Posts tagged science
Articles and news from the latest research reports.
Variation in bitter receptor mRNA expression affects taste perception
Do you love chomping on raw broccoli while your best friend can’t stand the healthy veggie in any form or guise? Part of the reason may be your genes, particularly your bitter taste genes.
Over the past decade, scientists at the Monell Center and elsewhere have made headway in understanding how variants of bitter taste receptor genes can help account for how people differ with regard to taste perception and food choice.
However, some perplexing pieces of the puzzle remained, as two people with exactly the same genetic makeup can still differ markedly regarding how bitter certain foods and liquids taste to them.
Now, findings from Monell reveal that a person’s sensitivity to bitter taste is shaped not only by which taste genes that person has, but also by how much messenger RNA – the gene’s instruction guide that tells a taste cell to build a specific receptor – their cells make.
Under normal circumstances, people whose taste receptor cells make more messenger RNA (mRNA) for a given gene make more of the encoded receptor.
The findings add a new level of complexity to our understanding of the cellular mechanisms of taste perception, which may ultimately lend insight into individual differences in food preferences and dietary choices.
"The amount of messenger RNA that taste cells choose to make may be the missing link in explaining why some people with ‘moderate-taster’ genes still are extremely sensitive to bitterness in foods and drinks," said Monell taste geneticist Danielle Reed, PhD, who is an author on the study.
In the study, reported online in the American Journal of Clinical Nutrition, small biopsies of papillae – the little bumps on the tongue that contain taste receptors – were taken from 18 people known to have the same moderate-taster (heterozygous) genotype for the TASR38 bitter taste receptor and the amount of mRNA expression for this genotype was measured.
Before the biopsy, people rated the intensity of various bitter and non-bitter solutions, including broccoli juice. Even though the subjects had the same ‘middle-of-the road’ genotype, their responses to some of the bitter substances varied over four orders of magnitude. Analyses revealed a direct relationship between mRNA expression and bitterness ratings of broccoli juice, with subjects having the most mRNA rating the juice as most bitter.
"The next step involves learning more about what causes these individual differences in mRNA expression; does diet drive expression or is it the reverse? And, can differences in expression explain why children are more sensitive to bitter than adults with the same genotype?" said co-author Julie Mennella PHD, a developmental psychobiologist at Monell.
How schizophrenia affects the brain
UI study documents the illness’s effect on brain tissue
It’s hard to fully understand a mental disease like schizophrenia without peering into the human brain. Now, a study by University of Iowa psychiatry professor Nancy Andreasen uses brain scans to document how schizophrenia impacts brain tissue as well as the effects of anti-psychotic drugs on those who have relapses.
Andreasen’s study, published in the American Journal of Psychiatry, documented brain changes seen in MRI scans from more than 200 patients beginning with their first episode and continuing with scans at regular intervals for up to 15 years. The study is considered the largest longitudinal, brain-scan data set ever compiled, Andreasen says.
Schizophrenia affects roughly 3.5 million people, or about one percent of the U.S. population, according to the National Institutes of Health. Globally, some 24 million are affected, according to the World Health Organization.
The scans showed that people at their first episode had less brain tissue than healthy individuals. The findings suggest that those who have schizophrenia are being affected by something before they show outward signs of the disease.
“There are several studies, mine included, that show people with schizophrenia have smaller-than-average cranial size,” explains Andreasen, whose appointment is in the Carver College of Medicine. “Since cranial development is completed within the first few years of life, there may be some aspect of earliest development—perhaps things such as pregnancy complications or exposure to viruses—that on average, affected people with schizophrenia.”
Andreasen’s team learned from the brain scans that those affected with schizophrenia suffered the most brain tissue loss in the two years after the first episode, but then the damage curiously plateaued—to the group’s surprise. The finding may help doctors identify the most effective time periods to prevent tissue loss and other negative effects of the illness, Andreasen says.
The researchers also analyzed the effect of medication on the brain tissue. Although results were not the same for every patient, the group found that in general, the higher the anti-psychotic medication doses, the greater the loss of brain tissue.
“This was a very upsetting finding,” Andreasen says. “We spent a couple of years analyzing the data more or less hoping we had made a mistake. But in the end, it was a solid finding that wasn’t going to go away, so we decided to go ahead and publish it. The impact is painful because psychiatrists, patients, and family members don’t know how to interpret this finding. ‘Should we stop using antipsychotic medication? Should we be using less?’”
The group also examined how relapses could affect brain tissue, including whether long periods of psychosis could be toxic to the brain. The results suggest that longer relapses were associated with brain tissue loss.
The insight could change how physicians use anti-psychotic drugs to treat schizophrenia, with the view that those with the disorder can lead productive lives with the right balance of care.
“We used to have hundreds of thousands of people chronically hospitalized. Now, most are living in the community, and this is thanks to the medications we have,” Andreasen notes. “But antipsychotic treatment has a negative impact on the brain, so … we must get the word out that they should be used with great care, because even though they have fewer side effects than some of the other medications we use, they are certainly not trouble free and can have lifelong consequences for the health and happiness of the people and families we serve.”
(Source: now.uiowa.edu)
Alzheimer’s: newly identified protein pathology impairs RNA splicing
Researchers at Emory University School of Medicine’s Alzheimer’s Disease Research Center have identified a previously unrecognized type of pathology in the brains of patients with Alzheimer’s disease.
These tangle-like structures appear at early stages of Alzheimer’s and are not found in other neurodegenerative diseases such as Parkinson’s disease.
What makes these tangles distinct is that they sequester proteins involved in RNA splicing, the process by which instructional messages from genes are cut and pasted together. The researchers show that the appearance of these tangles is linked to widespread changes in RNA splicing in Alzheimer’s brains compared to healthy brains.
The finding could change scientists’ understanding of how the disease develops and progresses, by explaining how genes that have been linked to Alzheimer’s contribute their effects, and could lead to new biomarkers, diagnostic approaches, and therapies.
The results are published in the Proceedings of the National Academy of Sciences, Early Edition.
"We were very surprised to find alterations in proteins that are responsible for RNA splicing in Alzheimer’s, which could have major implications for the disease mechanism," says Allan Levey, MD, PhD, chair of neurology at Emory University School of Medicine and director of the Emory ADRC.
"This is a brand new arena," says James Lah, MD, PhD, associate professor of neurology at Emory University School of Medicine and director of the Cognitive Neurology program. "Many Alzheimer’s investigators have looked at how the disease affects alternative splicing of individual genes. Our results suggest a global distortion of RNA processing is taking place."
This research was led by Drs. Levey, Lah, and Junmin Peng, PhD, who was previously associate professor of genetics at Emory and is now a faculty member at St Jude Children’s Research Hospital. They were aided by collaborators at University of Kentucky, Rush University, and University of Washington as well as colleagues at Emory.
Accumulations of plaques and tangles in the brains of patients with Alzheimer’s disease were first observed more than a century ago. Investigating the proteins in these pathological structures has been central to the study of the disease.
Most experimental treatments for Alzheimer’s have aimed at curbing beta-amyloid, an apparently toxic protein fragment that is the dominant component of amyloid plaques. Other approaches target the abnormal accumulation of the protein tau in neurofibrillary tangles. Yet the development of Alzheimer’s is not solely explained by amyloid and tau pathologies, Lah says.
"Two individuals may harbor similar amounts of amyloid plaques and tau tangles in their brains, but one may be completely healthy while the other may have severe memory loss and dementia," he says.
These discrepancies led Emory investigators to take a “back to basics” proteomics approach, cataloguing the proteins that make up insoluble deposits in the brains of Alzheimer’s patients.
"The Alzheimer’s field has been very focused on amyloid and tau, and we wanted to use today’s proteomics technologies to take a comprehensive, unbiased approach," Levey says.
The team identified 36 proteins that were much more abundant in the detergent-resistant deposits in brain tissue from Alzheimer’s patients. This list included the usual suspects: tau and beta-amyloid. Also on the list were several “U1 snRNP” proteins, which are involved in RNA splicing.
These U1 proteins are normally seen in the nucleus of normal cells, but in Alzheimer’s brains they accumulated in tangle-like structures. Accumulation of insoluble U1 protein was seen in samples from patients with mild cognitive impairment (MCI), a precursor stage to Alzheimer’s, but the U1 pathology was not seen in any other brain diseases that were examined.
According to Chad Hales, MD, PhD, one of the study’s lead authors, “U1 aggregation is occurring early in the disease, and U1 tangles can be seen independently of tau pathology. In some cases, we see accumulation of insoluble U1 proteins before the appearance of insoluble tau, suggesting that it is a very early event.”
For most genes, after RNA is read out from the DNA (transcription), some of the RNA must be spliced out. When brain cells accumulate clumps of U1 proteins, that could mean the process of splicing is impaired. To test this, the Emory team examined RNA from the brains of Alzheimer’s patients. In comparison to RNA from healthy brains, more of the RNA from Alzheimer’s brain samples was unspliced.
The finding could explain how many genes that have been linked to Alzheimer’s are having their effects. In cells, U1 snRNP plays multiple roles in processing RNA including the process of alternative splicing, by which one gene can make instructions for two or more proteins.
"U1 dysfunction might produce changes in RNA processing affecting many genes or specific changes affecting a few key genes that are important in Alzheimer’s," Lah says. "Understanding the disruption of such a fundamental process will almost certainly identify new ways to understand Alzheimer’s and new approaches to treating patients."
Faulty stem cell regulation may contribute to cognitive deficits associated with Down syndrome
The learning and physical disabilities that affect people with Down syndrome may be due at least in part to defective stem cell regulation throughout the body, according to researchers at the Stanford University School of Medicine. The defects in stem cell growth and self-renewal observed by the researchers can be alleviated by reducing the expression of just one gene on chromosome 21, they found.
The finding marks the first time Down syndrome has been linked to stem cells, and addresses some long-standing mysteries about the disorder. Although the gene, called Usp16, is unlikely to be the only contributor to the disease, the finding raises the possibility of an eventual therapy based on reducing its expression.
“There appear to be defects in the stem cells in all the tissues that we tested, including the brain,” said Michael Clarke, MD, Stanford’s Karel H. and Avice N. Beekhuis Professor in Cancer Biology. The researchers conducted their studies in both mouse and human cells. “We believe Usp16 overexpression is a major contributor to the neurological deficits seen in Down syndrome.”
Clarke is the senior author of the research, published Sept. 11 in Nature. Postdoctoral scholar Maddalena Adorno, PhD, is the lead author.
“Conceptually, this study suggests that drug-based strategies to slow the rate of stem cell use could have profound effects on cognitive function, aging and risk for Alzheimer’s disease in people with Down syndrome,” said co-author Craig Garner, PhD, who is the co-director of Stanford’s Center for Research and Treatment of Down Syndrome and a professor of psychiatry and behavioral sciences.
Down syndrome, which is caused by an extra copy of chromosome 21, affects about 400,000 people in the United States and 6 million worldwide. It causes both physical and cognitive problems. While many of the physical issues, such as vulnerability to heart problems, can now be treated, no treatments exist for poor cognitive function.
The new study’s findings suggest answers to many long-standing mysteries about the condition, including why people with Down syndrome appear to age faster and exhibit early Alzheimer’s disease.
“This study is the first to provide a possible explanation for these tendencies,” said Garner. The fact that people with Down syndrome have three copies of chromosome 21 and the Usp16 gene “accelerates the rate at which stem cells are used during early development, which likely exhausts stem cell pools and impairs tissue regeneration in adults with Down syndrome. As a result, their brains age faster and are susceptible to early onset neurodegenerative disorders.”
The researchers didn’t confine their studies to laboratory mice. They also investigated the effect of Usp16 overexpression in human cells. Adorno and colleagues in the laboratory of co-author Samuel Cheshier, MD, assistant professor of neurosurgery, found that the presence of excess Usp16 caused skin cells from unaffected people to grow more slowly. Furthermore, neural progenitor cells (those self-renewing cellular factories responsible for the development and maintenance of many of the cell types in the brain) were less able to form balls of cells called neurospheres — a laboratory test that reflects the number and robustness of nerve stem cells in a culture. Conversely, reducing Usp16 expression in skin and nerve-progenitor cells from people with Down syndrome allowed the cells, which usually proliferate slowly, to assume normal growth patterns.
“This gene is clearly regulating processes that are central to aging in mice and humans,” said Clarke, “and stem cells are severely compromised. Reducing Usp16 expression gives an unambiguous rescue at the stem cell level. The fact that it’s also involved in this human disorder highlights how critical stem cells are to our well-being.”
Adorno and Clarke didn’t set out to study Down syndrome. Clarke’s past research has focused on how normal stem cells and cancer stem cells regenerate themselves, and Adorno was searching for genes that could inhibit a specific molecular pathway involved in the self-renewal of these cells. Understanding how normal stem cells regenerate themselves could help to repair tissue and organ damage from disease, and understanding how cancer stem cells maintain themselves could help explain why they are unusually resistant to chemotherapy or radiation therapy — often resulting in a patient’s relapse after seemingly successful treatment. Usp16 seemed to fit the bill; it plays a critical role in a self-renewal pathway previously identified by Clarke and his colleagues.
But Adorno and Clarke soon realized that Usp16 had another interesting property: in humans, it is found on chromosome 21.
They turned to Garner and Cheshier to help them evaluate a possible link to Down syndrome. Garner supplied two strains of mice commonly used to study the condition. One, Ts65Dn, has three copies of 132 genes found on human chromosome 21 — including Usp16. The second, Ts1Cje, has three copies of 79 genes from the chromosome, but only two copies of Usp16. Although both mice display some symptoms of the disorder, Ts65Dn more closely mimics the craniofacial structure and learning and memory disabilities seen in affected humans.
Colleagues in the Cheshier laboratory found that neural stem cells from the more-severely affected Ts65Dn mice were less able to self-renew and grow normally than were cells from the Ts1Cje mice. Reducing the expression of Usp16 in the cells from the Ts65Dn mice to more normal levels largely corrected these functional defects.
“We demonstrated that central nervous system stem cells in Down syndrome mice were defective in their ability to self-renew — the process by which stem cells regenerate themselves upon cell division. Blocking Usp16 expression in these cells restored this ability,” said Cheshier. “We hope in the future that correcting this Usp16 defect can lead to therapeutics that will ameliorate the central nervous system defects seen in patients with Down syndrome.”
Finally, the researchers created a new, Ts65Dn-derived mouse strain in which one of the three copies of Usp16 was mutated. This normalized the level of expression of that gene, without affecting the overexpression of the other 131 triplicated genes in these mice. Nerve progenitor cells from these mice were equally able as normal cells to form neurospheres. The researchers are now continuing their studies of these mice.
“We are really interested in learning how other genes in this chromosomal region may be affecting stem cell renewal,” said Clarke. “We also want to understand how much we’re able to rescue the neurological defect by normalizing the expression of Usp16 in this mouse model. How does this compare to what is happening in humans? We’re sure it plays some significant role.”
(Source: med.stanford.edu)
The eyes have it: Scientists reveal how organic mercury can interfere with vision
More than one billion people worldwide rely on fish as an important source of animal protein, states the United Nations Food and Agriculture Organization. And while fish provide slightly over 7 per cent of animal protein in North America, in Asia they represent about 23 per cent of consumption.
Humans consume low levels of methylmercury by eating fish and seafood. Methylmercury compounds specifically target the central nervous system, and among the many effects of their exposure are visual disturbances, which were previously thought to be solely due to methylmercury-induced damage to the brain visual cortex. However, after combining powerful synchrotron X-rays and methylmercury-poisoned zebrafish larvae, scientists have found that methylmercury may also directly affect vision by accumulating in the retinal photoreceptors, i.e. the cells that respond to light in our eyes.
(Image: A cross section of a zebrafish eye shows the localization of mercury in the outer segments of photoreceptor cells.)
Dr. Gosia Korbas, BioXAS staff scientist at the Canadian Light Source (CLS), says the results of this experiment show quite clearly that methylmercury localizes in the part of the photoreceptor cell called the outer segment, where the visual pigments that absorb light reside.
“There are many reports of people affected by methylmercury claiming a constricted field of vision or abnormal colour vision,” said Korbas. “Now we know that one of the reasons for their symptoms may be that methylmercury directly targets photoreceptors in the retina.”
Korbas and the team of researchers from the University of Saskatchewan including Profs. Graham George, Patrick Krone and Ingrid Pickering conducted their experiments using three X-ray fluorescence imaging beamlines (2-ID-D, 2-ID-E and 20-ID-B) at the Advanced Photon Source, Argonne National Laboratory near Chicago, US, as well as the scanning X-ray transmission beamline (STXM) at the Canadian Light Source in Saskatoon, Canada.
After exposing zebrafish larvae to methylmercury chloride in water, the team was able to obtain high-resolution maps of elemental distributions, and pinpoint the localization of mercury in the outer segments of photoreceptor cells in both the retina and pineal gland of zebrafish specimens. The results of the research were published in ACS Chemical Biology under the title “Methylmercury Targets Photoreceptor Outer Segments”.
Korbas said zebrafish are an excellent model for investigating the mechanisms of heavy metal toxicity in developing vertebrates. One of the reasons for that is their high degree of correlation with mammals. Recent studies have demonstrated that about 70 per cent of protein-coding human genes have their counterparts in zebrafish, and 84 per cent of genes linked to human diseases can be found in zebrafish.
“Researchers are studying the potential effects of low level chronic exposure to methylmercury, which is of global concern due to methylmercury presence in fish, but the message that I want to get across is that such exposures may negatively affect vision. Our study clearly shows that we need more research into the direct effects of methylmercury on the eye,” Korbas concluded.
(Source: lightsource.ca)
Fat Marker Predicts Cognitive Decline in People With HIV
Similarities found between HIV-associated brain damage and impairment from genetic fat-storage disease
Johns Hopkins scientists have found that levels of certain fats found in cerebral spinal fluid can predict which patients with HIV are more likely to become intellectually impaired.
The researchers believe that these fat markers reflect disease-associated changes in how the brain metabolizes these fat molecules. These changes disrupt the brain cells’ ability to regulate the activity of cells’ “garbage disposals” meant to degrade and flush the brain of molecular debris. In this case, too much cholesterol and a fat known as sphingomyelin build up in the lysosomes — the garbage disposals — backing up waste and leading to often debilitating cognitive declines.
As many as half of patients infected with HIV will develop some form of cognitive impairment, ranging from mild (trouble counting change or driving a car) to frank dementia (an inability to manage activities of every day life), but no tests have been available to predict which people were more likely to suffer cognitive losses.
“Every researcher of neurodegenerative disease is chasing biomarkers for the same reason: It’s better to identify problems before they strike,” says Norman J. Haughey, Ph.D., an associate professor in the departments of neurology and psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. He led the current study described online in the journal Neurology.
“It’s very hard to reverse brain damage after it starts,” he says. “Instead, we want to figure out who is likely to lose cognitive function and stop the damage before it happens.”
Haughey and his team analyzed 321 cerebral spinal fluid samples collected from seven test sites across the continental United States, Hawaii and Puerto Rico. The samples came from 291 HIV-positive participants and 30 HIV-negative subjects. The investigators found that early accumulations of a small number of these fat molecules could predict the probability of cognitive decline. As cognitive function declined in these patients, the number of different types of fat molecules that accumulated increased. The types of accumulating fat molecules in HIV were very similar to those that accumulate in inherited forms of a class of diseases called lysosomal storage disorders. This suggests that in some HIV-infected patients, the brain is retaining more of these fats, and this may disrupt the function of lysosomes.
Haughey says he believes some of these impairments in the metabolism of these fats found in people with HIV stems from the infection itself, while others may be linked to the lifesaving antiretroviral therapy taken by most people with HIV. The medications have been associated with elevated blood cholesterol and triglycerides, along with a host of other side effects. Those with HIV are now taking these drugs for decades and the complications from long-term use have not been well studied, he says.
The similarities between the metabolic disturbances in HIV-infected individuals and those apparent in lysosomal storage disorders are enabling Haughey and his team to collaborate with researchers who study genetic lysosomal storage diseases, and who are developing experimental treatments to clear the fat buildup. They are currently exploring dietary and pharmacological interventions designed to restore balance that could potentially restore brain metabolism in HIV-infected individuals, and in doing so could promote good brain health by ensuring the lysosomes function properly.
(Source: hopkinsmedicine.org)
New System Uses Nanodiamonds to Deliver Chemotherapy Directly to Brain Tumors
Researchers at UCLA’s Jonsson Comprehensive Cancer Center have developed a new drug delivery system using nanodiamonds (NDs) that allows for direct application of chemotherapy to brain tumors with fewer harmful side effects and better cancer-killing efficiency than existing treatments.
The study was a collaboration between Dean Ho, professor, division of oral biology and medicine, division of advanced prosthodontics, and department of bioengineering and co-director of the Weintraub Center for Reconstructive Biotechnology at UCLA School of Dentistry and colleagues from the Lurie Children’s Hospital of Chicago and Northwestern University Feinberg School of Medicine.
Glioblastoma is the most common and lethal type of brain tumor. Despite treatment with surgery, radiation and chemotherapy, median survival time of patients with glioblastoma is less than 1.5 years. This tumor is notoriously difficult to treat in part because chemotherapy drugs injected on their own often are unable to cross the blood-brain barrier, which is the system of protective blood vessels that surround the brain. Also, most drugs do not stay concentrated in the tumor tissue long enough to be effective.
The drug doxorubicin (DOX) is a common chemotherapy agent that is a promising treatment for a broad range of cancers, and served as a model drug for treatment of brain tumors when injected directly into the tumor. Ho’s team originally developed a strategy for strongly attaching DOX molecules to ND surfaces, creating a combined substance called ND-DOX.
Nanodiamonds can carry a broad range of drug compounds and prevent the ejection of drug molecules that are injected on their own by proteins found in cancer cells. Thus the ND-DOX stays in the tumor longer than DOX alone, exposing the tumor cells to the drug much longer without affecting the tissue surrounding the tumor.
Ho and colleagues hypothesized that glioblastoma might be efficiently treated with a nanodiamond-modified drug using a technique called convection enhanced delivery (CED), by which they injected ND-DOX directly into brain tumors in rodent models.
The researchers found that the ND-DOX levels in the tumor were retained for a duration far beyond that of DOX alone. The DOX was taken into the tumor and stayed in the tumor longer when attached to NDs. ND-DOX also increased programmed cell death (apoptosis) and decreased cell viability in glioma (brain cancer) cell lines.
Their results also showed for the first time that ND- DOX delivery limited the amount of DOX that was distributed outside the tumor and reduced toxic side effects while keeping the drug in the tumor longer and increasing tumor-killing efficiency for brain cancer treatment. Treatment was more effective and survival time increased significantly in rats treated with ND-DOX compared to those given unmodified DOX. Further research will expand the list of brain cancer chemotherapy drugs that can be attached to the ND surface to improve treatment and reduce side effects.
“Nanomaterials are promising vehicles for treating different types of cancer,” Ho said, “We’re looking for the drugs and situations where nanotechnology actually helps chemotherapy function better, making it easier on the patient and harder on the cancer.” Ho adds that a project of this scale has been successful due to the multi-disciplinary and proactive interactions between his team of bioengineers and outstanding clinical collaborators from Northwestern and Lurie Children’s Hospital.
Ho went on to say that the ND has many facets, almost like the surface of a soccer ball, and can bind to DOX very strongly and quickly. To have a nanoparticle that has translational significance it has to have as many benefits as possible engineered into one system as simply as possible. CED of ND-DOX offers a powerful treatment delivery system against these very difficult and deadly brain tumors.
The study appears in the advance online issue of the peer-reviewed journal Nanomedicine: Nanotechnology, Biology and Medicine.
(Source: newswise.com)
Multiple Sclerosis Appears to Originate in Different Part of Brain Than Long Believed
The search for the cause of multiple sclerosis, a debilitating disease that affects up to a half million people in the United States, has confounded researchers and medical professionals for generations. But Steven Schutzer, a physician and scientist at Rutgers New Jersey Medical School, has now found an important clue why progress has been slow – it appears that most research on the origins of MS has focused on the wrong part of the brain.
Look more to the gray matter, the new findings published in the journal PLOS ONE suggest, and less to the white. That change of approach could give physicians effective tools to treat MS far earlier than ever before.
Until recently, most MS research has focused on the brain’s white matter, which contains the nerve fibers. And for good reason: Symptoms of the disease, which include muscle weakness and vision loss, occur when there is deterioration of a fatty substance called myelin, which coats nerves contained in the white matter and acts as insulation for them. When myelin in the brain is degraded, apparently by the body’s own immune system, and the nerve fiber is exposed, transmission of nerve impulses can be slowed or interrupted. So when patients’ symptoms flare up, the white matter is where the action in the brain appears to be.
But Schutzer attacked the problem from a different direction. He is one of the first scientists to analyze patients’ cerebrospinal fluid (CSF) by taking full advantage of a combination of technologies called proteomics and high-resolution mass spectrometry. “Proteins present in the clear liquid that bathes the central nervous system can be a window to physical changes that accompany neurological disease,” says Schutzer, “and the latest mass spectrometry techniques allow us to see them as never before.” In this study, he used that novel approach to compare the cerebrospinal fluid of newly diagnosed MS patients with that of longer term patients, as well as fluid taken from people with no signs of neurological disease.
What Schutzer found startled one of his co-investigators, Patricia K. Coyle of Stony Brook University in New York, one of the leading MS clinicians and researchers in the country. The proteins in the CSF of the new MS patients suggested physiological disruptions not only in the white matter of the brain where the myelin damage eventually shows up. They also pointed to substantial disruptions in the gray matter, a different part of the brain that contains the axons and dendrites and synapses that transfer signals between nerves.
Several scientists had in fact hypothesized that there might be gray matter involvement in early MS, but the technology needed to test their theories did not yet exist. Schutzer’s analysis, which Coyle calls “exquisitely sensitive,” provides the solid physical evidence for the very first time. It includes a finding that nine specific proteins associated with gray matter were far more abundant in patients who had just suffered their first attack than in longer term MS patients or in the healthy controls. “This evidence indicates gray matter may be the critical initial target in MS rather than white matter,” says Coyle. “We may have been looking in the wrong area.”
According to Coyle, that realization presents exciting possibilities. One, she says, is that patients who suffer attacks that appear related to MS could have their cerebrospinal fluid tested quickly. If proteins that point to early MS are found, helpful therapy could begin at once, before the disease can progress further.
Coyle says Schutzer’s findings may also lead one day to more effective treatments for MS with far fewer side effects. Without specific knowledge of what causes multiple sclerosis, patients now need to take medications that can broadly weaken their immune systems. These drugs slow the body’s destruction of myelin in the brain, but also degrade the immune system’s ability to keep the body healthy in other ways. By suggesting an exciting new direction for MS research, Schutzer and his team may have set the stage for more targeted treatments that attack MS while preserving other important immune functions.
Schutzer sees an even broader future for the work he is now doing. He also has used advanced analysis of cerebrospinal fluid to identify physical markers for neurological ailments that include Lyme disease, in which he has been a world leader in research for many years, as well as chronic fatigue syndrome. He says, “When techniques are refined, more medical conditions are examined, and costs per patient come down, one day there could be a broad panel of tests through which patients and their doctors can get early evidence of a variety of disorders, and use that knowledge to treat them both more quickly and far more effectively than is possible now. “
Study Suggests Possibility of Selectively Erasing Unwanted Memories
The human brain is exquisitely adept at linking seemingly random details into a cohesive memory that can trigger myriad associations—some good, some not so good. For recovering addicts and individuals suffering from post-traumatic stress disorder (PTSD), unwanted memories can be devastating. Former meth addicts, for instance, report intense drug cravings triggered by associations with cigarettes, money, even gum (used to relieve dry mouth), pushing them back into the addiction they so desperately want to leave.
Now, for the first time, scientists from the Florida campus of The Scripps Research Institute (TSRI) have been able to erase dangerous drug-associated memories in mice and rats without affecting other more benign memories.
The surprising discovery, published this week online ahead of print by the journal Biological Psychiatry, points to a clear and workable method to disrupt unwanted memories while leaving the rest intact.
“Our memories make us who we are, but some of these memories can make life very difficult,” said Courtney Miller, a TSRI assistant professor who led the research. “Not unlike in the movie Eternal Sunshine of the Spotless Mind, we’re looking for strategies to selectively eliminate evidence of past experiences related to drug abuse or a traumatic event. Our study shows we can do just that in mice — wipe out deeply engrained drug-related memories without harming other memories.”
Changing the Structure of Memory
To produce a memory, a lot has to happen, including the alteration of the structure of nerve cells via changes in the dendritic spines—small bulb-like structures that receive electrochemical signals from other neurons. Normally, these structural changes occur via actin, the protein that makes up the infrastructure of all cells.
In the new study, the scientists inhibited actin polymerization—the creation of large chainlike molecules—by blocking a molecular motor called myosin II in the brains of mice and rats during the maintenance phase of methamphetamine-related memory formation.
Behavioral tests showed the animals immediately and persistently lost memories associated with methamphetamine—with no other memories affected.
In the tests, animals were trained to associate the rewarding effects of methamphetamine with a rich context of visual, tactile and scent cues. When injected with the inhibitor many days later in their home environment, they later showed a complete lack of interest when they encountered drug-associated cues. At the same time, the response to other memories, such as food rewards, was unaffected.
While the scientists are not yet sure why powerful methamphetamine-related memories are also so fragile, they think the provocative findings could be related to the role of dopamine, a neurotransmitter involved in reward and pleasure centers in the brain and known to modify dendritic spines. Previous studies had shown dopamine is released during both learning and drug withdrawal. Miller adds, “We are focused on understanding what makes these memories different. The hope is that our strategies may be applicable to other harmful memories, such as those that perpetuate smoking or PTSD.”
(Source: scripps.edu)
Study creates new memories by directly changing the brain
Findings could prove helpful in understanding and resolving learning and memory disorders
By studying how memories are made, UC Irvine neurobiologists created new, specific memories by direct manipulation of the brain, which could prove key to understanding and potentially resolving learning and memory disorders.
Research led by senior author Norman M. Weinberger, a research professor of neurobiology & behavior at UC Irvine, and colleagues has shown that specific memories can be made by directly altering brain cells in the cerebral cortex, which produces the predicted specific memory. The researchers say this is the first evidence that memories can be created by direct cortical manipulation. Study results appeared in the August 29 issue of Neuroscience.
During the research, Weinberger and colleagues played a specific tone to test rodents then stimulated the nucleus basalis deep within their brains, releasing acetylcholine (ACh), a chemical involved in memory formation. This procedure increased the number of brain cells responding to the specific tone. The following day, the scientists played many sounds to the animals and found that their respiration spiked when they recognized the particular tone, showing that specific memory content was created by brain changes directly induced during the experiment. Created memories have the same features as natural memories including long-term retention.
"Disorders of learning and memory are a major issue facing many people and since we’ve found not only a way that the brain makes memories, but how to create new memories with specific content, our hope is that our research will pave the way to prevent or resolve this global issue," said Weinberger, who is also a fellow with the Center for the Neurobiology of Learning & Memory and the Center for Hearing Research at UC Irvine.
The creation of new memories by directly changing the cortex is the culmination of several years of research in Weinberger’s lab implicating the nucleus basalis and ACh in brain plasticity and specific memory formation. Previously, the authors had also shown that the strength of memory is controlled by the number of cells in the auditory cortex that process a sound.