Posts tagged science
Articles and news from the latest research reports.
Two-way traffic in the spinal cord
The progress a baby makes in the first year of life is amazing: a newborn can only wave its arms and legs about randomly, but not so long after the baby can reach out and pick up a crumb from the carpet. What happens in the nervous system that enables this change from random waving to finely coordinated movement? Scientists from the Max Planck Institute of Neurobiology in Martinsried near Munich, working with colleagues from New York and Philadelphia, have described a new type of nerve cell in mice which provides a valuable insight into this developmental phenomenon. During embryonic development, the projections from these cells grow from the spinal cord towards the brain. They may pave the way for other nerve cells which control voluntary movement and which only grow from the brain into the spinal cord after birth.
When we reach out towards an object with our hand or push our foot into a boot, our movements are coordinated and controlled by the brain. For this to be possible there must be a neural pathway for the brain to transmit instructions, for example to the foot; and also in the reverse direction, for stimuli from the surroundings of the foot to be passed back to the brain. Such neural pathways are formed when the projections (axons) grow out from nerve cells during development. Depending on the organism and the body part to be connected, the axons can grow to many centimetres in length. Rüdiger Klein and his team at the Max Planck Institute of Neurobiology investigate how the axons navigate through the body, and which molecules play a part in their pathfinding. In particular, the scientists have been focusing on the signalling molecules known as ephrins and their binding partners, the Eph receptors. Ephrins and Eph receptors are located on the surface of nerve cells, among other places, and help the growing cells find their way and locate their partner cells.
Some time ago, Rüdiger Klein and his team discovered in the mouse that ephrins and Eph receptors play a key role in the development of the neural networks which control our movements. The neurobiologists have been able to demonstrate that the ephrin/Eph system guides nerve cells which, after birth, send their axons from the brain into the spinal cord and direct voluntary movement in the arms and legs. In their investigations into axons which run in the opposite direction, namely from the spinal cord into the brain, the researchers came across a new cell type which also contained Eph receptors. “Just where the ‘descending’ axons were growing, we found the ‘ascending’ axons running in parallel”, says Rüdiger Klein. “That obviously raised the question in our minds as to how this parallel growth is controlled during development.”
Subsequent research by the neurobiologists uncovered something surprising: in contrast with the known cells, the ascending axons of the new cell type did not grow only after birth, but instead already during embryonic development. Moreover, their growth was guided by the same ephrin/Eph signalling system as that involved in the growth of the descending axons. “It would seem that during embryonic development the ascending axons would ‘pre-drill’ a channel for the descending axons which do not grow out until after birth”, explains Rüdiger Klein.
Further investigations into the new, ascending nerve cells have made it clear that they obtain their input from specialised, touch-sensitive cells. A new feedback system could thus be involved here: voluntary movements are refined by signals from touch-sensitive cells, so adapting the intended movement to the environment and your foot slips into the boot. “What we found surprising is the fact that one and the same guidance system directs both the descending and the ascending axons”, says Klein. “This is a wonderful example of how a highly complex nervous system can be built up by making flexible use of individual molecules, and thus a small number of genes.” The next job for the scientists is to find out whether the suspected feedback system actually exists, i.e. whether the ascending and descending cells are connected via synapses. Their aim is to unravel step by step the developmental processes which enable the brain to coordinate sequences of movements.
Narcolepsy confirmed as autoimmune disease
Results also partly explain why the 2009 swine flu virus, and a vaccine against it, led to spikes in the sleep disorder.
As the H1N1 swine flu pandemic swept the world in 2009, China saw a spike in cases of narcolepsy — a mysterious disorder that involves sudden, uncontrollable sleepiness. Meanwhile, in Europe, around 1 in 15,000 children who were given Pandemrix — a now-defunct flu vaccine that contained fragments of the pandemic virus — also developed narcolepsy, a chronic disease.
Immunologist Elizabeth Mellins and narcolepsy researcher Emmanuel Mignot at Stanford University School of Medicine in California and their collaborators have now partly solved the mystery behind these events, while also confirming a longstanding hypothesis that narcolepsy is an autoimmune disease, in which the immune system attacks healthy cells.
Narcolepsy is mostly caused by the gradual loss of neurons that produce hypocretin, a hormone that keeps us awake. Many scientists had suspected that the immune system was responsible, but the Stanford team has found the first direct evidence: a special group of CD4+ T cells (a type of immune cell) that targets hypocretin and is found only in people with narcolepsy.
“Up till now, the idea that narcolepsy was an autoimmune disorder was a very compelling hypothesis, but this is the first direct evidence of autoimmunity,” says Mellins. “I think these cells are a smoking gun.” The study is published today in Science Translational Medicine.
Thomas Scammell, a neurologist at Harvard Medical School in Boston, Massachusetts, says that the results are welcome after “years of modest disappointment”, marked by many failures to find antibodies made by a person’s body against their own hypocretin. “It’s one of the biggest things to happen in the narcolepsy field for some time.”
Loose ends
It is not clear why some people make these T cells and others do not, but genetics may play a part. In earlier work, Mignot showed that 98% of people with narcolepsy have a variant of the gene HLA that is found in only 25% of the general population.
Environmental factors, such as infections, probably matter too. Mellins’ working model is that narcolepsy happens when people with a genetic predisposition, which involves having several narcolepsy-related gene variants, encounter an environmental factor that mimics hypocretin, triggering a response from the immune system. The 2009 H1N1 virus was one such trigger: the team found that these same special CD4+ T cells also recognize a protein from the pandemic H1N1 virus.
Narcolepsy of course was around long before the 2009 pandemic. And since new cases of the disease tend to arise right after winter — following the seasonal peak in flu — it’s possible that other strains or even other viruses are involved, too.
But the results do not fully explain the Pandemrix mystery, because other flu vaccines contained the same proteins but did not lead to a spike in narcolepsy cases. Regardless, Mellins says that it should be possible to avoid repeating the same mistake by ensuring that future flu vaccines do not contain components that resemble hypocretin.
Another loose end is that “they don’t show how these T cells are actually killing the hypocretin neurons”, adds Scammell. “It’s like a murder mystery and we don’t know who the real killer is.” He thinks that it is unlikely that the T cells are the true culprits; instead, they could be acting through an intermediary, or might merely be a symptom of some other destructive event.
“The results are very important, but they need to do a replication study in a large group of patients and controls,” says Gert Lammers, a neurologist at Leiden University Medical Center in the Netherlands and president of the European Narcolepsy Network. “If the findings are confirmed, the first important spin-off might be the development of a new diagnostic test.”
The ability to recognize objects in the environment is mediated by the brain’s ability to integrate and process massive amounts of visual information. A research group led by Takayuki Sato and Manabu Tanifuji from the RIKEN Brain Science Institute has now discovered that in macaque monkeys, this remarkable ability is supported by mosaic-like structures in the anterior inferior temporal (IT) cortex, where localized clusters of neurons encode different visual features in an organized hierarchy.
Two competing models have been proposed to explain the functional organization of brain regions that underlies object recognition in primates. One model states that discrete brain ‘modules’ process stimuli from particular categories, such as faces, with object recognition arising from communication among the modules. The other model postulates that the visual cortex extracts generic features, which are then composited to recognize specific objects. Since both models are based on measurements of functional signals produced by metabolic changes associated with neural activity rather than measurements of the neuronal activity itself, the precise underlying mechanism responsible for object recognition has remained unclear.
To resolve this debate, the researchers undertook dense electrophysiological mapping of neural activity in anesthetized macaque monkeys exposed to a series of color images from different object categories: faces, hands, bodies, food and various other objects. Sato and his colleagues directly recorded neuronal activity from multiple locations within the anterior IT cortex, which allowed them to track the location of neurons that responded to a particular object category.
The team found that some regions responded best to faces and others to monkey bodies. While there were also regions that responded worst to faces, none appeared to respond preferentially to hands, food or manufactured items.
Interestingly, small neuron clusters within a region appeared to be selective to different facial features, responding differently to human and monkey faces and to scrambled and normal faces. This indicates that a region in the anterior IT cortex that is selective for an object category consists of smaller-scale neuron clusters that are selective for particular visual features.
“The cortical mosaics that encode visual information seem to be efficient functional structures where object-category information and information about constituent features are represented within the limited space of the brain,” explains Sato. “This could also be the way that the brain organizes information in other sensory modalities, such as hearing.” If the results are also found to extend to humans, they may offer insight into the visual recognition of objects and the development of language.
New study reveals insight into how the brain processes shape and color
A new study by Wellesley College neuroscientists is the first to directly compare brain responses to faces and objects with responses to colors. The paper, by Bevil Conway, Wellesley Associate Professor of Neuroscience, and Rosa Lafer-Sousa, a 2009 Wellesley graduate currently studying in the Brain and Cognitive Sciences program at MIT, reveals new information about how the brain’s inferior temporal cortex processes information.
Located at the base of the brain, the inferior temporal cortex (IT) is a large expanse of tissue that has been shown to be critical for object perception. This region of the brain is commonly divided into posterior, central, and anterior parts, but it remains unclear as to whether these partitions constitute distinct areas. An existing, popular theory is that the parts represent a hierarchical organization of information processing, a notion that has previously been supported by functional magnetic resonance imaging (fMRI) in monkeys. For their study, Conway and Lafer-Sousa used non-invasive fMRI to measure responses across the brains of rhesus monkeys to a range of different stimuli and obtained responses to images of objects, faces, places and colored stripes. “The technique enabled us to determine the spatial distribution of responses across the brain, and has been useful in figuring out how the visual brain is organized,” Conway said.
Conway, a visual neuroscientist and artist, examines the way the nervous system processes color using physiological, behavioral, and modeling techniques. Conway and Lafer-Sousa assert that color provides a useful tool for tackling questions about processing in the IT region, as it has little “low-level” feature similarity with shapes (psychological work shows that color can be perceived independent of shape)—therefore any relationship between color-responsive and shape-responsive regions should reflect fundamental organizational principles.
"Shape and color are both properties of objects and are processed by the parts of the brain known to be important for detecting and discriminating objects. However, the way this part of brain is organized has not been clear, for example, is color computed by different parts of this region than those that compute shape?" The answer to this question, Conway said, has deep implications for understanding the general computational principles used by the brain and how the brain evolved.
"Our work showed that, to a large extent, color and faces are handled by separate, parallel streams, and that these pieces of information are processed by connected, serial stages," Conway said. "One can imagine the processing as an assembly line, where some aspect of faces – and some aspect of color – is computed first. The output is then sent to another region downstream that makes a subsequent computation."
They hypothesized that the earliest stages in color processing involve detecting and discriminating hue, while the later stages compute color-memory association. For example, the brain may first compute that yellow is diagnostic of banana, then later, color categories are recognized; for example, limes, grass, and fern leaves are all “green.”
"The most striking aspect of the study is what it reveals about the precision of the organization of the brain. We often think that because the brain consists of billions of neurons, that at some level it must be quite variable how the neurons are organized," Conway said. "The study shows that there is a remarkable precision in organization of the neural circuits for high-level vision, which will make tractable many questions bridging cognitive science and systems neuroscience."
As a visual artist, Conway said the aspect of the research he finds most satisfying is the beauty of the organizational patterns that, he said, are “clearly are the result of a set of underlying organizational principles.” He continued, “It is interesting to think that the brain reflects what artists have long recognized: that color and shape can be decoupled, each represented somewhat independently—think of color monochromes versus black-and-white line drawings. The neural architecture provides a reason why this is effective or possible.”
The researchers note that it remains unclear whether the organizational principles found in humans apply to monkeys, an important issue that bears on cortical evolution. However, their results suggest that the IT comprises parallel, multi-stage processing networks subject to one organizing principle.
Musical brain-reading sheds light on neural processing of music
Finnish and Danish researchers have developed a new method that performs decoding, or brain-reading, during continuous listening to real music. Based on recorded brain responses, the method predicts how certain features related to tone color and rhythm of the music change over time, and recognizes which piece of music is being listened to. The method also allows pinpointing the areas in the brain that are most crucial for the processing of music. The study was published in the journal NeuroImage.
Using functional magnetic resonance imaging (fMRI), the research team at the Finnish Centre of Excellence in Interdisciplinary Music Research in the Universities of Jyväskylä and Helsinki, and the Center for Functionally Integrative Neuroscience in Aarhus University, Denmark, recorded the brain responses of participants while they were listening to a 16-minute excerpt of the album Abbey Road by the Beatles. Following this, they used computational algorithms to extract a collection of musical features from the musical recording. Subsequently, they employed a collection of machine-learning methods to train a computer model that predicts how the features of the music change over time. Finally, they develop a classifier that predicts which part of the music the participant was listening to at each time.
The researchers found that most of the musical features included in the study could be reliably predicted from the brain data. They also found that the piece being listened to could be predicted significantly better than chance. Fairly large differences were however found between participants in terms of the prediction accuracy. An interesting finding was that areas outside of the auditory cortex, including motor, limbic, and frontal areas, had to be included in the models to obtain reliable predictions, providing thus evidence for the important role of these areas in the processing of musical features.
"We believe that decoding provides a method that complements other existing methods to obtain more reliable information about the complex processing of music in the brain", says Professor Petri Toiviainen from the University of Jyväskylä. "Our results provide additional evidence for the important involvement of emotional and motor areas in music processing."
(Source: jyu.fi)
The logistics of learning
Learning requires constant reconfiguration of the connections between nerve cells. Two new studies now yield new insights into the molecular mechanisms that underlie the learning process.
Learning and memory are made possible by the incessant reorganization of nerve connections in the brain. Both processes are based on targeted modifications of the functional interfaces between nerve cells – the so-called synapses – which alter their form, molecular composition and functional properties. In effect, connections between cells that are frequently co-activated together are progressively altered so that they respond to subsequent signals more rapidly and more strongly. This way, information can be encoded in patterns of synaptic activity and promptly recalled when needed. The converse is also true: learned behaviors can be lost by disuse, because inactive synapses are themselves less likely to transmit an incoming impulse, leading to the decay of such connections.
How exactly an individual synapse is altered without simultaneously affecting nearby nerve cells or other synapses on the same cell is a question that is central to Michael Kiebler’s research. Kiebler, a biochemist, holds the Chair of Cell Biology in the Faculty of Medicine at LMU. “It is now clear that the changes take place in the cell that is stimulated by synaptic input – the post-synaptic cell – and in particular in its so-called dendritic spines,” he says, “and particles that are known as “neuronal RNA granules” deliver mRNA molecules to these sites“. These mRNAs represent the blueprints for the synthesis of the proteins responsible for reconfiguring the synapses. Kiebler‘s team has developed a model, which postulates that these granules migrate from dendrite to dendrite, and release their mRNAs specifically at sites that are repeatedly activated. This would ensure that the relevant proteins are synthesized only where they are needed within the cell.
In spite of the potential significance of the model, the molecular mechanisms required for its realization have remained obscure. mRNA-binding proteins, including Staufen2 (Stau2) and Barentsz, are essential components of the granules, and Kiebler’s team, in collaboration with Giulio Superti-Furga’s group (CeMM, Vienna), have now used specific antibodies to isolate and characterize neuronal granules that contain either Stau2 or Barentsz.
Surprising diversity
It has generally been assumed that all neuronal RNA granules have essentially similar compositions. However, the new findings indicate that this is not the case. A comparison between Stau2- and Barentsz-containing granules reveals that they differ in about two-thirds of their proteins. “This suggests that the RNA granules are highly heterogeneous and dynamic in their composition,” says Kiebler. “And that makes sense to me, because it would mean that the granules can perform different functions depending on which mRNAs they carry.” Furthermore, the researchers have shown that the granules contain virtually none of the factors known to promote the translation of mRNAs into proteins. On the contrary, they include many molecules that repress protein synthesis. This in turn implies that the process of mRNA transport is uncoupled from the subsequent production of the proteins they encode.
In a complementary study, Kiebler’s team also characterized the mRNA cargoes associated with the granules. “Until now, none of the RNA molecules present in Stau2-containing granules in mammalian nerve cells had been defined, but we have now been able to identify many specific mRNAs,” Kiebler explains. Further experiments revealed that Stau2 stabilizes the mRNAs, allowing them to be used more often for the production of proteins. Moreover, the researchers have shown that specialized structures within these mRNAs, called “Staufen-Recognized Structures” (SRS), are essential for their recognition and stabilization by Stau2. “This allows us to propose a molecular mechanism for RNA recognition for the first time,” says Kiebler.
Taken together, the two new papers (1, 2) provide novel insights into the molecular mechanisms that underlie learning and memory. The scientists now want to dissect out the details in future studies. “In the long term, we are particularly interested in the question of how an activated synapse can alter the state of the granules and induce the production of protein,” Kiebler notes. It is becoming increasingly clear that RNA-binding proteins play essential roles in nerve cells. Disruption of their action can lead to neurodegenerative diseases and neurological dysfunction. Clearly, not only classical conditions such as Alzheimer‘s or Parkinson’s disease, in which RNA-binding proteins are always involved, but also cognitive defects or age-associated impairment of learning ability must be viewed in this context,” Kiebler concludes.
(Source: en.uni-muenchen.de)
Anti-epilepsy drugs can cause inflammations
Glial cells play a crucial role in the nervous system
Hannes Dambach from the Department for Neuroanatomy and Molecular Brain Research, together with a team of colleagues, studied how anti-epilepsy drugs affect the survival of glial cells in cultures. Glial cells are the largest cell group in the brain; they are crucial for supplying neurons with nutrients and affect immune and inflammatory responses. The question of how glial cells are affected by anti-epilepsy drugs had previously not been studied in depth. The RUB work group Clinical Neuroanatomy, headed by Prof Dr Pedro Faustmann, analysed four substances: valproic acid, gabapentin, phenytoin and carbamazepine.
Four anti-epilepsy drugs affect glial cells in different ways
Glial cells treated by the researchers with valproic adic and gabapentin had better survival chances than those treated with phenytoin and carbamazepine. However, carbamazepine had a positive effect, too: it reduced inflammatory responses. Valproic acid, on the other hand, turned out to be pro-inflammatory. In how far the anti-epilepsy drugs affected inflammations was also determined by the applied dose. Consequently, different drugs affected glial cells – and hence indirectly the neurons – in different ways.
Inflammatory responses should be taken under consideration in clinical studies
“Clinical studies should focus not only on the question in how far anti-epilepsy drugs affect the severity and frequency of epileptic seizures,” says Pedro Faustmann. “It is also necessary to test them with regard to the role they play in inflammatory responses in the central nervous system.” Thus, doctors could take the underlying inflammatory condition under consideration when selecting the right anti-epilepsy drug.
Epilepsy may have different causes
In Germany, between 0.5 and 1 percent of the population suffer from epilepsy that requires drug treatment. The disease may have many causes: genetic predisposition, disorders of the central nervous system after meningitis, traumatic brain injury and stroke. Inflammatory responses may also be caused by damage to the brain.
Brain research provides insight into language learning
Anyone who has tried to learn a second language knows how difficult it is to absorb new words and use them to accurately express ideas in a completely new cultural format. Now, research into some of the fundamental ways the brain accepts information and tags it could lead to new, more effective ways for people to learn a second language.
Tests have shown that the human brain uses the same neuron system to see an action and to understand an action described in language. Researchers at Arizona State University have been testing the boundaries of this hypothesis, which focuses on the operation of the mirror neuron system (MNS). The ASU group has found that the MNS can be modified by language use, and that the modification can slightly change visual perception.
The work focuses on how the brain receives and classifies information that a person sees (an action, like one person giving another a pencil), and tests how the brain receives the information from a description of an action (simulation), like “Cameron gives Annagrace a pencil.”
“We tested the idea that the mirror neuron system, which is part of the motor system, is used in the simulation process,” said Arthur Glenberg, an ASU professor of psychology. “The MNS is active both when a person takes an action (e.g., giving a pencil), and when that action is observed (witnessing the pencil being given). Supposedly, the MNS allows us to infer the intentions of other people so that when Jane sees Cameron act, her MNS resonates, and then Jane understands why she would give Annagrace the pencil and infers that that is the reason why Cameron gives Annagrace the pencil.”
Glenberg, Noah Zarr, formerly an ASU psychology major and now a graduate student at Indiana University, and Ryan Ferguson, a graduate student in ASU’s Cognitive Science training area in the Department of Psychology, recently published their findings in the paper “Language comprehension warps the mirror neuron system,” in Frontiers in Human Neuroscience. This research began with Zarr’s honors thesis.
“The MNS has been associated with many social behaviors, such as action, understanding and empathy, as well as language understanding,” Glenberg explained. “Previous work has demonstrated that adapting the MNS can affect language comprehension. But no one had yet shown that the process of language comprehension can itself change the MNS.
“The question becomes, when Jane reads, ‘Cameron gives Annagrace the pencil,’ is she using her MNS just like when she sees Cameron give the pencil?” Glenberg asks. “To test this idea, we used the fact that the MNS is used in both action and perception of action, and the idea that repeated use of a neural system leads to adaptation of that system.
“So, in the tests, participants read a bunch of transfer sentences,” Glenberg explained. “We then show them a bunch of videos of transfer. We have shown that after reading the sentences, people are impaired (a little bit) in perceiving the transfer in the videos, which means the reading modifies the same MNS used in action understanding.”
While the work explores the boundaries of a theory on comprehension, there are applications in which it could be employed, Glenberg said.
“If language comprehension is a simulation process that uses neural systems of action, then perhaps we can better teach kids how to understand what they read by getting them to literally simulate the actions,” he explained.
Glenberg added that part of his on going research into the MNS, the system that allows us to decipher what we see and understand the intent of language, is to test the idea of simulation and how it can help Latino English language learners read better in English.
(Source: asunews.asu.edu)
Brain repair after injury and Alzheimer’s disease
Researchers at Penn State University have developed an innovative technology to regenerate functional neurons after brain injury, and also in model systems used for research on Alzheimer’s disease. The scientists have used supporting cells of the central nervous system, glial cells, to regenerate healthy, functional neurons, which are critical for transmitting signals in the brain.
Gong Chen, a professor of biology, the Verne M. Willaman Chair in Life Sciences at Penn State, and the leader of the research team, calls the method a breakthrough in the long journey toward brain repair. “This technology may be developed into a new therapeutic treatment for traumatic brain and spinal cord injuries, stroke, Alzheimer’s disease, Parkinson’s disease, and other neurological disorders,” Chen said. The research will be posted online by the journal Cell Stem Cell on 19 December 2013.
When the brain is harmed by injury or disease, neurons often die or degenerate, but glial cells become more branched and numerous. These “reactive glial cells” initially build a defense system to prevent bacteria and toxins from invading healthy tissues, but this process eventually forms glial scars that limit the growth of healthy neurons. “A brain-injury site is like a car-crash site,” Chen explained. “Reactive glial cells are like police vehicles, ambulances, and fire trucks immediately rushing in to help — but these rescue vehicles can cause problems if too many of them get stuck at the scene. The problem with reactive glial cells is that they often stay at the injury site, forming a glial scar and preventing neurons from growing back into the injured areas,” he explained.
So several years ago, Chen’s lab tested new ways to transform glial scar tissue back to normal neural tissue. “There are more reactive glial cells and fewer functional neurons in the injury site,” Chen said, “so we hypothesized that we might be able to convert glial cells in the scar into functional neurons at the site of injury in the brain. This research was inspired by the Nobel prize-winning technology of induced pluripotent stem cells (iPSCs) developed in Shinya Yamanaka’s group, which showed how to reprogram skin cells into stem cells,” Chen recalled.
Chen and his team began by studying how reactive glial cells respond to a specific protein, NeuroD1, which is known to be important in the formation of nerve cells in the hippocampus area of adult brains. They hypothesized that expressing NeuroD1 protein into the reactive glial cells at the injury site might help to generate new neurons — just as it does in the hippocampus. To test this hypothesis, his team infected reactive glial cells with a retrovirus that specifies the genetic code for the NeuroD1 protein. “The retrovirus we used is replication-deficient and thus cannot kill infected cells like other viruses found in the wild,” Chen said. “More importantly, a retrovirus can infect only dividing cells such as reactive glial cells, but it does not affect neurons, which makes it ideal for therapeutic use with minimal side effect on normal brain functions.”
In a first test, Chen and his team investigated whether reactive glial cells can be converted into functional neurons after injecting NeuroD1 retrovirus into the cortex area of adult mice. The scientists found that two types of reactive glial cells — star-shaped astroglial cells and NG2 glial cells — were reprogrammed into neurons within one week after being infected with the NeuroD1 retrovirus. “Interestingly, the reactive astroglial cells were reprogrammed into excitatory neurons, whereas the NG2 cells were reprogrammed into both excitatory and inhibitory neurons, making it possible to achieve an excitation-inhibition balance in the brain after reprogramming,” Chen said. His lab also performed electrophysiological tests, which demonstrated that the new neurons converted by the NeuroD1 retrovirus could receive neurotransmitter signals from other nerve cells, suggesting that the newly converted neurons had successfully integrated into local neural circuits.
In a second test, Chen and his team used a transgenic-mouse model for Alzheimer’s disease, and demonstrated that reactive glial cells in the mouse’s diseased brain also can be converted into functional neurons. Furthermore, the team demonstrated that even in 14-month-old mice with Alzheimer’s disease — an age roughly equivalent to 60 years old for humans — injection of the NeuroD1 retrovirus into a mouse cortex can still induce a large number of newborn neurons reprogrammed from reactive glial cells. “Therefore, the conversion technology that we have demonstrated in the brains of mice potentially may be used to regenerate functional neurons in people with Alzheimer’s disease,” Chen said.
To ensure that the glial cell-to-neuron conversion method is not limited to rodent animals, Chen and his team further tested the method on cultured human glial cells. “Within 3 weeks after expression of the NeuroD1 protein, we saw in the microscope that human glial cells were reinventing themselves: they changed their shape from flat sheet-like glial cells into normal-looking neurons with axon and dendritic branches,” Chen said. The scientists further tested the function of these newly converted human neurons and found that, indeed, they were capable of both releasing and responding to neurotransmitters.
"Our dream is to develop this in vivo conversion method into a useful therapy to treat people suffering from neural injury or neurological disorders," Chen said. "Our passionate motivation for this research is the idea that an Alzheimer’s patient, who for a long time was not able to remember things, could start to have new memories after regenerating new neurons as a result of our in vivo conversion method, and that a stroke victim who could not even move his legs might start to walk again."
A New—and Reversible—Cause of Aging
Researchers have discovered a cause of aging in mammals that may be reversible.
The essence of this finding is a series of molecular events that enable communication inside cells between the nucleus and mitochondria. As communication breaks down, aging accelerates. By administering a molecule naturally produced by the human body, scientists restored the communication network in older mice. Subsequent tissue samples showed key biological hallmarks that were comparable to those of much younger animals.
“The aging process we discovered is like a married couple—when they are young, they communicate well, but over time, living in close quarters for many years, communication breaks down,” said Harvard Medical School Professor of Genetics David Sinclair, senior author on the study. “And just like with a couple, restoring communication solved the problem.”
This study was a joint project between Harvard Medical School, the National Institute on Aging, and the University of New South Wales, Sydney, Australia, where Sinclair also holds a position.
The findings are published Dec. 19 in Cell.
Communication breakdown
Mitochondria are often referred to as the cell’s “powerhouse,” generating chemical energy to carry out essential biological functions. These self-contained organelles, which live inside our cells and house their own small genomes, have long been identified as key biological players in aging. As they become increasingly dysfunctional overtime, many age-related conditions such as Alzheimer’s disease and diabetes gradually set in.
Researchers have generally been skeptical of the idea that aging can be reversed, due mainly to the prevailing theory that age-related ills are the result of mutations in mitochondrial DNA—and mutations cannot be reversed.
Sinclair and his group have been studying the fundamental science of aging—which is broadly defined as the gradual decline in function with time—for many years, primarily focusing on a group of genes called sirtuins. Previous studies from his lab showed that one of these genes, SIRT1, was activated by the compound resveratrol, which is found in grapes, red wine and certain nuts.
Ana Gomes, a postdoctoral scientist in the Sinclair lab, had been studying mice in which this SIRT1 gene had been removed. While they accurately predicted that these mice would show signs of aging, including mitochondrial dysfunction, the researchers were surprised to find that most mitochondrial proteins coming from the cell’s nucleus were at normal levels; only those encoded by the mitochondrial genome were reduced.
“This was at odds with what the literature suggested,” said Gomes.
As Gomes and her colleagues investigated potential causes for this, they discovered an intricate cascade of events that begins with a chemical called NAD and concludes with a key molecule that shuttles information and coordinates activities between the cell’s nuclear genome and the mitochondrial genome. Cells stay healthy as long as coordination between the genomes remains fluid. SIRT1’s role is intermediary, akin to a security guard; it assures that a meddlesome molecule called HIF-1 does not interfere with communication.
For reasons still unclear, as we age, levels of the initial chemical NAD decline. Without sufficient NAD, SIRT1 loses its ability to keep tabs on HIF-1. Levels of HIF-1 escalate and begin wreaking havoc on the otherwise smooth cross-genome communication. Over time, the research team found, this loss of communication reduces the cell’s ability to make energy, and signs of aging and disease become apparent.
“This particular component of the aging process had never before been described,” said Gomes.
While the breakdown of this process causes a rapid decline in mitochondrial function, other signs of aging take longer to occur. Gomes found that by administering an endogenous compound that cells transform into NAD, she could repair the broken network and rapidly restore communication and mitochondrial function. If the compound was given early enough—prior to excessive mutation accumulation—within days, some aspects of the aging process could be reversed.
Cancer connection
Examining muscle from two-year-old mice that had been given the NAD-producing compound for just one week, the researchers looked for indicators of insulin resistance, inflammation and muscle wasting. In all three instances, tissue from the mice resembled that of six-month-old mice. In human years, this would be like a 60-year-old converting to a 20-year-old in these specific areas.
One particularly important aspect of this finding involvesHIF-1. More than just an intrusive molecule that foils communication, HIF-1 normally switches on when the body is deprived of oxygen. Otherwise, it remains silent. Cancer, however, is known to activate and hijack HIF-1. Researchers have been investigating the precise role HIF-1 plays in cancer growth.
“It’s certainly significant to find that a molecule that switches on in many cancers also switches on during aging,” said Gomes. “We’re starting to see now that the physiology of cancer is in certain ways similar to the physiology of aging. Perhaps this can explain why the greatest risk of cancer is age.”
“There’s clearly much more work to be done here, but if these results stand, then certain aspects of aging may be reversible if caught early,” said Sinclair.
The researchers are now looking at the longer-term outcomes of the NAD-producing compound in mice and how it affects the mouse as a whole. They are also exploring whether the compound can be used to safely treat rare mitochondrial diseases or more common diseases such as Type 1 and Type 2 diabetes. Longer term, Sinclair plans to test if the compound will give mice a healthier, longer life.
(Source: hms.harvard.edu)