Posts tagged neuroscience
Articles and news from the latest research reports.
3-D imaging sheds light on Apert Syndrome development
Three-dimensional imaging of two different mouse models of Apert Syndrome shows that cranial deformation begins before birth and continues, worsening with time, according to a team of researchers who studied mice to better understand and treat the disorder in humans.
Apert Syndrome is caused by mutations in FGFR2 — fibroblast growth factor receptor 2 — a gene, which usually produces a protein that functions in cell division, regulation of cell growth and maturation, formation of blood vessels, wound healing, and embryonic development. With certain mutations, this gene causes the bones in the skull to fuse together early, beginning in the fetus. These mutations also cause mid-facial deformation, a variety of neural, limb and tissue malformations and may lead to cognitive impairment.
Understanding the growth pattern of the head in an individual, the ability to anticipate where the bones will fuse and grow next, and using simulations “could contribute to improved patient-centered outcomes either through changes in surgical approach, or through more realistic modeling and expectation of surgical outcome,” the researchers said in today’s (Feb. 28) issue of BMC Developmental Biology.
Joan T. Richtsmeier, Distinguished Professor of Anthropology, Penn State, and her team looked at two sets of mice, each having a different mutation that causes Apert Syndrome in humans and causes similar cranial problems in the mice. They checked bone formation and the fusing of sutures, soft tissue that usually exists between bones n the skull, in the mice at 17.5 days after conception and at birth — 19 to 21 days after conception.
"It would be difficult, actually impossible, to observe and score the exact processes and timing of abnormal suture closure in humans as the disease is usually diagnosed after suture closure has occurred," said Richtsmeier. "With these mice, we can do this at the anatomical level by visualizing the sutures prenatally using micro-computed tomography — 3-D X-rays — or at the mechanistic level by using immunohistochemistry, or other approaches to see what the cells are doing as the sutures close."
The researchers found that both sets of mice differed in cranial formation from their littermates that were not carrying the mutation and that they differed from each other. They also found that the changes in suture closure in the head progressed from 17.5 days to birth, so that the heads of newborn mice looked very different at birth than they did when first imaged prenatally.
Apert syndrome also causes early closure of the sutures between bones in the face. Early fusion of bones of the skull and of the face makes it impossible for the head to grow in the typical fashion. The researchers found that the changed growth pattern contributes significantly to continuing skull deformation and facial deformation that is initiated prenatally and increases over time.
"Currently, the only option for people with Apert syndrome is rather significant reconstructive surgery, sometimes successive planned surgeries that occur throughout infancy and childhood and into adulthood," said Richtsmeier. "These surgeries are necessary to restore function to some cranial structures and to provide a more typical morphology for some of the cranial features."
Using 3-D imaging, the researchers were able to estimate how the changes in the growth patterns caused by either of the two different mutations produced the head and facial deformities.
"If what we found in mice is analogous to the processes at work in humans with Apert syndrome, then we need to decide whether or not a surgical approach that we know is necessary is also sufficient," said Richtsmeier. "If it is not in at least some cases, then we need to be working towards therapies that can replace or further improve surgical outcomes."
Muscle-controlling Neurons Know When They Mess Up
Whether it is playing a piano sonata or acing a tennis serve, the brain needs to orchestrate precise, coordinated control over the body’s many muscles. Moreover, there needs to be some kind of feedback from the senses should any of those movements go wrong. Neurons that coordinate those movements, known as Purkinje cells, and ones that provide feedback when there is an error or unexpected sensation, known as climbing fibers, work in close concert to fine-tune motor control.
A team of researchers from the University of Pennsylvania and Princeton University has now begun to unravel the decades-spanning paradox concerning how this feedback system works.
At the heart of this puzzle is the fact that while climbing fibers send signals to Purkinje cells when there is an error to report, they also fire spontaneously, about once a second. There did not seem to be any mechanism by which individual Purkinje cells could detect a legitimate error signal from within this deafening noise of random firing.
Using a microscopy technique that allowed the researchers to directly visualize the chemical signaling occurring between the climbing fibers and Purkinje cells of live, active mice, the Penn team has for the first time shown that there is a measurable difference between “true” and “false” signals.
This knowledge will be fundamental to future studies of fine motor control, particularly with regards to how movements can be improved with practice.
The research was conducted by Javier Medina, assistant professor in the Department of Psychology in Penn’s School of Arts and Sciences, and Farzaneh Najafi, a graduate student in the Department of Biology. They collaborated with postdoctoral fellow Andrea Giovannucci and associate professor Samuel S. H. Wang of Princeton University.
It was published in the journal Cell Reports.
The cerebellum is one of the brain’s motor control centers. It contains thousands of Purkinje cells, each of which collects information from elsewhere in the brain and funnels it down to the muscle-triggering motor neurons. Each Purkinje cell receives messages from a climbing fiber, a type of neuron that extends from the brain stem and sends feedback about the associated muscles.
“Climbing fibers are not just sensory neurons, however,” Medina said. “What makes climbing fibers interesting is that they don’t just say, ‘Something touched my face’; They say, ‘Something touched my face when I wasn’t expecting it.’ This is something that our brains do all the time, which explains why you can’t tickle yourself. There’s part of your brain that’s already expecting the sensation that will come from moving your fingers. But if someone else does it, the brain can’t predict it in the same way and it is that unexpectedness that leads to the tickling sensation.”
Not only does the climbing fiber feedback system for unexpected sensations serve as an alert to potential danger — unstable footing, an unseen predator brushing by — it helps the brain improve when an intended action doesn’t go as planned.
“The sensation of muscles that don’t move in the way the Purkinje cells direct them to also counts as unexpected, which is why some people call climbing fibers ‘error cells,’” Medina said. “When you mess up your tennis swing, they’re saying to the Purkinje cells, ‘Stop! Change! What you’re doing is not right!’ That’s where they help you learn how to correct your movements.
“When the Purkinje cells get these signals from climbing fibers, they change by adding or tweaking the strength of the connections coming in from the rest of the brain to their dendrites. And because the Purkinje cells are so closely connected to the motor neurons, the changes to those synapses are going to result in changes to the movements that Purkinje cell controls.”
This is a phenomenon known as neuroplasticity, and it is fundamental for learning new behaviors or improving on them. That new neural pathways form in response to error signals from the climbing fibers allows the cerebellum to send better instructions to motor neurons the next time the same action is attempted.
The paradox that faced neuroscientists was that these climbing fibers, like many other neurons, are spontaneously activated. About once every second, they send a signal to their corresponding Purkinje cell, whether or not there were any unexpected stimuli or errors to report.
“So if you’re the Purkinje cell,” Medina said, “how are you ever going to tell the difference between signals that are spontaneous, meaning you don’t need to change anything, and ones that really need to be paid attention to?”
Medina and his colleagues devised an experiment to test whether there was a measurable difference between legitimate and spontaneous signals from the climbing fibers. In their study, the researchers had mice walk on treadmills while their heads were kept stationary. This allowed the researchers to blow random puffs of air at their faces, causing them to blink, and to use a non-invasive microscopy technique to look at how the relevant Purkinje cells respond.
The technique, two-photon microscopy, uses an infrared laser and a reflective dye to look deep into living tissue, providing information on both structure and chemical composition. Neural signals are transmitted within neurons by changing calcium concentrations, so the researchers used this technique to measure the amount of calcium contained within the Purkinje cells in real time.
Because the random puffs of air were unexpected stimuli for the mice, the researchers could directly compare the differences between legitimate and spontaneous signals in the eyelid-related Purkinje cells that made the mice blink.
“What we have found is that the Purkinje cell fills with more calcium when its corresponding climbing fiber sends a signal associated with that kind of sensory input, rather than a spontaneous one,” Medina said. “This was a bit of a surprise for us because climbing fibers had been thought of as ‘all or nothing’ for more than 50 years now.”
The mechanism that allows individual Purkinje cells to differentiate between the two kinds of climbing fiber signals is an open question. These signals come in bursts, so the number and spacing of the electrical impulses from climbing fiber to Purkinje cell might be significant. Medina and his colleagues also suspect that another mechanism is at play: Purkinje cells might respond differently when a signal from a climbing fiber is synchronized with signals coming elsewhere from the brain.
Whether either or both of these explanations are confirmed, the fact that individual Purkinje cells are able to distinguish when their corresponding muscle neurons encounter an error must be taken into account in future studies of fine motor control. This understanding could lead to new research into the fundamentals of neuroplasticity and learning.
“Something that would be very useful for the brain is to have information not just about whether there was an error but how big the error was — whether the Purkinje cell needs to make a minor or major adjustment,” Medina said. “That sort of information would seem to be necessary for us to get very good at any kind of activity that requires precise control. Perhaps climbing fiber signals are not as ‘all-or-nothing’ as we all thought and can provide that sort of graded information”
Researchers Identify Brain Differences Linked to Insomnia
Johns Hopkins researchers report that people with chronic insomnia show more plasticity and activity than good sleepers in the part of the brain that controls movement.
"Insomnia is not a nighttime disorder," says study leader Rachel E. Salas, M.D., an assistant professor of neurology at the Johns Hopkins University School of Medicine. "It’s a 24-hour brain condition, like a light switch that is always on. Our research adds information about differences in the brain associated with it."
Salas and her team, reporting in the March issue of the journal Sleep, found that the motor cortex in those with chronic insomnia was more adaptable to change - more plastic - than in a group of good sleepers. They also found more “excitability” among neurons in the same region of the brain among those with chronic insomnia, adding evidence to the notion that insomniacs are in a constant state of heightened information processing that may interfere with sleep.
Researchers say they hope their study opens the door to better diagnosis and treatment of the most common and often intractable sleep disorder that affects an estimated 15 percent of the United States population.
To conduct the study, Salas and her colleagues from the Department of Psychiatry and Behavioral Sciences and the Department of Physical Medicine and Rehabilitation used transcranial magnetic stimulation (TMS), which painlessly and noninvasively delivers electromagnetic currents to precise locations in the brain and can temporarily and safely disrupt the function of the targeted area. TMS is approved by the U.S. Food and Drug Administration to treat some patients with depression by stimulating nerve cells in the region of the brain involved in mood control.
The study included 28 adult participants - 18 who suffered from insomnia for a year or more and 10 considered good sleepers with no reports of trouble sleeping. Each participant was outfitted with electrodes on their dominant thumb as well as an accelerometer to measure the speed and direction of the thumb.
The researchers then gave each subject 65 electrical pulses using TMS, stimulating areas of the motor cortex and watching for involuntary thumb movements linked to the stimulation. Subsequently, the researchers trained each participant for 30 minutes, teaching them to move their thumb in the opposite direction of the original involuntary movement. They then introduced the electrical pulses once again.
The idea was to measure the extent to which participants’ brains could learn to move their thumbs involuntarily in the newly trained direction. The more the thumb was able to move in the new direction, the more likely their motor cortexes could be identified as more plastic.
Because lack of sleep at night has been linked to decreased memory and concentration during the day, Salas and her colleagues suspected that the brains of good sleepers could be more easily retrained. The results, however, were the opposite. The researchers found much more plasticity in the brains of those with chronic insomnia.
Salas says the origins of increased plasticity in insomniacs are unclear, and it is not known whether the increase is the cause of insomnia. It is also unknown whether this increased plasticity is beneficial, the source of the problem or part of a compensatory mechanism to address the consequences of sleep deprivation associated with chronic insomnia. Patients with chronic phantom pain after limb amputation and with dystonia, a neurological movement disorder in which sustained muscle contractions cause twisting and repetitive movements, also have increased brain plasticity in the motor cortex, but to detrimental effect.
Salas says it is possible that the dysregulation of arousal described in chronic insomnia - increased metabolism, increased cortisol levels, constant worrying - might be linked to increased plasticity in some way. Diagnosing insomnia is solely based on what the patient reports to the provider; there is no objective test. Neither is there a single treatment that works for all people with insomnia. Treatment can be a hit or miss in many patients, Salas says.
She says this study shows that TMS may be able to play a role in diagnosing insomnia, and more importantly, she says, potentially prove to be a treatment for insomnia, perhaps through reducing excitability.
(Source: hopkinsmedicine.org)
Scientists wake up to causes of sleep disruption in Alzheimer’s disease
Being awake at night and dozing during the day can be a distressing early symptom of Alzheimer’s disease, but how the disease disrupts our biological clocks to cause these symptoms has remained elusive.
Now, scientists from Cambridge have discovered that in fruit flies with Alzheimer’s the biological clock is still ticking but has become uncoupled from the sleep-wake cycle it usually regulates. The findings – published in Disease Models & Mechanisms – could help develop more effective ways to improve sleep patterns in people with the disease.
People with Alzheimer’s often have poor biological rhythms, something that is a burden for both patients and their carers. Periods of sleep become shorter and more fragmented, resulting in periods of wakefulness at night and snoozing during the day. They can also become restless and agitated in the late afternoon and early evening, something known as ‘sundowning’.
Biological clocks go hand in hand with life, and are found in everything from single celled organisms to fruit flies and humans. They are vital because they allow organisms to synchronise their biology to the day-night changes in their environments.
Until now, however, it has been unclear how Alzheimer’s disrupts the biological clock. According to Dr Damian Crowther of Cambridge’s Department of Genetics, one of the study’s authors: “We wanted to know whether people with Alzheimer’s disease have a poor behavioural rhythm because they have a clock that’s stopped ticking or they have stopped responding to the clock.”
The team worked with fruit flies – a key species for studying Alzheimer’s. Evidence suggests that the A-beta peptide, a protein, is behind at least the initial stages of the disease in humans. This has been replicated in fruit flies by introducing the human gene that produces this peptide.
Taking a group of healthy flies and a group with this feature of Alzheimer’s, the researchers studied sleep-wake patterns in the flies, and how well their biological clocks were working.
They measured sleep-wake patterns by fitting a small infrared beam, similar to movement sensors in burglar alarms, to the glass tubes housing the flies. When the flies were awake and moving, they broke the beam and these breaks in the beam were counted and recorded.
To study the flies’ biological clocks, the researchers attached the protein luciferase – an enzyme that emits light – to one of the proteins that forms part of the biological clock. Levels of the protein rise and fall during the night and day, and the glowing protein provided a way of tracing the flies’ internal clock.
"This lets us see the brain glowing brighter at night and less during the day, and that’s the biological clock shown as a glowing brain. It’s beautiful to be able to study first hand in the same organism the molecular working of the clock and the corresponding behaviours," Dr Crowther said.
They found that healthy flies were active during the day and slept at night, whereas those with Alzheimer’s sleep and wake randomly. Crucially, however, the diurnal patterns of the luciferase-tagged protein were the same in both healthy and diseased flies, showing that the biological clock still ticks in flies with Alzheimer’s.
"Until now, the prevailing view was that Alzheimer’s destroyed the biological clock," said Crowther.
"What we have shown in flies with Alzheimer’s is that the clock is still ticking but is being ignored by other parts of the brain and body that govern behaviour. If we can understand this, it could help us develop new therapies to tackle sleep disturbances in people with Alzheimer’s."
Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, who helped to fund the study, said: “Understanding the biology behind distressing symptoms like sleep problems is important to guide the development of new approaches to manage or treat them. This study sheds more light on the how features of Alzheimer’s can affect the molecular mechanisms controlling sleep-wake cycles in flies.
"We hope these results can guide further studies in people to ensure that progress is made for the half a million people in the UK with the disease."
Why do some neurons respond so selectively to words, objects and faces?
So why do neurons respond in this remarkable way? A new study by Professor Jeff Bowers and colleagues at the University of Bristol argues that highly selective neural representations are well suited to co-activating multiple things, such as words, objects and faces, at the same time in short-term memory.
The researchers trained an artificial neural network to remember words in short-term memory. Like a brain, the network was composed of a set of interconnected units that activated in response to inputs; the network ‘learnt’ by changing the strength of connections between units. The researchers then recorded the activation of the units in response to a number of different words.
When the network was trained to store one word at a time in short-term memory, it learned highly distributed codes such that each unit responded to many different words. However, when it was trained to store multiple words at the same time in short-term memory it learned highly selective (‘grandmother cell’) units – that is, after training, single units responded to one word but not any other. This is much like the neurons in the cortex that respond to one face amongst many.
Why did the network learn such highly specific representations when trained to co-activate multiple words at the same time? Professor Bowers and colleagues argue that the non-selective representations can support memory for a single word, given that a pattern of activation across many non-selective units can uniquely represent a specific word. However, when multiple patterns are mixed together, the resulting blend pattern is often ambiguous (the so-called ‘superposition catastrophe’).
This ambiguity is easily avoided, however, when the network learns to represent words in a highly selective manner, for example, if one unit codes for the word RACHEL, another for MONICA, and yet another JOEY, there is no ambiguity when the three units are co-activated.
Professor Bowers said: “Our research provides a possible explanation for the discovery that single neurons in the cortex respond to information in a highly selective manner. It’s possible that the cortex learns highly selective codes in order to support short-term memory.”
The study is published in Psychological Review.
(Source: bristol.ac.uk)
After death, twin brains show similar patterns of neuropathologic changes
Despite widespread use of a single term, Alzheimer’s disease is actually a diverse collection of diseases, symptoms and pathological changes. What’s happening in the brain often varies widely from patient to patient, and a trigger for one person may be harmless is another.
In a unique study, an international team of researchers led by USC psychologist Margaret Gatz compared the brains of twins where one or both died of Alzheimer’s disease. They found that many of the twin pairs not only had similar progressions of Alzheimer’s disease and dementia prior to death, but they also had similar combinations of pathologies — two-or-more unconnected areas of damage to the brain.
The paper is part of Gatz’s landmark body of work on aging and cognition with the Swedish Twin Registry, a large cohort study of more than 14,000 Swedish twins, now over the age of 65. Across nearly 30 years, Gatz’s work with twins — including genetically identical pairs — has shifted the study of Alzheimer’s disease to include the entire lifespan, including the effects of developmental exposure, periodontal disease, mental health, obesity and diabetes on later-life Alzheimer’s risk.
The current paper provides more evidence that there may not be a single smoking-gun cause of Alzheimer’s, but rather a range of potential causes to which we may be susceptible largely depending on our genetics. It appears in the current issue of the journal Brain Pathology.
“We try to make inferences based on tests and diagnoses, but we have to assume that what we’re seeing is a manifestation of what’s going on in these twins’ brains,” said Gatz, professor of psychology, gerontology and preventive medicine in USC Dornsife College. “For this reason, we wanted to compare the brains of twins to ask whether identical twins’ brains are actually more identical?”
The researchers had the rare opportunity to directly autopsy the brains of seven pairs of twins who both died after being receiving diagnostic evaluations over many years, including a pair of identical twins who were both diagnosed with Alzheimer’s and died within a year of one another at the age of 98.
“There may be risk factors that start to accumulate but don’t lead to a clinical diagnosis,” explained lead author Diego Iacono of the Karolinska Institute in Sweden and the Biomedical Research Institute. “We found that the presence of Alzheimer’s disease doesn’t preclude the presence of other damage. Looking at co-pathologies in twin pairs may present new areas for research aside from the typical factors.”
For example, while there’s wide consensus among experts about the course of Alzheimer’s disease and the presence of amyloid plaques and tangles in the brain, what starts the process going is less clear, including the role of lesions, Lewy bodies and vascular or ventricle damage, more often associated with specific types of dementia such as Parkinson’s disease.
“Identical twins tended to have similar combinations of pathologies. We looked not just at the hallmark indicators of Alzheimer’s, but at all the other damage in the brain. Across the whole array of neuropathological changes, the identical twins appeared to have more similar pathologies,” Gatz said. “This is fascinating: it’s not just a key pathology related to the twins’ diagnoses but the combination of things happening in their brains. We’re going to keep looking for what these combinations are.”
(Image: Getty)
Researchers Find Inherited Pathway of Risk for Schizophrenia
Schizophrenia is one of the most disabling of all psychiatric illnesses. Sadly, it is not uncommon and it strikes early in life.
Many studies have looked into causes and potential interventions, and it has been long known that genetic factors play a role in determining the risk of developing schizophrenia. However, recent work has shown that there will be no simple answers as to why some people get schizophrenia: No single gene or small number of genes explains much of the risk for illness. Instead, future studies must focus on larger numbers of interacting genes.
In a new paper published in PLOS ONE, researchers led by Bruce Cohen of Harvard Medical School and McLean Hospital report promising evidence on what one of those important groups of genes may be.
Previous studies of schizophrenia have shown abnormalities in the brain’s white matter—its wiring and insulation—but these studies could not definitively separate inherited from environmental causes. For this study, researchers used previously discovered anomalies to select likely assortments of genes that, as a group, might be highly determinative of the risk for schizophrenia. The choice of genes was based on convergent results of past studies conducted locally and around the world, and included genes that control the insulation of the nerve cells in the brain.
The results of this study strongly suggest that the abnormalities of wiring and insulation are substantially determined by genes.
“There is abundant evidence from our center and from other laboratories that this insulation is compromised in schizophrenia,” said Cohen, HMS Robertson-Steele Professor of Psychiatry and director of the Shervert Frazier Research Institute at McLean Hospital. “Based on this lead, we tested whether the genes required for the activities of the cells that make this insulation (oligodendrocytes) were associated with schizophrenia. In a primary analysis, followed by three separate means of confirmatory analysis, we found strong evidence that genes for oligodendrocytes, as a group, were indeed associated with schizophrenia.”
The findings suggest a concrete reason why insulation is disrupted in the brain in schizophrenia. This disruption in turn may explain why thinking is altered in schizophrenia: Nerve cells are unable to pass exact messages if they lack proper insulation.
Further, the findings show that the abnormality in insulation is at least in part genetically determined, rather than solely due to environmental factors such as years of treatment, different life activities or exposure to toxins.
Finally, the results identify a specific cell-level abnormality, in oligodendrocytes, in schizophrenia.
Similar findings, using different techniques, were recently reported by an independent group of investigators, working separately but contemporaneously with the authors of this study.
“Knowing that one of the pathways of risk for schizophrenia is in this set of genes and in these cells may help identify who is at risk and in what way they are at risk,” said Cohen. “The cells themselves will next be studied to define the problem and seek methods to prevent or reverse it. Thus, the findings can point us towards new ways to reduce the risk and burden of schizophrenia.”
Additional researchers from HMS, Harvard School of Public Health, McLean Hospital, Massachusetts General Hospital, The Broad Institute of MIT and Harvard, and the Cardiff University School of Medicine in Wales contributed to the study.
(Source: hms.harvard.edu)
Scientists Uncover Trigger for Most Common Form of Intellectual Disability and Autism
A new study led by Weill Cornell Medical College scientists shows that the most common genetic form of mental retardation and autism occurs because of a mechanism that shuts off the gene associated with the disease. The findings, published today in Science, also show that a drug that blocks this silencing mechanism can prevent fragile X syndrome — suggesting similar therapy is possible for 20 other diseases that range from mental retardation to multisystem failure.
(Image caption: A key brain signaling protein, seen here in green, that is normally lost in Fragile X syndrome neurons is restored by an experimental drug. Image: Dilek Colak)
Fragile X syndrome occurs mostly in boys, causing intellectual disability as well as telltale physical, behavioral and emotional traits. While researchers have known for more than two decades that the culprit behind the disease is an unusual mutation characterized by the excess repetition of a particular segment of the genetic code, they weren’t sure why the presence of a large number of these repetitions — 200 or more — sets the disease process in motion.
Using stem cells from donated human embryos that tested positive for fragile X syndrome, the scientists discovered that early on in fetal development, messenger RNA — a template for protein production — begins sticking itself onto the fragile X syndrome gene’s DNA. This binding appears to gum up the gene, making it inactive and unable to produce a protein crucial to the transmission of signals between brain cells.
"Until 11 weeks of gestation, the fragile X syndrome gene is active — it produces its messenger RNA and protein normally. Then, all of a sudden it turns off, and stays off for the rest of the patient’s lifetime, causing fragile X syndrome. But scientists have not understood why this gene gets shut off," says senior author Dr. Samie Jaffrey, a professor of pharmacology at Weill Cornell Medical College. "We discovered that the messenger RNA can jam up one strand of the gene’s DNA, shutting down the gene — which was not known before.
"This is new biology — an interaction between the RNA and the DNA of the fragile X syndrome gene causes disease," Dr. Jaffrey says. "We are coming to understand that RNAs are powerful molecules that can regulate gene expression, but this mechanism is completely novel — and very exciting."
The malfunction occurs suddenly — before the end of the first trimester in humans and after 50 days in laboratory embryonic stem cells. At that point, the messenger RNA produced by the fragile X syndrome gene makes what the researchers call an RNA-DNA duplex — a particular arrangement of molecules in which the messenger RNA is stuck onto its DNA complement. (DNA produces two complementary strands of the genetic code responsible for human development and function. The four nucleic acids in the genomic code — A, C, G, T — have specific complements. In the case of fragile X syndrome, the repeat sequence in question is CGG. Therefore, RNA binds to its GCC complement on one strand of DNA.)
The RNA-DNA duplex then shuts down production of the fragile X syndrome gene, causing the loss of a protein needed for communication between brain cells. The gene then remains inactive for life. A normal fragile X gene — one with fewer than 200 CGG repeats — stays active in a person without the disorder, and produces the necessary protein. However, the mutant fragile X gene contains more than 200 CGG repeats, resulting in fragile X syndrome. Fragile X occurs in about 1 in 4,000 males and 1 in 8,000 females.
"Because the fragile X syndrome mutation is a repeat sequence, it is very easy for just a small portion of this sequence in the messenger RNA to find a matching repeat sequence on the DNA," Dr. Jaffrey says. "This is a unique feature of repeat sequences. When there are 200 or more repeats, the RNA-DNA interaction locks into place."
Hope for treatment — and other disorders
Dr. Jaffrey and his team, which includes researchers from The Scripps Research Institute in Florida and Albert Einstein College of Medicine in the Bronx, sought to find out why the disease is switched on when the CGG repeat is present in 200 to as many as 1,000 copies.
"Utilizing traditional ways to solve this puzzle has been impossible," he says. "Human fragile X syndrome genes introduced into mice and cells in the laboratory never turn off, no matter how many CGG repeats the genes have."
So the scientists turned to human embryonic stem cells. Co-authors Dr. Zev Rosenwaks, director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and director of the Stem Cell Derivation Laboratory of Weill Cornell Medical College, and Dr. Nikica Zaninovic, assistant professor of reproductive medicine, generated stem cell lines from donated embryos that tested positive for fragile X syndrome. “These stem cells were critical to the success of this research, because they alone allowed us to mimic what happens to the fragile X gene during embryonic development,” says Dr. Dilek Colak, a postdoctoral scientist in Dr. Jaffrey’s laboratory and the first author of the study.
The stem cells were coaxed to become brain neurons, and at about 50 days, they differentiated in the same way that an embryo’s brain is developing at 11-plus weeks when the fragile X syndrome gene is switched off.
The researchers then used a drug developed by co-author Dr. Matthew Disney of the Scripps Research Institute that binds to CGG in the fragile X gene’s RNA before and after the 50-day switch. Strikingly, the gene never stopped producing its beneficial protein.
That suggests a potential prevention or treatment strategy for fragile X syndrome, Dr. Jaffrey says. “If a pregnant woman is told that her fetus carries the genetic mutation causing fragile X syndrome, we could potentially intervene and give the drug during gestation. This may delay or prevent the silencing of the fragile X gene, which could potentially significantly improve the outcome of these patients,” he says.
The researchers are now looking for similar RNA-DNA duplexes in other trinucleotide repeat diseases, including Huntington’s disease (a degenerative brain disease), myotonic dystrophy 1 and 2 (a multisystem progressive disease), Friedrich’s ataxia (a progressive nervous system disorder), Jacobsen syndrome (an intellectual disorder), and familial amyotrophic lateral sclerosis (a motor neuron disease), among others.
"This completely new mechanism by which RNAs can direct gene silencing may be involved in a lot of other diseases," Dr. Jaffrey says. "Our hope is that we can find drugs that interfere with this new type of disease process."
(Source: weill.cornell.edu)
Study first to offer detailed map of mouse’s cerebral cortex
The mammalian cerebral cortex, long thought to be a dense single interrelated tangle of neural networks, actually has a “logical” underlying organizational principle, according to a study appearing in the journal Cell.
Researchers have identified eight distinct neural subnetworks that together form the connectivity infrastructure of the mammalian cortex — the part of the brain involved in higher-order functions such as cognition, emotion and consciousness.
“This study is the first comprehensive mapping of the most developed region of the mammalian brain: the cerebral cortex. The cortex is highly complex and made up of many densely interconnected structures, but when you strip it down, is organized into a small number of subnetworks,” said senior author Hongwei Dong of the USC Institute for Neuroimaging and Informatics (INI).
The cerebral cortex is the outermost layer of neural tissue in the brain and is one of the most extensively studied brain structures in the field of neuroscience. However, before this study, its underlying organizational principle was still largely unclear.
“Think about it: The brain is built for logic, so it’s organization must be logical. The brain’s architectural organization is arranged such that all of its substructures most efficiently work in conjunction to produce appropriate behaviors,” said Dong, associate professor of neurology at the Keck School of Medicine of USC. “We want to find the code to how the brain is structurally organized.”
The study is also a reminder that while there is more data than ever, the quality and reliability of information still matters. In contrast to past patchwork attempts, Dong and his team undertook an effort to directly develop a whole-brain mouse atlas of brain pathways. Across the cortex, they injected fluorescent molecules. These molecules were then transported along the brain’s “cellular highways” — the neuronal pathways — and meticulously tracked using a high-resolution microscope.
The uniformity and completeness of the scientists’ effort across the entire cortex provided for a searchable image database of cortical connections, which the researchers are making open-access and publicly available.
It also allowed them to reliably see patterns: the seemingly inscrutable mass of connections in the cerebral cortex is highly organized, consisting of eight distinct subnetworks that are relatively segregated.
“The systematic and comprehensive manner in which the data were collected lent itself to a detailed analysis through which these subnetworks emerged,” explained co-lead author Houri Hintiryan of the USC Laboratory of Neuro Imaging.
So that scientists around the world may continue to look for fundamental structural insights, the full, interactive imaging dataset is viewable at Mouse Connectome Project, providing a resource for researchers interested in studying the anatomy and function of cortical networks throughout the brain.
“It really is quite tedious,” Dong said of collecting the data, “and labor-intensive, and it requires highly specialized skills and technology. But think of the Human Genome Project and how much it accelerated the process of discovery and the whole field when infrastructures existed for people to share and compare. That was our motivation.”
How these subnetworks interact will provide a crucial baseline from which to better understand diseases of “disconnection” such as autism and Alzheimer’s disease, in which the manifestations of symptoms are potentially a result of disordered or damaged connections.
The researchers’ map of the mouse cerebral cortex can be compared to data on disease-affected brains, brains in development and genetic information. It will also offer necessary context for humans, who behaved just like other mammals only a few thousand years ago and who still share most underlying basic behavioral characteristics such as hunger and pain.
“The fundamental logic of mammalian brains is the same, particularly when it comes to basic behaviors such as eating, sleeping and social behaviors” said Dong, who noted that similar studies in humans have thus far not gotten to the cellular level. “There are lots of organizing principles to brain structures that we are just beginning to understand.”
The researchers identified the brain subnetworks based on their high degree of interconnectivity — though relatively independent, several structures provide communication routes through which the subnetworks interact. Combined with behavioral data from past research and information about subcortical targets, these interconnections imply remarkable functional significance for the subnetworks.
Four of the eight identified subnetworks in the mouse cortex relate to sensation and movement of the body — what the researchers dub somatic sensorimotor. In particular, the researchers identified separate subnetworks for movements in the face, upper limbs, lower limbs and trunk, and whiskers. Together, these networks facilitate motor behaviors such as eating and drinking, reaching and grabbing, locomotion and exploration of the environment.
Two other subnetworks are comprised of structures located along the midline of the cerebral cortex. These medial subnetworks seem devoted to the integration of visual, auditory and somatic sensory information, according to the study. Several other structures located along the side of the brain form two lateral subnetworks, one of which potentially serves to regulate the internal status of the body (i.e., taste, hunger, visceral information) and the other as a “mega-integration” subnetwork that allows the interaction of information from nearly the entire cortex.
Study ties father’s age at childbearing to higher rates of psychiatric, academic problems in kids
An Indiana University study in collaboration with medical researchers from Karolinska Institute in Stockholm has found that advancing paternal age at childbearing can lead to higher rates of psychiatric and academic problems in offspring than previously estimated.
Examining an immense data set — everyone born in Sweden from 1973 until 2001 — the researchers documented a compelling association between advancing paternal age at childbearing and numerous psychiatric disorders and educational problems in their children, including autism, ADHD, bipolar disorder, schizophrenia, suicide attempts and substance abuse problems. Academic problems included failing grades, low educational attainment and low IQ scores.
Among the findings: When compared to a child born to a 24-year-old father, a child born to a 45-year-old father is 3.5 times more likely to have autism, 13 times more likely to have ADHD, two times more likely to have a psychotic disorder, 25 times more likely to have bipolar disorder and 2.5 times more likely to have suicidal behavior or a substance abuse problem. For most of these problems, the likelihood of the disorder increased steadily with advancing paternal age, suggesting there is no particular paternal age at childbearing that suddenly becomes problematic.
"We were shocked by the findings," said Brian D’Onofrio, lead author and associate professor in the Department of Psychological and Brain Sciences in the College of Arts and Sciences at IU Bloomington. "The specific associations with paternal age were much, much larger than in previous studies. In fact, we found that advancing paternal age was associated with greater risk for several problems, such as ADHD, suicide attempts and substance use problems, whereas traditional research designs suggested advancing paternal age may have diminished the rate at which these problems occur."
The study, “Parental Age at Childbearing and Offspring Psychiatric and Academic Morbidity,” was published today in JAMA Psychiatry.
Notably, the researchers found converging evidence for the associations with advancing paternal age at childbearing from multiple research designs for a broad range of problems in offspring. By comparing siblings, which accounts for all factors that make children living in the same house similar, researchers discovered that the associations with advancing paternal age were much greater than estimates in the general population. By comparing cousins, including first-born cousins, the researchers could examine whether birth order or the influences of one sibling on another could account for the findings.
The authors also statistically controlled for parents’ highest level of education and income, factors often thought to counteract the negative effects of advancing paternal age because older parents are more likely to be more mature and financially stable. The findings were remarkably consistent, however, as the specific associations with advancing paternal age remained.
"The findings in this study are more informative than many previous studies," D’Onofrio said. "First, we had the largest sample size for a study on paternal age. Second, we predicted numerous psychiatric and academic problems that are associated with significant impairment. Finally, we were able to estimate the association between paternal age at childbearing and these problems while comparing differentially exposed siblings, as well as cousins. These approaches allowed us to control for many factors that other studies could not."
In the past 40 years, the average age for childbearing has been increasing steadily for both men and women. Since 1970 for instance, the average age of first-time mothers in the U.S. has gone up four years from 21.5 to 25.4. For men the average is three years older. In the northeast, the ages are higher. Yet the implications of this fact — both socially and in terms of the long-term effects on the health and well-being of the population as a whole — are not yet fully understood.
Moreover, while maternal age has been under scrutiny for a number of years, a more recent body of research has begun to explore the possible effects of advancing paternal age on a variety of physical and mental health issues in offspring. Existing studies have pointed to increasing risks for some psychological disorders with advancing paternal age. Yet the results are often inconsistent with one another, statistically inconclusive or unable to take certain confounding factors into account.
The working hypothesis for D’Onofrio and his colleagues who study this phenomenon is that unlike women, who are born with all their eggs, men continue to produce new sperm throughout their lives. Each time sperm replicate, there is a chance for a mutation in the DNA to occur. As men age, they are also exposed to numerous environmental toxins, which have been shown to cause mutations in the DNA found in sperm. Molecular genetic studies have, in fact, shown that sperm of older men have more genetic mutations.
This study and others like it, however, perhaps signal some of the unforeseen, negative consequences of a relatively new trend in human history. As such, D’Onofrio said, it may have important social and public policy implications. Given the increased risk associated with advancing paternal age at childbearing, policy-makers may want to make it possible for men and women to accommodate children earlier in their lives without having to set aside other goals.
"While the findings do not indicate that every child born to an older father will have these problems," D’Onofrio said, "they add to a growing body of research indicating that advancing paternal age is associated with increased risk for serious problems. As such, the entire body of research can help to inform individuals in their personal and medical decision-making."