New Brain Circuit Sheds Light on Development of Voluntary Movements
All parents know the infant milestones: turning over, learning to crawl, standing, and taking that first unassisted step. Achieving each accomplishment presumably requires the formation of new connections among subsets of the billions of nerve cells in the infant’s brain. But how, when and where those connections form has been a mystery.
Now researchers at Duke Medicine have begun to find answers. In a study reported Jan. 23, 2013, in the scientific journal Neuron, the research team describes the entire network of brain cells that are connected to specific motor neurons controlling whisker muscles in newborn mice.
A better understanding of such motor control circuits could help inform how human brains develop, potentially leading to new ways of restoring movement in people who suffer paralysis from brain injuries, or to the development of better prosthetics for limb replacement.
“Whiskers to mice are like fingers to humans, in that both are moving touch sensors,” said lead investigator Fan Wang, PhD, associate professor of cell biology and member of the Duke Institute for Brain Sciences. “Understanding how the mouse’s brain controls whisker movements may tell us about neural control of finger movements in people.”
Mice are active at night, so they rely heavily on whiskers to detect and discriminate objects in the dark, brushing their whiskers against objects in a rhythmic back-and-forth sweeping pattern referred to as “whisking”. But this whisking behavior does not appear until about two weeks after birth, when young mice start to explore the world outside their nest.
To learn how motor control of whiskers takes place, Wang and postdoctoral fellow Jun Takatoh used a new technique that takes advantage of the rabies virus’ ability to spread through connected nerve cells. A disabled form of the virus used to vaccinate pets was created with the ability to express a fluorescent protein. The researchers were able to trace its path through a network of brain cells directly connected to the motor neurons controlling whisker movement.
“The precision of this mapping method allowed us to ask a key question, namely are parts of the whisker motor control circuitry not yet connected in newborn mice, and are such missing links added later to enable whisking?” Wang said.
By taking a series of pictures in the fluorescently labeled brains during the first two weeks after birth, the research team chronicled the developing circuits before and after mice start whisking.
“When we traced the circuit it was stunning in the sense that we didn’t realize there are so many pools of neurons located throughout the brainstem that are connected to whisker motor neurons,” said Wang. “It’s remarkable that a single motor neuron receives so many inputs, and somehow is able to integrate them.”
At the same time whisking movements emerge, motor neurons receive a new set of inputs from a region of the brainstem called the LPGi. A single LPGi neuron is connected to motor neurons on both sides of the face, putting them in perfect position to synchronize the movements of left and right whiskers.
To learn more about the new circuit formed between LPGi and motor neurons, Wang and Takatoh drew on the expertise of Duke colleague Richard Mooney, PhD, professor of neurobiology, and his student Anders Nelson. Together, the researchers were able to record the labeled neurons and found the LPGi neurons communicate with motor neurons using glutamate, the main neurotransmitter that stimulates the brain. They further discovered that LPGi neurons receive direct inputs from the motor cortex.
“This makes sense because exploratory whisking is a voluntary movement under control of the motor cortex,” Wang said. “Excitatory input is needed for initiating such movements, and LPGi may be critical for relaying signals from the motor cortex to whisker motor neurons.”
The researchers will next explore the connectivity by using genetic, viral and optical tools to see what happens when certain components of the circuits are activated or silenced during various motor tasks.
Filed under nerve cells brain cells motor neurons whiskers neuroscience science
Socially Isolated Rats are More Vulnerable to Addiction
Rats that are socially isolated during a critical period of adolescence are more vulnerable to addiction to amphetamine and alcohol, found researchers at The University of Texas at Austin. Amphetamine addiction is also harder to extinguish in the socially isolated rats.
These effects, which are described this week in the journal Neuron, persist even after the rats are reintroduced into the community of other rats.
“Basically the animals become more manipulatable,” said Hitoshi Morikawa, associate professor of neurobiology in the College of Natural Sciences. “They’re more sensitive to reward, and once conditioned the conditioning takes longer to extinguish. We’ve been able to observe this at both the behavioral and neuronal level.”
Morikawa said the negative effects of social isolation during adolescence have been well documented when it comes to traits such as anxiety, aggression, cognitive rigidity and spatial learning. What wasn’t clear until now is how social isolation affects the specific kind of behavior and brain activity that has to do with addiction.
“Isolated animals have a more aggressive profile,” said Leslie Whitaker, a former doctoral student in Morikawa’s lab and now a researcher at the National Institute on Drug Abuse. “They are more anxious. Put them in an open field and they freeze more. We also know that those areas of the brain that are more involved in conscious memory are impaired. But the kind of memory involved in addiction isn’t conscious memory. It’s an unconscious preference for the place in which you got the reward. You keep coming back to it without even knowing why. That kind of memory is enhanced by the isolation.”
Filed under social isolation addiction brain activity neuron adolescence neuroscience science
Astrocytes Identified as Target for New Depression Therapy
Neuroscience researchers from Tufts University have found that our star-shaped brain cells, called astrocytes, may be responsible for the rapid improvement in mood in depressed patients after acute sleep deprivation. This in vivo study, published in the current issue of Translational Psychiatry, identified how astrocytes regulate a neurotransmitter involved in sleep. The researchers report that the findings may help lead to the development of effective and fast-acting drugs to treat depression, particularly in psychiatric emergencies.
Drugs are widely used to treat depression, but often take weeks to work effectively. Sleep deprivation, however, has been shown to be effective immediately in approximately 60% of patients with major depressive disorders. Although widely-recognized as helpful, it is not always ideal because it can be uncomfortable for patients, and the effects are not long-lasting.
During the 1970s, research verified the effectiveness of acute sleep deprivation for treating depression, particularly deprivation of rapid eye movement sleep, but the underlying brain mechanisms were not known.
Most of what we understand of the brain has come from research on neurons, but another type of largely-ignored cell, called glia, are their partners. Although historically thought of as a support cell for neurons, the Phil Haydon group at Tufts University School of Medicine has shown in animal models that a type of glia, called astrocytes, affect behavior.
Haydon’s team had established previously that astrocytes regulate responses to sleep deprivation by releasing neurotransmitters that regulate neurons. This regulation of neuronal activity affects the sleep-wake cycle. Specifically, astrocytes act on adenosine receptors on neurons. Adenosine is a chemical known to have sleep-inducing effects.
During our waking hours, adenosine accumulates and increases the urge to sleep, known as sleep pressure. Chemicals, such as caffeine, are adenosine receptor antagonists and promote wakefulness. In contrast, an adenosine receptor agonist creates sleepiness.
“In this study, we administered three doses of an adenosine receptor agonist to mice over the course of a night that caused the equivalent of sleep deprivation. The mice slept as normal, but the sleep did not reduce adenosine levels sufficiently, mimicking the effects of sleep deprivation. After only 12 hours, we observed that mice had decreased depressive-like symptoms and increased levels of adenosine in the brain, and these results were sustained for 48 hours,” said first author Dustin Hines, Ph.D., a post-doctoral fellow in the department of neuroscience at Tufts University School of Medicine (TUSM).
“By manipulating astrocytes we were able to mimic the effects of sleep deprivation on depressive-like symptoms, causing a rapid and sustained improvement in behavior,” continued Hines.
“Further understanding of astrocytic signaling and the role of adenosine is important for research and development of anti-depressant drugs. Potentially, new drugs that target this mechanism may provide rapid relief for psychiatric emergencies, as well as long-term alleviation of chronic depressive symptoms,” said Naomi Rosenberg, Ph.D., dean of the Sackler School of Graduate Biomedical Sciences and vice dean for research at Tufts University School of Medicine. “The team’s next step is to further understand the other receptors in this system and see if they, too, can be affected.”
(Image: Paul De Koninck)
Filed under brain cells neuronal activity sleep deprivation depression astrocytes neuroscience science
Study of how eye cells become damaged could help prevent blindness
Light-sensing cells in the eye rely on their outer segment to convert light into neural signals that allow us to see. But because of its unique cylindrical shape, the outer segment is prone to breakage, which can cause blindness in humans. A study published by Cell Press on January 22nd in the Biophysical Journal provides new insight into the mechanical properties that cause the outer segment to snap under pressure. The new experimental and theoretical findings help to explain the origin of severe eye diseases and could lead to new ways of preventing blindness.
"To our knowledge, this is the first theory that explains how the structural rigidity of the outer segment can make it prone to damage," says senior study author Aphrodite Ahmadi of the State University of New York Cortland. "Our theory represents a significant advance in our understanding of retinal degenerative diseases."
The outer segment of photoreceptors consists of discs packed with a light-sensitive protein called rhodopsin. Discs made at nighttime are different from those produced during the day, generating a banding pattern that was first observed in frogs but is common across species. Mutations that affect photoreceptors often destabilize the outer segment and may damage its discs, leading to cell death, retinal degeneration, and blindness in humans. But until now, it was unclear which structural properties of the outer segment determine its susceptibility to damage.
To address this question, Ahmadi and her team examined tadpole photoreceptors under the microscope while subjecting them to fluid forces. They found that high-density bands packed with a high concentration of rhodopsin were very rigid, which made them more susceptible to breakage than low-density bands consisting of less rhodopsin. Their model confirmed their experimental results and revealed factors that determine the critical force needed to break the outer segment.
The findings support the idea that mutations causing rhodopsin to aggregate can destabilize the outer segment, eventually causing blindness. “Further refinement of the model could lead to novel ways to stabilize the outer segment and could delay the onset of blindness,” says Ahmadi.
Filed under retinal degeneration blindness photoreceptors eye cells neuroscience science
Uncovering the secrets of 3D vision: How glossy objects can fool the human brain
It’s a familiar sight at the fairground: rows of people gaping at curvy mirrors as they watch their faces and bodies distort. But while mirrored surfaces may be fun to look at, new findings by researchers from the Universities of Birmingham, Cambridge and Giessen, suggest they pose a particular challenge for the human brain in processing images for 3D vision.
The researchers have taken advantage of the unusual visual behaviour of curved mirrors to study stereopsis: the process by which the brain combines images from the two eyes to see in 3D.
The work, published online in the Proceedings of the National Academy of Sciences (PNAS), used mathematical analysis and perceptual measurements to show that people often see the ‘wrong’ shape for glossy objects (like chrome bumpers or brass door knobs) because of the way the brain employs ‘quality control’ mechanisms when it views the world with two eyes. This reveals how the brain checks the ‘usefulness’ of the signals it receives from the senses, explaining why we sometimes misperceive shapes and distances. It also has some connections with the design of robotic systems.
‘We often think that the 3D information we get from having two eyes provides the gold standard for seeing in depth; but glossy objects pose a difficult challenge to the brain because the stereoscopic information often indicates depths that don’t match the physical shape of the object’ explains Dr Andrew Welchman, a Wellcome Trust Senior Research Fellow at the University of Birmingham. ‘We found that the brain is sometimes ‘fooled’ into seeing the wrong 3D shape, but this depends on statistical properties of the stereo images that indicate how ‘useful’ the information is,’ he adds.
To carry out the project, the team developed mathematical models that calculate the pattern of reflections seen when viewing glossy objects, and measured the perceived 3D appearance of these shapes.
‘When a curved mirrored object reflects its surroundings, the reflections appear at a different depth than the glossy surface itself. This makes it difficult for the brain to work out the true 3D distance to the surface’ explains Dr Alex Muryy, a research fellow at Birmingham who conducted the analyses. ‘We found that even simple objects can produce very complex depth profiles, and reflections can behave very differently from normal stereoscopic information.’ Understanding these differences provided the key to reveal the generalised way in which the brain analyses incoming information to judge the circumstances in which information should be trusted.
‘Stereoscopic information is often highly informative, but in certain circumstances it can tell us the wrong thing or be unreliable. The challenge is therefore to understand how the brain knows when it should or should not trust this 3D information,’ says Professor Roland Fleming, Giessen University in Germany. ‘We have uncovered signals that are likely to be important in guiding the brain’s use of the information by studying glossy objects. In particular, we can understand people’s misperceptions because in these circumstances 3D reflections fall within the normal range of values, meaning that the brain takes the depth signals at face value.’
Filed under 3D vision stereopsis perception depth perception mathematical model neuroscience science
FDA Approves Clinical Trial of Auditory Brainstem Implant Procedure for Children in the U.S.
L.A.-based House Research Institute and Children’s Hospital Los Angeles announced today that the United States Food and Drug Administration (FDA) has given final approval to begin a clinical trial of an Auditory Brainstem Implant (ABI) procedure for children. The trial is a surgical collaboration sponsored by the House Research Institute in partnership with Children’s Hospital Los Angeles and Vittorio Colletti, MD of the University of Verona Hospital, Verona, Italy.
The ABI was developed at the House Research Institute and is the world’s first successful prosthetic hearing device to stimulate neurons directly at the human brainstem, bypassing the inner ear and hearing nerve entirely. Since the procedure began, more than 1,000 adults worldwide have received the ABI, with surgeons at the House Clinic leading the way.
“This will be the first FDA-approved trial of its kind, and represents a major step forward to bring a sense of hearing to deaf children in the U.S. who are born without a hearing nerve or cochlea (hearing organ) and therefore are unable to benefit from hearing aids or cochlear implants,” said Neil Segil, Ph.D, executive vice president for research, House Research Institute. “Since its development at the House Research Institute in 1979 by Drs. William House and William Hitselberger, the ABI has been successful in providing a sense of sound to many adults in the U.S., however it has never been approved by the FDA for treating deafness in children. This study has the potential to expand the use of this remarkable device, which represents the only effective sensory prosthetic for direct brain stimulation in use today.”
The Pediatric ABI team includes physicians and researchers from the House Research Institute, including Eric Wilkinson, MD, Laurie Eisenberg, Ph.D., Robert Shannon, Ph.D.; Marc Schwartz, MD; Laurel Fisher, Ph.D.; Steve Otto, M.A., and Margaret Winter, M.S., as well as Children’s Hospital Los Angeles’ Mark Krieger, MD and Gordon McComb, MD; and Verona Hospital’s Vittorio Colletti, MD; Marco Carner, MD; and Liliana Colletti, Ph.D.
“We’re excited to have reached this milestone and look forward to being able to offer this amazing technology to children in the United States who currently have no other option for hearing rehabilitation,” said Eric Wilkinson, MD, co-principal investigator and lead physician for the clinical trial.
Filed under brain implants Auditory Brainstem Implant prosthetics hearing device deafness science
Chronic drinking is known to have detrimental health effects such as cardiac and liver problems, cognitive impairments, and brain damage. Binge drinking in particular is known to increase the risk of developing dementia and/or brain damage, yet little is known about an exact threshold for the damaging effects of alcohol. A study using rodents to examine various markers of neurodegeneration has found that brain damage can occur with as little as 24 hours of binge-like alcohol exposure.
Results will be published in the March 2013 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.
"We know that the extent of damage following alcohol exposure depends heavily on the manner in which it is consumed," said Kimberly Nixon, associate professor of pharmaceutical sciences at The University of Kentucky as well as corresponding author for the study. "Human studies suggest that binge-pattern drinking is more closely associated with brain damage. One study, for example, reported that binge drinking at least once per month in adulthood significantly increases the risk of developing dementia later in life. Animal models help provide the critical information that binge drinking, which produces high blood alcohol levels, directly causes damage."
"The exact threshold for the damaging effects of alcohol on the brain is unclear," commented Fulton T. Crews, John Andrews Distinguished Professor and director of the Center for Alcohol Studies at the University of North Carolina. "It is likely that the higher the blood alcohol level the greater the damage, however, this manuscript only studies binge drinking, using vimentin and flurojade B as markers of neurotoxicity."
"People hear from multiple sources that low-moderate alcohol consumption can be beneficial, and then we come along and say that heavy alcohol use leads to detrimental outcomes," said Nixon. "People then want to know what the line is between beneficial and detrimental Unfortunately, we don’t know exactly. However, our study suggests that it may be even less than previously thought."
Nixon and her colleagues administered a nutritionally complete liquid diet to adult male Sprague-Dawley rats that additionally contained either alcohol (25% w/v) or isocaloric dextrose every eight hours for either one or two days. The rodents were sacrificed immediately following, two days after, or seven days after alcohol exposure and their brain tissues were examined.
"This was really a simple study that took advantage of some new ‘tools’ to look for evidence of brain damage," explained Nixon. "In other words, we didn’t look for dying cells themselves, but we looked at more indirect indices of damage by looking at what happens to astroglia, one of the ‘supporting’ cells for neurons. Astroglia react to brain damage by expressing several proteins that they do not normally express under healthy, happy conditions, one of which is an intermediate filament protein called vimentin. We saw a remarkable number of cells expressing this marker It is one of those ‘here is your brain, here is your brain on drugs’ kind of findings where the expression was obvious to the naked eye in many brains with as little as 24 hours of high blood alcohol levels."
Nixon added that, because rodents metabolize alcohol significantly faster than humans do, it is important to look at the actual concentration of alcohol in the blood in order to translate this to the human condition. “These rats had blood alcohol levels that were more than four times the legal driving limit, which for humans would require excessive drinking in the nature of a 12-pack of beer, a couple bottles of wine, or half of fifth of whisky. Unfortunately, drinking self-reports and blood alcohol level data from emergency rooms confirm that this level of drinking is common in those with alcohol use disorders.”
"Rodent brain damage can model human damage," noted Crews. "Vimentin seems to be a good marker of glial activation that shows that one day of binge drinking can cause some brain damage that persists and grows after a week of abstinence. However, both rodent and human brain damage generally require long-term alcohol consumption that models alcoholism and not the acute responses studied in this manuscript."
Nixon agreed. “The lack of overt neuronal deterioration suggests that a single, short-term, high-level binge probably does not result in functional changes and/or cognitive deficits,” she said. “However, since alcoholics experience multiple binges throughout their lifetime, it is important to consider that each successive binge, starting with the very first one, affords some level of damage to the brain. Therefore, theoretically, with multiple binges comes a cumulative detrimental effect where pronounced cognitive, behavioral, and structural effects are observed.”
Nixon said this study demonstrates that new discoveries are always possible. “You have to know where and when to look for some of these effects,” she said. “The reason why this discovery wasn’t made previously is merely due to groups, ourselves included, not taking the time to thoroughly investigate these lower threshold doses with some pretty specific time points. Chasing down a threshold is not a sexy topic and it was actually fairly risky in that it was possible that we would have had all negative effects. Nonetheless, the take-home message of our data is that even one short-duration binge-alcohol experience – which is unfortunately similar to what young adults may experience during spring break or weekend partying - may start a cascade that leads to brain damage.”
(Source: eurekalert.org)
Filed under alcohol binge drinking brain cognitive impairment brain damage vimentin science
Reviewing alcohol’s effects on normal sleep
Sleep is supported by natural cycles of activity in the brain and consists of two basic states: rapid eye movement (REM) sleep and non-rapid eye movement (NREM) sleep. Typically, people begin the sleep cycle with NREM sleep followed by a very short period of REM sleep, then continue with more NREM sleep and more REM sleep, this 90 minute cycle continuing through the night. A review of all known scientific studies on the impact of drinking on nocturnal sleep has clarified that alcohol shortens the time it takes to fall asleep, increases deep sleep, and reduces REM sleep.
Results will be published in the April 2013 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.
"This review has for the first time consolidated all the available literature on the immediate effects of alcohol on the sleep of healthy individuals," said Irshaad Ebrahim, medical director at The London Sleep Centre as well as corresponding author for the study.
"Certainly a mythology seems to have developed around the impact of alcohol on sleep," added Chris Idzikowski, director of the Edinburgh Sleep Centre. "It is a good time to review the research as the mythology seems to be flourishing more rapidly than the research itself. Also, our understanding of sleep has accelerated in the past 30 years, which has meant that some of the initial interpretations need to be revisited."
Some of the review’s key themes are:
- At all dosages, alcohol causes a reduction in sleep onset latency, a more consolidated first half sleep, and an increase in sleep disruption in the second half of sleep.
"This review confirms that the immediate and short-term impact of alcohol is to reduce the time it takes to fall asleep," said Ebrahim. "In addition, the higher the dose, the greater the impact on increasing deep sleep. This effect on the first half of sleep may be partly the reason some people with insomnia use alcohol as a sleep aid. However, the effect of consolidating sleep in the first half of the night is offset by having more disrupted sleep in the second half of the night."
- The majority of studies, across alcohol dose, age, and gender, confirm an increase in slow-wave sleep (SWS) in the first half of the night. SWS, often referred to as deep sleep, consists of stages 3 and 4 of NREM. During SWS, the body repairs and regenerates tissues, builds bone and muscle, and appears to strengthen the immune system. Alcohol’s impact on SWS in the first half of the night appears to be more robust than its effect on REM sleep.
"SWS or deep sleep generally promotes rest and restoration," said Ebrahim. "However, when alcohol increases SWS, this may also increase vulnerability to certain sleep problems such as sleepwalking or sleep apnoea in those who are predisposed."
- Alcohol’s effects on REM sleep in the first half of sleep appear to be dose related. Low and moderate doses show no clear effects on REM sleep in the first half of the night, whereas at high doses, REM sleep reduction in the first part of sleep is significant. Total night REM sleep percent is decreased in the majority of studies at moderate and high doses.
"Dreams generally occur in the REM stage of sleep," said Ebrahim. "During REM sleep the brain is more active, and may be regarded as ‘defragmenting the drive.’ REM sleep is also important because it can influence memory and serve restorative functions. Conversely, lack of REM sleep can have a detrimental effect on concentration, motor skills, and memory. REM sleep typically accounts for 20 to 25 percent of the sleep period."
- The onset of the first REM sleep period is significantly delayed at all doses and appears to be the most recognizable effect of alcohol on REM sleep, followed by a reduction in total night REM sleep.
"One consequence of a delayed onset of the first REM sleep would be less restful sleep," said Idzikowski. "The first REM episode is often delayed in stressful environments. There is also a linkage with depression."
Filed under alcohol sleep REM sleep brain activity memory depression science
Brain structure of infants predicts language skills at 1 year
Using a brain-imaging technique that examines the entire infant brain, researchers have found that the anatomy of certain brain areas – the hippocampus and cerebellum – can predict children’s language abilities at 1 year of age.
The University of Washington study is the first to associate these brain structures with future language skills. The results are published in the January issue of the journal Brain and Language.
“The brain of the baby holds an infinite number of secrets just waiting to be uncovered, and these discoveries will show us why infants learn languages like sponges, far surpassing our skills as adults,” said co-author Patricia Kuhl, co-director of the UW’s Institute for Learning & Brain Sciences.
Children’s language skills soar after they reach their first birthdays, but little is known about how infants’ early brain development seeds that path. Identifying which brain areas are related to early language learning could provide a first glimpse of development going awry, allowing for treatments to begin earlier.
“Infancy may be the most important phase of postnatal brain development in humans,” said Dilara Deniz Can, lead author and a UW postdoctoral researcher. “Our results showing brain structures linked to later language ability in typically developing infants is a first step toward examining links to brain and behavior in young children with linguistic, psychological and social delays.”
Filed under brain cerebellum hippocampus neuroimaging language science
Discovering ‘Needle in a Haystack’ For Muscular Dystrophy Patients
Muscular dystrophy is caused by the largest human gene, a complex chemical leviathan that has confounded scientists for decades. Research conducted at the University of Missouri and described this month in the Proceedings of the National Academy of Sciences has identified significant sections of the gene that could provide hope to young patients and families.
MU scientists Dongsheng Duan, PhD, and Yi Lai, PhD, identified a sequence in the dystrophin gene that is essential for helping muscle tissues function, a breakthrough discovery that could lead to treatments for the deadly hereditary disease. The MU researchers “found the proverbial needle in a haystack,” according to Scott Harper, PhD, a muscular dystrophy expert at The Ohio State University who is not involved in the study.
Duchenne muscular dystrophy (DMD), predominantly affecting males, is the most common type of muscular dystrophy. Children with DMD face a future of rapidly weakening muscles, which usually leads to death by respiratory or cardiac failure before their 30th birthday.
Patients with DMD have a gene mutation that disrupts the production of dystrophin, a protein essential for muscle cell survival and function. Absence of dystrophin starts a chain reaction that eventually leads to muscle cell degeneration and death. While dystrophin is vital for muscle development, the protein also needs several “helpers” to maintain the muscle tissue. One of these “helper” molecular compounds is nNOS, which produces nitric oxide that can keep muscle cells healthy during exercise.
"Dystrophin not only helps build muscle cells, it’s also a key factor to attracting nNOS to the muscle cell membrane, which is important during exercise," Lai said. "Prior to this discovery, we didn’t know how dystrophin made nNOS bind to the cell membrane. What we found was that dystrophin has a special ‘claw’ that is used to grab nNOS and bring it to the muscle cell membrane. Now that we have that key, we hope to begin the process of developing a therapy for patients."
Filed under muscular dystrophy dystrophin gene muscle tissue genetic mutation genetics science
