Posts tagged science
Articles and news from the latest research reports.
Neurons express ‘gloss’ using three perceptual parameters
Japanese researchers showed monkeys a number of images representing various glosses and then they measured the responses of 39 neurons by using microelectrodes. They found that a specific population of neurons changed the intensities of the responses linearly according to either the contrast-of-highlight, sharpness-of-highlight, or brightness of the object. This shows that these 3 perceptual parameters are used as parameters when the brain recognizes a variety of glosses. They also found that different parameters are represented by different populations of neurons. This was published in the Journal of Neuroscience.
The gloss of an object surface provides information about the condition of that object. For instance, whether it is wet or dry, whether food is fresh or old. Several gloss-related physical parameters such as specular reflectance and diffuse reflectance have been described and used in computer graphics so far. However, the parameters used when neurons respond to gloss have not yet been found.
A Japanese research group led by Hidehiko Komatsu, professor of the National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences (NINS), in collaboration with the Advanced Telecommunications Research Institute International (ATR) prepared 16 images representing various glosses and showed them to monkeys. In a circumscribed area in the inferior temporal cortex of the brain, neurons strengthened their responses proportionately as the contrast-of-highlight and/or sharpness-of-highlight got higher. Neural responses also vary greatly depending on the brightness, for instance, whether the object is black, gray, or white. Furthermore, the perceptual gloss parameters of the presented image could be fairly precisely predicted from the strengths of the population neural responses.
By the application of these findings in an artificial image recognition system, the researchers are expecting that it would be able to develop robots that recognize gloss like humans.
In a novel brain-imaging study among trauma victims, researchers at NYU Langone Medical Center have linked an opioid receptor in the brain — associated with emotions — to a narrow cluster of trauma symptoms, including sadness, emotional detachment and listlessness. The study, published online today in the journal JAMA Psychiatry, holds important implications for targeted, personalized treatment of post-traumatic stress disorder, or PTSD, a psychiatric condition affecting more than 8 million Americans that can cause a wide range of debilitating psychiatric symptoms.
“Our study points toward a more personalized treatment approach for people with a specific symptom profile that’s been linked to a particular neurobiological abnormality,” says lead author Alexander Neumeister, MD, director of the molecular imaging program in the Departments of Psychiatry and Radiology at NYU School of Medicine, and Co-Director of NYU Langone’s Steven and Alexandra Cohen Veterans Center for the Study of Post-Traumatic Stress Disorder and Traumatic Brain Injury. “Understanding more about where and how symptoms of PTSD manifest in the brain is a critical part of research efforts to develop more effective medications and treatment modalities.”
The new study confirms a growing body of evidence linking a particular set of symptoms to specific brain circuits and chemicals, and bolsters a shift within the field of psychiatry away from “one-size-fits-all treatments” and toward more individualized medication regimens that target highly specific neurobiological components. “We know from previous clinical trials that antidepressants, for example, do not work well for dysphoria and the numbing symptoms often found in PTSD,” Dr. Neumeister added. “Currently available antidepressants are just not linked specifically enough to the neurobiological basis of these symptoms in PTSD. Going forward, our study will help pave the way toward development of better options.”
“People with cancer have a variety of different treatment options available based on the type of cancer that they have,” adds Dr. Neumeister. “We aim to do the same thing in psychiatry. We’re deconstructing PTSD symptoms, linking them to different brain dysfunction, and then developing treatments that target those symptoms. It’s really a revolutionary step forward that has been supported by the National Institute of Mental Health (NIMH) over the past few years in their Research Domain Criteria Project.”
The study, funded by the National Institute of Mental Health (NIMH), compared the brain scans of healthy volunteers with those of clinically diagnosed trauma victims with PTSD, major depression, and generalized anxiety disorder whose symptoms ranged from emotional detachment to isolation. Participants received a harmless radioactive tracer that binds to and illuminates a class of opioid receptors, known as kappa, when exposed to high-resolution positron emission tomography (PET). Kappa opioid receptors bind a potent natural opioid known as dynorphin, which is released by the body during times of stress to help relieve dysphoria or numbing.
Chronic exposure to stress, such as the case with PTSD, taxes kappa opioid receptors, however, causing the receptors to retract inside cells, leaving dynorphin without a place to dock. As a result, patients can experience dysphoria, characterized by feelings of hopelessness, detachment and emotional unease.
Results showed that fewer available kappa opioid receptors in the brain regions believed to govern emotions were associated with more intense feelings of dysphoria, but not feelings of anxious arousal. The findings confirm previous studies in animals linking the opioid-receptor system expressed in these specific brain regions to symptoms of dysphoria. The study also found an association between lower levels of cortisol, a stress hormone, and unavailable kappa opioid receptors, suggesting a new role for cortisol as a biomarker for certain types of PTSD symptoms.
“This is the first brain-imaging study to explore any psychiatric condition using a protein that binds to the kappa opioid receptor system,” notes Dr. Neumeister, who says the data support clinical trials under way at NYU Langone and other institutions of new medications that target kappa opioid receptors and other brain systems that can be linked to specific symptoms in trauma survivors. Such medications could be widely available for the treatment of PTSD in the future if ongoing clinical trials yield encouraging results.
(Image: Alamy)
Gambling with confidence: Are you sure about that?
Life is a series of decisions, ranging from the mundane to the monumental. And each decision is a gamble, carrying with it the chance to second-guess. Did I make the right turn at that light? Did I choose the right college? Was this the right job for me?
Our desire to persist along a chosen path is almost entirely determined by our confidence in the decision: when you are confident that your choice is correct, you are willing to stick it out for a lot longer.
Confidence determines much of our path through life, but what is it? Most people would describe it as an emotion or a feeling. In contrast, scientists at Cold Spring Harbor Laboratory (CSHL) have found that confidence is actually a measureable quantity, and not reserved just for humans. The team, led by CSHL Associate Professor Adam Kepecs, has identified a brain region in rats whose function is required for the animals to express confidence in their decisions.
How do we know when a rat is exhibiting confidence? The researchers devised a method to study decision making in these animals. The rats were offered an odor that they were trained to associate with one of two doors. When they chose the correct door, they were rewarded. This part was easy for the animals: their selections were almost always correct. Things got trickier when Kepecs and his team offered a mixture of the two scents, with one dominating over the other by only a very small percentage. The rats now needed to choose the door representing the dominant odor in order to get their reward – a choice that reflects their best guess.
In work published today in Neuron, the team describes how confidence can be measured simply by challenging a rat to wait for the reward to be revealed behind the door. The time they are willing wait serves as a measure of the confidence in their original decision. “We found that the rats are willing to ‘gamble’ with their time,” Kepecs explains, sometimes waiting as much as 15 seconds, which is an eternity for these animals. “This is something that we can measure and create mathematical models to explain,” says Kepecs. “The time rats are willing to wait predicts the likelihood of correct decisions and provides an objective measure to track the feeling of confidence.”
The researchers hypothesized that a distinct region of the brain might control confidence. Previous work has suggested that the orbitofrontal cortex (OFC), a part of the brain involved in making predictions, might have a role in decision confidence. Kepecs and his team specifically shut off neurons in the OFC, inactivating it, and found that rats no longer exhibited appropriate levels of confidence in their decisions.
“With an inactive OFC, the rats retained the ability to make decisions – their accuracy did not change,” says Kepecs. “And they spent the same amount of time waiting for a reward on average. The only difference is that animals’ willingness to wait for a reward was no longer guided by confidence. They would often wait a long time even when they were wrong.”
The discovery offers a rare glimpse into the neuronal basis of a higher-level cognitive process, and is likely to have implications in human decision-making as well. As Kepecs describes, “we now know that the OFC is critical for making on-the-fly predictions in rats. The human OFC is just a more sophisticated version of the rodent counterpart.” The team is expanding their research to explore how the elusive feelings of confidence are based on objective predictions that influence human decisions as well.
Single dose of antidepressant changes the brain
A single dose of antidepressant is enough to produce dramatic changes in the functional architecture of the human brain. Brain scans taken of people before and after an acute dose of a commonly prescribed SSRI (serotonin reuptake inhibitor) reveal changes in connectivity within three hours, say researchers who report their observations in the Cell Press journal Current Biology on September 18.
"We were not expecting the SSRI to have such a prominent effect on such a short timescale or for the resulting signal to encompass the entire brain," says Julia Sacher of the Max Planck Institute for Human Cognitive and Brain Sciences.
While SSRIs are among the most widely studied and prescribed form of antidepressants worldwide, it’s still not entirely clear how they work. The drugs are believed to change brain connectivity in important ways, but those effects had generally been thought to take place over a period of weeks, not hours.
The new findings show that changes begin to take place right away. Sacher says what they are seeing in medication-free individuals who had never taken antidepressants before may be an early marker of brain reorganization.
Study participants let their minds wander for about 15 minutes in a brain scanner that measures the oxygenation of blood flow in the brain. The researchers characterized three-dimensional images of each individual’s brain by measuring the number of connections between small blocks known as voxels (comparable to the pixels in an image) and the change in those connections with a single dose of escitalopram (trade name Lexapro).
Their whole-brain network analysis shows that one dose of the SSRI reduces the level of intrinsic connectivity in most parts of the brain. However, Sacher and her colleagues observed an increase in connectivity within two brain regions, specifically the cerebellum and thalamus.
The researchers say the new findings represent an essential first step toward clinical studies in patients suffering from depression. They also plan to compare the functional connectivity signature of brains in recovery and those of patients who fail to respond after weeks of SSRI treatment.
Understanding the differences between the brains of individuals who respond to SSRIs and those who don’t “could help to better predict who will benefit from this kind of antidepressant versus some other form of therapy,” Sacher says. “The hope that we have is that ultimately our work will help to guide better treatment decisions and tailor individualized therapy for patients suffering from depression.”
World Alzheimer Report 2014: Evidence for dementia risk reduction
The World Alzheimer Report 2014 ‘Dementia and Risk Reduction: An analysis of protective and modifiable factors’, released today, calls for dementia to be integrated into both global and national public health programmes alongside other major non communicable diseases (NCDs).
Alzheimer’s Disease International (ADI) commissioned a team of researchers, led by Professor Martin Prince from King’s College London, to produce the report. ADI is publishing this report, in conjunction with World Alzheimer’s Day (21 September) and as a part of World Alzheimer’s Month, an international campaign to raise awareness and challenge stigma.
The report reveals that control of diabetes and high blood pressure as well as measures to encourage smoking cessation and to reduce cardiovascular risk, have the potential to reduce the risk of dementia even in late-life. The report found that diabetes can increase the risk of dementia by 50%. Obesity and lack of physical activity are important risk factors for diabetes and hypertension, and should, therefore, also be targeted.
While cardiovascular health is improving in many high income countries, many low and middle income countries show a recent pattern of increasing exposure to cardiovascular risk factors, with rising rates of diabetes, heart disease and stroke.
Smoking cessation is strongly linked in the report with a reduction in dementia risk. For example, studies of dementia incidence among people aged 65 years and over show that ex-smokers have a similar risk to those who have never smoked, while those who continue to smoke are at much higher risk.
Furthermore, the study revealed that those who have had better educational opportunities have a lower risk of dementia in late-life. Evidence suggests that education has no impact on the brain changes that lead to dementia, but reduces their impact on intellectual functioning.
The evidence in the report suggest that if we enter old age with better developed, healthier brains we are likely to live longer, happier and more independent lives, with a much reduced chance of developing dementia. Brain health promotion is important across the life span, but particularly in mid-life, as changes in the brain can begin decades before symptoms appear.
The report also urges NCD programs to be more inclusive of older people, with the message that it’s never too late to make a change, as the future course of the global dementia epidemic is likely to depend crucially upon the success or failure of efforts to improve global public health, across the population. Combining efforts to tackle the increasing global burden of NCDs will be strategically important, efficient and cost effective. Leading a healthier lifestyle is a positive step towards preventing a range of long-term diseases, including cancer, heart disease, stroke and diabetes.
However, survey data released by Bupa* has shown that many people are unclear about the causes and actions they can take to potentially reduce their risk of dementia. Just over a sixth (17%) of people realised that social interaction with friends and family could impact on the risk. Only a quarter (25%) identified being overweight as a possible factor, and only one in five (23%) said physical activity could affect the risk of developing dementia and losing their memories. The survey also revealed that over two thirds (68%) of people surveyed around the world are concerned about getting dementia in later life.
Professor Martin Prince, from King’s College London’s Institute of Psychiatry, Psychology & Neuroscience (IoPPN) and author of the report, commented: “There is already evidence from several studies that the incidence of dementia may be falling in high income countries, linked to improvements in education and cardiovascular health. We need to do all we can to accentuate these trends. With a global cost of over US$ 600 billion, the stakes could hardly be higher.”
Marc Wortmann, Executive Director, Alzheimer’s Disease International said: “From a public health perspective, it is important to note that most of the risk factors for dementia overlap with those for the other major non communicable diseases (NCDs). In high income countries, there is an increased focus on healthier lifestyles, but this is not always the case with lower and middle income countries. By 2050, we estimate that 71% of people living with dementia will live in these regions, so implementing effective public health campaigns may help to reduce the global risk.”
Professor Graham Stokes, Global Director of Dementia Care, Bupa, said: “While age and genetics are part of the disease’s risk factors, not smoking, eating more healthily, getting some exercise, and having a good education, coupled with challenging your brain to ensure it is kept active, can all play a part in minimising your chances of developing dementia. People who already have dementia, or signs of it, can also do these things, which may help to slow the progression of the disease.”
* These figures, unless otherwise stated, are from YouGov Plc. Total sample size was 8,513, from the UK (2,401), Australia (1,000), Chile (1,000), China (1,031), Poland (1,002), and Spain (1,077). Fieldwork was undertaken online, between 17–25 July 2014. The figures have been weighted and are representative of all adults (aged 18+) in each country. An even weighting was applied to each country to find a ‘Global Average’.
Size at birth affects risk of adolescent mental health disorders
New research from the Copenhagen Centre for Social Evolution and Yale University offers compelling support for the general evolutionary theory that birth weight and -length can partially predict the likelihood of being diagnosed with mental health disorders such as autism and schizophrenia later in life. The study analyzed medical records of 1.75 million Danish births, and subsequent hospital diagnoses for up to 30 years, and adjusted for almost all other known risk factors. The study is published today in the Proceedings of the Royal Society, London B.
The number of people diagnosed with mental health disorders is on the rise in most affluent countries, but we do not yet have a comprehensive understanding of the factors that make people vulnerable to these disorders.
A new analysis of the extensive Danish public health database suggests that part of the answer may reside in genetic imprints established at conception that influence both size at birth and mental health during childhood and early adolescence.
The study tests predictions of the evolutionary theory of genomic imprinting – the idea that during fetal development some genes inherited from the mother are expressed differently to those inherited from the father. The potential consequence of this asymmetry is that maternal and paternal genes in a fetus will not cooperate fully during this period, even though they subsequently have shared interests due to their lifetime commitment to the same body.
Opposite forces balance each other
The reason for the conflict is that some of the genes known to be expressed in the placenta and the brain carry imprints that affect resource provisioning of the unborn child. When such genes come from the father, they favor investment of more of the mother’s resources in the developing fetus, whereas the maternally-imprinted genes will normally compensate for such paternally-influenced manipulative effects to lessen the drain on maternal resources. These opposite forces balance each other in most pregnancies, with the result that most children are born with close to average length and weight and with a high likelihood of balanced mental health development.
Small deviations may well be favorable in human populations, when somewhat heavier babies are more likely to develop abstract talents and somewhat lighter babies above average social talents, for instance. However, this incurs the risk of increasing the frequency of autistic- and schizophrenic-spectrum disorders in the rare cases where imprinting imbalances are larger. The theory may explain why natural selection has not removed this portion of the burden of mental disease from our ancestors.
The new study tests these predictions and its results are remarkably consistent. They show that the change to the risk of developing mental disorders when born smaller or larger than average are relatively small, but very consistent, clearly diametrical, and part of the single continuum that the theory predicts.
“When we started this large scale analysis four years ago, we hoped to find evidence that genetic imprinting happens, but we did not expect that the results would match the predictions as consistently as we found”, explains Professor Jacobus Boomsma, Director of the Centre for Social Evolution, University of Copenhagen, who coordinated the work.
Boomsma adds: “Our study confirms that larger babies have a higher risk for incurring autism-spectrum diagnoses later in life and lower risk for schizophrenia-spectrum disorders. For example, Danish newborns are on average 52 cm long and being born at 54 cm increases the autism risk by 20%. However, these are relative risks and these disorders remain rare: in this example the absolute risk increases from 0.65% to 0.78%. Risk patterns are opposite in smaller newborns, who have higher risks for schizophrenia and lower risks for autism. Only for the smallest, prematurely-born babies does this diametric pattern disappear, because they have elevated risks for almost all disease categories”.
Evolutionary conflicts
Boomsma also underlines that focused genomic studies will be needed to find out which genes are involved and how they affect brain function: ”Our Centre’s main objective is to develop and test evolutionary theory about the ways in which gene-level conflicts can corrupt even the most sophisticated forms of naturally evolved cooperation. It is no surprise that humans are vulnerable to such deep evolutionary conflicts, as are other mammals, and it is both useful and interesting to be aware of this part of our biological heritage”, says Professor Boomsma.
(Source: science.ku.dk)
Study links physical activity in older adults to brain white-matter integrity
Like everything else in the body, the white-matter fibers that allow communication between brain regions also decline with age. In a new study, researchers found a strong association between the structural integrity of these white-matter tracts and an older person’s level of daily activity – not just the degree to which he or she engaged in moderate or vigorous exercise, but also whether the person was sedentary the rest of the time.
The study, reported in the journal PLOS ONE, tracked physical activity in 88 healthy but “low-fit” participants aged 60 to 78. The participants agreed to wear accelerometers during most of their waking hours over the course of a week, and also submitted to brain imaging.
“To our knowledge, this is the first study of its kind that uses an objective measure of physical activity along with multiple measures of brain structure,” said University of Illinois postdoctoral researcher Agnieszka Burzynska, who conducted the research with U. of I. Beckman Institute director Arthur Kramer and kinesiology and community health professor Edward McAuley.
Most studies ask subjects to describe how much physical activity they get, which is subjective and imprecise, Burzynska said. The accelerometer continuously tracks a person’s movement, “so it’s not what they say they do or what they think they do, but we have measured what they are actually doing,” she said.
The researchers assumed that participants’ activity levels over a week accurately reflected their overall engagement, or lack of engagement, in physical activity.
The study also relied on two types of brain imaging. The first, diffusion tensor imaging, offers insight into the structural integrity of a tissue by revealing how water is diffused in the tissue. The second method looks for age-related changes in white matter, called lesions. Roughly 95 percent of adults aged 65 and older have such lesions, Burzynska said. While they are a normal part of aging, their early onset or rapid accumulation may spell trouble, she said.
The team found that the brains of older adults who regularly engaged in moderate-to-vigorous exercise generally “showed less of the white-matter lesions,” Burzynska said.
The association between physical activity and white-matter structural integrity was region-specific, the researchers reported. Older adults who engaged more often in light physical activity had greater structural integrity in the white-matter tracts of the temporal lobes, which lie behind the ears and play a key role in memory, language, and the processing of visual and auditory information.
In contrast, those who spent more time sitting had lower structural integrity in the white-matter tracts connecting the hippocampus, “a structure crucial for learning and memory,” Burzynska said.
“This relationship between the integrity of tracts connecting the hippocampus and sedentariness is significant even when we control for age, gender and aerobic fitness,” she said. “It suggests that the physiological effect of sitting too much, even if you still exercise at the end of the day for half an hour, will have a detrimental effect on your brain.”
The findings suggest that engaging in physical activity and avoiding a sedentary lifestyle are both important for brain health in older age, Burzynska said.
“We hope that this will encourage people to take better care of their brains by being more active,” she said.
Hypersensitivity to Non-Painful Events May Be Part of Pathology in Fibromyalgia
New research shows that patients with fibromyalgia have hypersensitivity to non-painful events based on images of the patients’ brains, which show reduced activation in primary sensory regions and increased activation in sensory integration areas. Findings published in Arthritis & Rheumatology, a journal of the American College of Rheumatology (ACR), suggest that brain abnormalities in response to non-painful sensory stimulation may cause the increased unpleasantness that patients experience in response to daily visual, auditory and tactile stimulation.
Fibromyalgia is a chronic, musculoskeletal syndrome characterized by widespread pain, affecting roughly two percent of the world population, say experts. According to the ACR, five million people in the U.S. have fibromyalgia, which is more prevalent among women. In previous studies fibromyalgia patients report reduced tolerance to normal sensory (auditory, visual, olfactory, and tactile) stimulation in addition to greater sensitivity to pain.
For the present study, researchers used functional magnetic resonance imaging (fMRI) to assess brain response to sensory stimulation in 35 women with fibromyalgia and 25 healthy, age-matched controls. Patients had an average disease duration of 7 years and a mean age of 47.
According to the study, patients reported increased unpleasantness in response to multisensory stimulation in daily life activities. Furthermore, fMRI displayed reduced activation of both the primary and secondary visual and auditory areas of the brain, and increased activation in sensory integration regions. These brain abnormalities mediated the increased unpleasantness to visual, auditory and tactile stimulation that patients reported to experience in daily life.
Lead study author, Dr. Marina López-Solà from the Institute of Cognitive Science, University of Colorado Boulder said, “Our study provides new evidence that fibromyalgia patients display altered central processing in response to multisensory stimulation, which are linked to core fibromyalgia symptoms and may be part of the disease pathology. The finding of reduced cortical activation in the visual and auditory brain areas that were associated with patient pain complaints may offer novel targets for neurostimulation treatments in fibromyalgia patients.”
(Source: eu.wiley.com)
Researchers debunk myth about Parkinson’s disease
Using advanced computer models, neuroscience researchers at the University of Copenhagen have gained new knowledge about the complex processes that cause Parkinson’s disease. The findings have recently been published in the prestigious Journal of Neuroscience.
The defining symptoms of Parkinson’s disease are slow movements, muscular stiffness and shaking. There is currently no cure for the condition, so it is essential to conduct innovative research with the potential to shed some light on this terrible disruption to the central nervous system that affects one person in a thousand in Denmark.
Dopamine is an important neurotransmitter which affects physical and psychological functions such as motor control, learning and memory. Levels of this substance are regulated by special dopamine cells. When the level of dopamine drops, nerve cells that constitute part of the brain’s ‘stop signal’ are activated.
“This stop signal is rather like the safety lever on a motorised lawn mower: if you take your hand off the lever, the mower’s motor stops. Similarly, dopamine must always be present in the system to block the stop signal. Parkinson’s disease arises because for some reason the dopamine cells in the brain are lost, and it is known that the stop signal is being over-activated somehow or other. Many researchers have therefore considered it obvious that long-term lack of dopamine must be the cause of the distinctive symptoms that accompanies the disease. However, we can now use advanced computer simulations to challenge the existing paradigm and put forward a different theory about what actually takes place in the brain when the dopamine cells gradually die,” explains Jakob Kisbye Dreyer, Postdoc at the Department of Neuroscience and Pharmacology, University of Copenhagen.
A thorn in the side
Scanning the brain of a patient suffering from Parkinson’s disease reveals that in spite of dopamine cell death, there are no signs of a lack of dopamine – even at a comparatively late stage in the process.
“The inability to establish a lack of dopamine until advanced cases of Parkinson’s disease has been a thorn in the side of researchers for many years. On the one hand, the symptoms indicate that the stop signal is over-activated, and patients are treated accordingly with a fair degree of success. On the other hand, data prove that they are not lacking dopamine,” says Postdoc Jakob Kisbye Dreyer.
Computer models predict the progress of the disease
“Our calculations indicate that cell death only affects the level of dopamine very late in the process, but that symptoms can arise long before the level of the neurotransmitter starts to decline. The reason for this is that the fluctuations that normally make up a signal become weaker. In the computer model, the brain compensates for the shortage of signals by creating additional dopamine receptors. This has a positive effect initially, but as cell death progresses further, the correct signal may almost disappear. At this stage, the compensation becomes so overwhelming that even small variations in the level of dopamine trigger the stop signal – which can therefore cause the patient to develop the disease.”
The new research findings may pave the way for earlier diagnosis of Parkinson’s disease.
(Source: healthsciences.ku.dk)
(Image caption: The hair cells of mice missing just Hey2 are neatly lined up in four rows (left) while those missing Hey1 and Hey2 are disorganized (right). The cells’ hairlike protrusions (pink) can be misoriented, too. Credit: Angelika Doetzlhofer)
Hey1 and Hey2 ensure inner ear ‘hair cells’ are made at the right time, in the right place
Two Johns Hopkins neuroscientists have discovered the “molecular brakes” that time the generation of important cells in the inner ear cochleas of mice. These “hair cells” translate sound waves into electrical signals that are carried to the brain and are interpreted as sounds. If the arrangement of the cells is disordered, hearing is impaired.
A summary of the research will be published in The Journal of Neuroscience on Sept. 16.
"The proteins Hey1 and Hey2 act as brakes to prevent hair cell generation until the time is right," says Angelika Doetzlhofer, Ph.D., an assistant professor of neuroscience. "Without them, the hair cells end up disorganized and dysfunctional."
The cochlea is a coiled, fluid-filled structure bordered by a flexible membrane that vibrates when sound waves hit it. This vibration is passed through the fluid in the cochlea and sensed by specialized hair cells that line the tissue in four precise rows. Their name comes from the cells’ hairlike protrusions that detect movement of the cochlear fluid and create electrical signals that relay the sound to the brain.
During development, “parent cells” within the cochlea gradually differentiate into hair cells in a precise sequence, starting with the cells at the base of the cochlea and progressing toward its tip. The signaling protein Sonic Hedgehog was known to be released by nearby nerve cells in a time- and space-dependent pattern that matches that of hair cell differentiation. But the mechanism of Sonic Hedgehog’s action was unclear.
Doetzlhofer and postdoctoral fellow Ana Benito Gonzalez bred mice whose inner ear cells were missing Hey1 and Hey2, two genes known to be active in the parent cells but turned off in hair cells. They found that, without those genes, the cells were generated too early and were abnormally patterned: Rows of hair cells were either too many or too few, and their hairlike protrusions were often deformed and pointing in the wrong direction.
"While these mice didn’t live long enough for us to test their hearing, we know from other studies that mice with disorganized hair cell patterns have serious hearing problems," says Doetzlhofer.
Further experiments demonstrated the role of Sonic Hedgehog in regulating the two key genes.
"Hey1 and Hey2 stop the parent cells from turning into hair cells until the time is right," explains Doetzlhofer. "Sonic Hedgehog applies those ‘brakes,’ then slowly releases pressure on them as the cochlea develops. If the brakes stop working, the hair cells are generated too early and end up misaligned."
She adds that Sonic Hedgehog, Hey1 and Hey2 are found in many other parent cell types throughout the developing nervous system and may play similar roles in timing the generation of other cell types.