicted specific memory. The researchers say this is the first evidence that memories can be created by direct cortical manipulation. Study results appeared in the August 29 issue of Neuroscience.
During the research, Weinberger and colleagues played a specific tone to test rodents then stimulated the nucleus basalis deep within their brains, releasing acetylcholine (ACh), a chemical involved in memory formation. This procedure increased the number of brain cells responding to the specific tone. The following day, the scientists played many sounds to the animals and found that their respiration spiked when they recognized the particular tone, showing that specific memory content was created by brain changes directly induced during the experiment. Created memories have the same features as natural memories including long-term retention.
"Disorders of learning and memory are a major issue facing many people and since we’ve found not only a way that the brain makes memories, but how to create new memories with specific content, our hope is that our research will pave the way to prevent or resolve this global issue," said Weinberger, who is also a fellow with the Center for the Neurobiology of Learning & Memory and the Center for Hearing Research at UC Irvine.
The creation of new memories by directly changing the cortex is the culmination of several years of research in Weinberger’s lab implicating the nucleus basalis and ACh in brain plasticity and specific memory formation. Previously, the authors had also shown that the strength of memory is controlled by the number of cells in the auditory cortex that process a sound.