Posts tagged genetic mutation
Articles and news from the latest research reports.
Different forms of Alzheimer’s have similar effects on brain networks
Brain networks break down similarly in rare, inherited forms of Alzheimer’s disease and much more common uninherited versions of the disorder, a new study has revealed.
Scientists at Washington University School of Medicine in St. Louis have shown that in both types of Alzheimer’s, a basic component of brain function starts to decline about five years before symptoms, such as memory loss, become obvious.
The breakdown occurs in resting state functional connectivity, which involves groups of brain regions with activity levels that rise and fall in coordination with each other. Scientists believe this synchronization helps the regions form networks that work together or stay out of each other’s way during mental tasks.
“The brain networks affected by inherited Alzheimer’s disease in a 30-year-old are very similar to the networks affected by uninherited Alzheimer’s disease in a 60-, 70- or 80-year-old,” said senior author Beau Ances, MD, PhD. “This affirms that what we learn by studying inherited Alzheimer’s, which appears at younger ages, will help us better understand and treat more common forms of the disease.”
The research appears online in JAMA Neurology.
According to Ances, the results show that functional connectivity may help scientists monitor the effects of treatment as patients progress through the transition between early disease and the first appearance of obvious symptoms.
“Right now, this period when functional connectivity begins breaking down is a time when family and loved ones may start noticing little changes in personality or mental function in someone with the disease, but not significant enough changes to cause real alarm,” Ances said. “The hope is that one day treatment already will be well underway before these sorts of changes begin — we want to slow or stop the damage caused by Alzheimer’s years earlier.”
Inherited Alzheimer’s disease can strike very early in life, causing symptoms in patients as young as their 30s or 40s. Identifying the mutations that cause these forms of the disease has helped scientists find proteins that become problematic in more common forms of Alzheimer’s, which typically appear decades later.
Researchers have long assumed that additional connections exist between inherited and uninherited Alzheimer’s disease, but until recently they have not had sufficient data to directly test many of those connections. Challenges have included the small number of people with inherited Alzheimer’s, and the slow development of both forms of the disease.
Scientists at the Charles F. and Joanne Knight Alzheimer’s Disease Research Center at Washington University began to tackle the first challenge five years ago by organizing the Dominantly Inherited Alzheimer’s Network (DIAN), an international network for identifying and studying families with inherited forms of the disease. The network now includes nearly 400 families.
To address the second challenge, Washington University researchers at the center have been gathering extensive health data on seniors through long-term projects such as the Healthy Aging and Senile Dementia Study, which is entering its 31st year.
These pools of data allowed Ances, an associate professor of neurology, to compare the effects of inherited and uninherited Alzheimer’s on functional connectivity. Scientists assess functional connectivity by scanning the brains of research participants while they daydream.
“The question was, where does the decline of functional connectivity fit in the whole picture of the development of Alzheimer’s disease?” Ances said. “And it clearly does have a place in the middle stages of the disease.”
That’s not the best place to look for an initial diagnosis, according to Ances. Ideally, scientists want to start treating Alzheimer’s disease as soon as possible.
“What this does tell us, though, is that functional connectivity may help us track the progression of Alzheimer’s in patients who are first diagnosed when they’re beginning to show early signs of dementia,” he said.
(Source: news.wustl.edu)
Changes in the eye can predict changes in the brain
Researchers at the Gladstone Institutes and University of California, San Francisco have shown that a loss of cells in the retina is one of the earliest signs of frontotemporal dementia (FTD) in people with a genetic risk for the disorder—even before any changes appear in their behavior.
Published today in the Journal of Experimental Medicine, the researchers, led by Gladstone investigator Li Gan, PhD and UCSF associate professor of neurology Ari Green, MD, studied a group of individuals who had a certain genetic mutation that is known to result in FTD. They discovered that before any cognitive signs of dementia were present, these individuals showed a significant thinning of the retina compared with people who did not have the gene mutation.
“This finding suggests that the retina acts as a type of ‘window to the brain,’” said Dr. Gan. “Retinal degeneration was detectable in mutation carriers prior to the onset of cognitive symptoms, establishing retinal thinning as one of the earliest observable signs of familial FTD. This means that retinal thinning could be an easily measured outcome for clinical trials.”
Although it is located in the eye, the retina is made up of neurons with direct connections to the brain. This means that studying the retina is one of the easiest and most accessible ways to examine and track changes in neurons.
Lead author Michael Ward, MD, PhD, a postdoctoral fellow at the Gladstone Institutes and assistant professor of neurology at UCSF, explained, “The retina may be used as a model to study the development of FTD in neurons. If we follow these patients over time, we may be able to correlate a decline in retinal thickness with disease progression. In addition, we may be able to track the effectiveness of a treatment through a simple eye examination.”
The researchers also discovered new mechanisms by which cell death occurs in FTD. As with most complex neurological disorders, there are several changes in the brain that contribute to the development of FTD. In the inherited form researched in the current study, this includes a deficiency of the protein progranulin, which is tied to the mislocalization of another crucial protein, TDP-43, from the nucleus of the cell out to the cytoplasm.
However, the relationship between neurodegeneration, progranulin, and TDP-43 was previously unclear. In follow-up studies using a genetic mouse model of FTD, the scientists were able to investigate this connection for the first time in neurons from the retina. They identified a depletion of TDP-43 from the cell nuclei before any signs of neurodegeneration occurred, signifying that this loss may be a direct cause of the cell death associated with FTD.
TDP-43 levels were shown to be regulated by a third cellular protein called Ran. By increasing expression of Ran, the researchers were able to elevate TDP-43 levels in the nucleus of progranulin-deficient neurons and prevent their death.
“With these findings,” said Dr. Gan, “we now not only know that retinal thinning can act as a pre-symptomatic marker of dementia, but we’ve also gained an understanding into the underlying mechanisms of frontotemporal dementia that could potentially lead to novel therapeutic targets.”
(Source: gladstoneinstitutes.org)
8,000-Year-Old Mutation Key to Human Life at High Altitudes
In an environment where others struggle to survive, Tibetans thrive in the thin air on the Tibetan Plateau, with an average elevation of 14,800 feet. A University of Utah led discovery that hinged as much on strides in cultural diplomacy as on scientific advancements, is the first to identify a genetic variation, or mutation, that contributes to the adaptation, and to reveal how it works. The research appears online in the journal Nature Genetics on Aug. 17, 2014.
“These findings help us understand the unique aspects of Tibetan adaptation to high altitudes, and to better understand human evolution,” said Josef Prchal, M.D., senior author and University of Utah professor of internal medicine.
For his research, Prchal needed Tibetans to donate blood, from which he could extract their DNA, a task that turned out to be more difficult than he ever imagined. It took several trips to Asia, meeting with Chinese officials and representatives of exiled Tibetans in India, to get the necessary permissions to recruit subjects for the study. But he quickly learned that official documents would not be enough. Wary of foreigners, the Tibetans refused to participate.
To earn the Tibetans’ trust, Prchal obtained a letter of support from the Tibetan spiritual leader, the Dalai Lama. “The Dalai Lama felt that a better understanding of the adaptation would be helpful not only to the Tibetan community but also to humanity at large,” said Prchal. He also enlisted the help of native Tibetan Tsewang Tashi, M.D., an author and clinical fellow at the Huntsman Cancer Institute at the University of Utah. More than 90 Tibetans, both from the U.S. and abroad, volunteered for the study.
Published in Science in 2010, Prchal’s group was the first to establish that there was a genetic basis to Tibetan high altitude adaptation. In the intervening years, first author Felipe Lorenzo, M.D., Ph.D., pioneered new techniques to tease out the secret to one of the adaptations from a “GC-rich” region of the Tibetans’ DNA that was particularly difficult to penetrate.
Their efforts were worth it; the DNA had a fascinating story to tell. About 8,000 years ago, the gene EGLN1 changed by a single DNA base pair. Today, a relatively short time later on the scale of human history, the vast majority of Tibetans – 88 percent - have the genetic variation, and it is virtually absent from closely related lowland Asians. The findings indicate the tiny genetic change endows its carriers with a selective advantage.
Prchal collaborated with experts throughout the world, including co-senior author Peppi Koivunen, Ph.D., from Biocenter Oulu in Finland, to determine that the newly identified genetic variation protects Tibetans by decreasing an aversive over-response to low oxygen. In those without the adaptation, the thin air causes their blood to become thick with oxygen-carrying red blood cells, often causing long-term complications such as heart failure. The EGLN1 variation, together with other unidentified genetic changes, collectively support life at high altitudes.
Prchal says the research also has broader implications. Because oxygen plays a central role in human physiology and disease, a deep understanding of how high altitude adaptations work may lead to novel treatments for various conditions, including cancer. “There is much more that needs to be done, and this is just the beginning,” he said.
When traveling with Tashi in Asia, Prchal was surprised at how he was able to get Tibetans to grasp the research they were being asked to take part in. Tashi simply helped them realize that their ability to adapt to life at high altitude was unique. “They usually responded by a little initial surprise quickly followed by agreement,” said Tashi. “It was as if I made them realize something new, which only then became obvious.”
Listen to an interview with Josef Prchal, Tsewang Tashi, and Felipe Lorenzo on The Scope Radio.
Scientists Pinpoint How Genetic Mutation Causes Early Brain Damage
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have shed light on how a specific kind of genetic mutation can cause damage during early brain development that results in lifelong learning and behavioral disabilities. The work suggests new possibilities for therapeutic intervention.
The study, which focuses on the role of a gene known as Syngap1, was published June 18, 2014, online ahead of print by the journal Neuron. In humans, mutations in Syngap1 are known to cause devastating forms of intellectual disability and epilepsy.
“We found a sensitive cell type that is both necessary and sufficient to account for the bulk of the behavioral problems resulting from this mutation,” said TSRI Associate Professor Gavin Rumbaugh, who led the study. “Because we found the root biological cause of this genetic brain disorder, we can now shift our research toward developing tailor-made therapies for people affected by Syngap1 mutations.”
In the study, Rumbaugh and his colleagues used a mouse model to show that mutations in Syngap1 damage the development of a kind of neuron known as glutamatergic neurons in the young forebrain, leading to intellectual disability. Higher cognitive processes, such as language, reasoning and memory arise in children as the forebrain develops.
Repairing damaging Syngap1 mutations in these specific neurons during development prevented cognitive abnormalities, while repairing the gene in other kinds of neurons and in other locations had no effect.
Rumbaugh noted prenatal diagnosis of some infant genetic disorders is on the horizon. Technological advances in genetic sequencing allow for individual genomes to be scanned for damaging mutations; it is possible to scan the entire genome of a child still in the womb. “Our research suggests that if Syngap1 function can be fixed very early in development, this should protect the brain from damage and permanently improve cognitive function,” said TSRI Research Associate Emin Ozkan, a first author of the study, along with TSRI Research Associate Thomas Creson. “In theory, patients then wouldn’t have to be subjected to a lifetime of therapies and worry that the drugs might stop working or have side effects from chronic use.”
Mutations to Syngap1 are a leading cause of “sporadic intellectual disability,” resulting from new, random mutations arising spontaneously in genes, rather than faulty genes inherited from parents. Intellectual disability affects approximately one to three percent of the population worldwide.
Rumbaugh and his colleagues are continuing to investigate. “Our findings have also identified exciting potential biomarkers in the brain of cognitive failure, allowing us to test new therapeutic strategies in our Syngap1 animal model,” said Creson.
(Source: newswise.com)
Newly Identified Brain Cancer Mutation Will Aid Drug Development
A collaborative effort between Duke Medicine researchers and neurosurgeons and scientists in China has produced new genetic insights into a rare and deadly form of childhood and young adult brain cancer called brainstem glioma.
The researchers identified a genetic mutation in the tumor cells that plays a role in both the growth and the death of a cell. Additionally, the mutation to the newly identified gene may also contribute to the tumor’s resistance to radiation.
The findings, published online in the journal Nature Genetics on June 1, 2014, provide both immediate and long-term benefits. Knowing that this mutation may render radiation ineffective, patients could be spared that therapy. The mutation would also serve as a strong candidate for drug development.
The researchers conducted genetic tests and found that many of the tumor cells had a mutation in a gene called PPM1D, which causes cells to proliferate and avoid natural death. It is the first time this mutation has been found to be a major driving force in the development of brainstem gliomas; it is not evident in other brain tumors.
If tumors have this PPM1D mutation, they do not have another more common genetic mutation to the TP53 gene, a tumor suppressor that, when defective, is linked to half of all cancers.
“This finding has immediate clinical applications, because either mutation - PPM1D or TP53 – cause the tumor cells to be resistant to radiation,” said senior author Hai Yan, M.D., Ph.D., a professor of pathology at Duke University School of Medicine. “Knowing that could spare patients from an ineffective treatment approach.”
Additionally, the PPM1D genetic mutation is a strong candidate for new drug development.
“This finding gives us a clue as to why these particular tumors are growing inappropriately,” said co-author Zachary Reitman, M.D., Ph.D., a research associate at Duke. “These clues may help us to design better treatments for this type of cancer.”
Yan said his lab is working to identify new treatments that could target the PPM1D genetic mutation and shut down its cancer-growing capabilities.
“PPM1D is itself a target for drug development, because the gene mutation causes cells to avoid death and proliferate,” Yan said. “In drug development, it’s easier to turn that growth function off than it is to switch on the cell’s defective tumor suppression mechanism.”
(Source: corporate.dukemedicine.org)
(Image caption:The image depicts mice having a normal nerve (left) as compared to an incomplete nerve, a condition resulting in permanent downward gaze in both mice and humans. Image courtesy of Jeremy Duncan)
Researchers track down cause of eye mobility disorder
Imagine you cannot move your eyes up, and you cannot lift your upper eyelid. You walk through life with your head tilted upward so that your eyes look straight when they are rolled down in the eye socket. Obviously, such a condition should be corrected to allow people a normal position of their head. In order to correct this condition, one would need to understand why this happens.
In a paper published in the April 16 print issue of the journal Neuron, University of Iowa researchers Bernd Fritzsch and Jeremy Duncan and their colleagues at Harvard Medical School, along with investigator and corresponding author Elizabeth Engle, describe how their studies on mutated mice mimic human mutations.
It all started when Engle, a researcher at the Howard Hughes Medical Institute (HHMI), and Fritzsch, professor and departmental executive officer in the UI College of Liberal Arts and Sciences Department of Biology, began their interaction on the stimulation of eye muscles by their nerves, or “innervation,” around 20 years ago.
Approximately 10 years ago, Engle had identified the mutated genes in several patients with the eye movement disorder and subsequently developed a mouse with the same mutation she had identified in humans. However, while the effect on eye muscle innervation was comparable, there still was no clue as to why this should happen.
Fritzsch and his former biology doctoral student, Jeremy Duncan, worked with the Harvard researchers on a developmental study to find the point at which normal development of eye muscle innervations departs from the mutants. To their surprise, it happened very early in development. In fact, they found—only in mutant mice—a unique swelling in one of the nerves to the eye muscle.
More detailed analysis showed that these swellings came about because fibers extending to the eyes from the brain tried to leave the nerve as if they were already in the orbit, or eye socket. Since it happened so early, the researchers reasoned that something must be transported more effectively by this mutation to the motor neurons trying to reach the orbit and the eye muscles; something must be causing these motor neurons to assume they have already reached their target, the orbit of the eye.
To verify this enhanced function, the researchers developed another mouse that lacked the specific protein and found no defects in muscle innervation. Moreover, when they bred mice that carried malformed proteins with those that had none of these proteins, the mice developed a normal innervation.
This data provided clear evidence of what was going wrong and why, but it did not provide a clue as to the possible product that was more effectively transported in the mutant mice and, by logical extension, in humans. Further analysis revealed that breeding their mutant mice with another mutant having eye muscle innervation defects could enhance the effect of either mutation.
With this finding, they had identified the mutated protein, its enhanced function, and at least some of the likely cargo transported by this protein to allow normal innervation of eye muscles. This data provides the necessary level of understanding to design rational approaches to block the defect from developing.
Knowing what goes wrong and at what time during development can allow the problem to be corrected before it develops through proper manipulations. Engle, Fritzsch, and their collaborators currently are designing new approaches to rescue normal innervation in mice. In the future, their work may help families carrying such genetic mutations to have children with normal eye movement.
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."
Meat, egg and dairy nutrient essential for brain development
Asparagine, found in foods such as meat, eggs, and dairy products, was until now considered non-essential because it is produced naturally by the body. Researchers at the University of Montreal and its affiliated CHU Sainte-Justine Hospital found that the amino acid is essential for normal brain development. This is not the case for other organs. “The cells of the body can do without it because they use asparagine provided through diet. Asparagine, however, is not well transported to the brain via the blood-brain barrier,” said senior co-author of the study Dr. Jacques Michaud, who found that brain cells depend on the local synthesis of asparagine to function properly. First co-author José-Mario Capo-Chichi and colleague Grant Mitchell also made major contributions to the study.
In April 2009, a Quebec family experienced the worst tragedy for parents: before the age of one, one of their sons died of a rare genetic disease causing congenital microcephaly, intellectual disability, cerebral atrophy, and refractory seizures. The event was even more tragic because it was the third infant to die in this family from the same disease.
This tragedy led Dr. Michaud to discover the genetic abnormality responsible for this developmental disorder. “We are not at the verge of a miracle drug,” Michaud said, “but we at least know where to look.”
The team identified the gene affected by the mutation code for asparagine synthetase, the enzyme responsible for synthesizing the amino acid asparagine. The study is the first to associate a specific genetic variant with a deficiency of this enzyme. “In healthy subjects, it seems that the level of asparagine synthetase in the brain is sufficient to supply neurons,” Michaud said. “In individuals with the disability, the enzyme is not produced in sufficient quantity, and the resulting asparagine depletion affects the proliferation and survival of cells during brain development.”
Potential treatment
Children who are carriers of this mutation suffer, to varying degrees, from a variety of symptoms, including intellectual disability and cerebral atrophy, which can lead to death. The Quebec family lost three infant sons to this disorder. Two of their other children are alive and healthy.
Knowledge about gene mutations can be used to develop treatments. “Our results not only open the door to a better understanding of the disease,” Michaud said, “but they also give us valuable information about the molecular mechanisms involved in brain development, which is important for the development of new treatments.”
For example, asparagine supplement could be given to infants to ensure an adequate level of asparagine in the brain and the latter’s normal development. “The amount of supplementation remains to be determined, as well as its effectiveness,” said the geneticist. “Since these children are already born with neurological abnormalities, it is uncertain whether this supplementation would correct the neurological deficits.”
Creating a pediatric clinical genomics centre
To date, nine children from four different families have been identified as carriers of the mutation: three infants from Quebec, three from a Bengali family living in Toronto, and three Israelis, whose symptoms are less severe.
Dr. Michaud’s team discovered the genetic mutation by comparing the complete DNA of the Quebec family’s children with symptoms of the disease. The researchers then identified children, among other families, who carried the single candidate gene. The gene was revealed only in the affected children, but not in the unaffected children of the families studied.
The discovery comes at a time when CHU Sainte-Justine Mother and Child University Hospital has reached an agreement with Génome Québec to create the first pediatric clinical genomic centre in Canada. “This initiative will transform the quality of care for younger patients to ensure better prevention from childhood,” says Dr. Michaud. “More than 80% of genetic diseases occur in childhood or adolescence. “This new technology will allow us to sequence all the genes in the genome and obtain a genetic portrait of the children more quickly to know which disease they suffer from and to provide treatment, if available, or when it becomes available.”
(Source: nouvelles.umontreal.ca)
A gene mutation for excessive alcohol drinking found
Researchers have discovered a gene that regulates alcohol consumption and when faulty can cause excessive drinking. They have also identified the mechanism underlying this phenomenon.
The study showed that normal mice show no interest in alcohol and drink little or no alcohol when offered a free choice between a bottle of water and a bottle of diluted alcohol.
However, mice with a genetic mutation to the gene Gabrb1 overwhelmingly preferred drinking alcohol over water, choosing to consume almost 85% of their daily fluid as drinks containing alcohol - about the strength of wine.
The consortium of researchers from five UK universities – Newcastle University, Imperial College London, Sussex University, University College London and University of Dundee – and the MRC Mammalian Genetics Unit at Harwell, funded by the Medical Research Council (MRC), Wellcome Trust and ERAB, publish their findings today in Nature Communications.
Dr Quentin Anstee, Consultant Hepatologist at Newcastle University, joint lead author said: “It’s amazing to think that a small change in the code for just one gene can have such profound effects on complex behaviours like alcohol consumption.
“We are continuing our work to establish whether the gene has a similar influence in humans, though we know that in people alcoholism is much more complicated as environmental factors come into play. But there is the real potential for this to guide development of better treatments for alcoholism in the future.”
Identifying the gene for alcohol preference
Working at the MRC Mammalian Genetics Unit, a team led by Professor Howard Thomas from Imperial College London introduced subtle mutations into the genetic code at random throughout the genome and tested mice for alcohol preference. This led the researchers to identify the gene Gabrb1 which changes alcohol preference so strongly that mice carrying either of two single base-pair point mutations in this gene preferred drinking alcohol (10% ethanol v/v - about the strength of wine), over water.
The group showed that mice carrying this mutation were willing to work to obtain the alcohol-containing drink by pushing a lever and, unlike normal mice, continued to do so even over long periods. They would voluntarily consume sufficient alcohol in an hour to become intoxicated and even have difficulty in coordinating their movements.
The cause of the excessive drinking was tracked down to single base-pair point mutations in the gene Gabrb1, which codes for the beta 1 subunit, an important component of the GABAA receptor in the brain. This receptor responds to the brain’s most important inhibitory chemical messenger (GABA) to regulate brain activity. The researchers found that the gene mutation caused the receptor to activate spontaneously even when the usual GABA trigger was not present.
These changes were particularly strong in the region of the brain that controls pleasurable emotions and reward, the nucleus accumbens, as Dr Anstee explains: “The mutation of the beta1 containing receptor is altering its structure and creating spontaneous electrical activity in the brain in this pleasure zone, the nucleus accumbens. As the electrical signal from these receptors increases, so does the desire to drink to such an extent that mice will actually work to get the alcohol, for much longer than we would have expected.”
Professor Howard Thomas said: “We know from previous human studies that the GABA system is involved in controlling alcohol intake. Our studies in mice show that a particular subunit of GABAA receptor has a significant effect and most importantly the existence of these mice has allowed our collaborative group to investigate the mechanism involved. This is important when we come to try to modify this process first in mice and then in man.”
Leading to a treatment for alcohol addiction
Initially funded by the MRC, the 10-year project aimed to find genes affecting alcohol consumption. Professor Hugh Perry, Chair of the MRC’s Neurosciences and Mental Health Board, said: “Alcohol addiction places a huge burden on the individual, their family and wider society. There’s still a great deal we don’t understand about how and why consumption progresses into addiction, but the results of this long-running project suggest that, in some individuals, there may be a genetic component. If further research confirms that a similar mechanism is present in humans, it could help us to identify those most at risk of developing an addiction and ensure they receive the most effective treatment.”
Genetic Defect Keeps Verbal Cues From Hitting the Mark
A genetic defect that profoundly affects speech in humans also disrupts the ability of songbirds to sing effective courtship tunes. This defect in a gene called FoxP2 renders the brain circuitry insensitive to feel-good chemicals that serve as a reward for speaking the correct syllable or hitting the right note, a recent study shows.
The research, which was conducted in adult zebrafinches, gives insight into how this genetic mutation impairs a network of nerve cells to cause the stuttering and stammering typical of people with FoxP2 mutations. It appears Nov. 21 in an early online edition of the journal Neuron.
"Our results integrate a lot of different observations that have accrued on the FoxP2 mutation and cast a different perspective on what this mutation is doing," said Richard Mooney, Ph.D., the George Barth Geller professor of neurobiology at Duke University School of Medicine and a member of the Duke Institute for Brain Sciences. "FoxP2 mutations do not simply result in a cognitive or learning deficit, but also produce an ongoing motor deficit. Individuals with these mutations can still learn and can still improve; it is just harder for them to reliably hit the right mark."
About 15 years ago, researchers discovered a British family with many members suffering from severe speech and language deficits. Geneticists eventually pinned down the culprit — a gene called forkhead box transcription factor or FoxP2 — that was mutated in all the affected individuals. The discovery led many to believe FoxP2 was a “language gene” that granted humans the ability to speak. But further studies showed that the gene wasn’t unique to humans, and in fact was conserved among all vertebrates, including songbirds.
Though the gene is present in every cell, it is “active,” or turned on, mostly in brain cells, particularly ones residing in a region deep within the brain known as the basal ganglia. This region is dysfunctional in Tourette syndrome, known for its vocal tics and outbursts, and is also shrunk in individuals with FoxP2 mutations.
To explore the complex circuitry involved in these deficits, Mooney and his former graduate student Malavika Murugan, Ph.D., decided to replicate the human mutation in this region of the brain in songbirds. Zebrafinches start learning how to sing 30 days after they hatch, listening to a male tutor and then practicing thousands of times a day until, 60 days later, they are able to make a very good copy of the tutor’s song. As good as that copy is at day 90, the male finch’s song gets even more precise when he “directs” it to a female as part of courtship.
To investigate the role of FoxP2 in the generation of this directed song, Murugan introduced specifically targeted sequences of RNA to suppress FoxP2 activity in the basal ganglia of male zebrafinches. The birds were placed in a glass cage that revealed a female sitting on the other side. Murugan then recorded sonograms of their song to capture the subtle vocal variations indistinguishable to the human ear when they produced directed songs at the female.
Murugan found that though the genetically manipulated males had already learned how to sing, their ability to hit the right note repeatedly in the presence of a female — a behavior critical to attracting a mate — was subpar. This indicates that in songbirds, FoxP2 has an ongoing role in vocal control separate from a role in learning, a distinction that has not been possible to make in humans with FOXP2 mutations.
Having deduced the behavior associated with this genetic mutation, the researchers then identified underlying neural deficits by recording brain activity in birds with normal and altered FoxP2 genes. In one set of experiments, Murugan sent an electrical signal into the input side of the basal ganglia pathway and then used an electrode on the output side to measure how quickly the signal traveled from one side to the other. Surprisingly, the signal moved more quickly through the basal ganglia of FoxP2 mutant songbirds than it did in songbirds with the functional gene.
Murugan also found that dopamine, an important brain chemical involved in brain signaling and the reinforcement of learned behaviors like singing or playing sports, could influence how fast basal ganglia signals propagated in birds with normal but not mutant forms of FoxP2.
"This switch between undirected and directed song is actually dependent on the influx of this neurotransmitter called dopamine," said Murugan, first author of the study. "So what we think is happening is knocking down FoxP2 makes the male incapable of reducing song variability in the presence of a female. An adult male sees the female, there is an influx of dopamine, but because the system is insensitive, the dopamine has no effect and the adult male continues to sing a variable tune." In juveniles, the inability to constrain variability and to respond to dopamine could also account for poor learning.
Though the researchers are cautious not to draw too many parallels between their findings in birds and the deficits in humans, they think their study does highlight the value of songbirds in studying human behaviors and disease.
"Birds are one of the few non-human animals that learn to vocalize," said Mooney. "They produce songs for courtship that they culturally transmit from one generation to the next. Their brains might be a thousandth the size of ours, but in this one dimension, vocal learning, they are our equal."
(Source: today.duke.edu)