Posts tagged science
Articles and news from the latest research reports.
Quality of waking hours determines ease of falling asleep
The quality of wakefulness affects how quickly a mammal falls asleep, UT Southwestern Medical Center researchers report in a study that identifies two proteins never before linked to alertness and sleep-wake balance.
“This study supports the idea that subjective sleepiness is influenced by the quality of experiences right before bedtime. Are you reluctantly awake or excited to be awake?” said Dr. Masashi Yanagisawa, professor of molecular genetics and a Howard Hughes Medical Institute investigator at UT Southwestern. He is principal author of the study published online in May in the Proceedings of the National Academy of Sciences.
Co-author Dr. Robert Greene, UT Southwestern professor of psychiatry and a physician at the Dallas VA Medical Center, said the study is unique in showing that the need for sleep (called sleep homeostasis) can be separated from wakefulness both behaviorally and biochemically, meaning the two processes can now be studied individually.
“Two of the great mysteries in neuroscience are why do we sleep and what is sleep’s function? Separating sleep need from wakefulness and identifying two different proteins involved in these steps represents a fundamental advance,” he said.
If borne out by further research, this study could lead to new ways of assessing and possibly treating sleep disorders, perhaps by focusing more attention on the hours before bedtime because the quality of wakefulness has a profound effect on sleep, Dr. Yanagisawa said.
The experiment featured three groups of mice with virtually identical genes. The control group slept and woke at will and followed the usual mouse pattern of sleeping during the day and being awake at night. The two test groups were treated the same and had the same amount of sleep delay – six hours – but they were kept awake in different ways, said lead author Dr. Ayako Suzuki, a postdoctoral researcher who works in the laboratories of both Dr. Yanagisawa and Dr. Greene.
The first test group’s sleep was delayed by a series of cage changes. Mice are intensely curious, so each cage change was followed by an hour spent vigorously exploring the new surroundings. This behavior would roughly correspond to teenagers voluntarily delaying bedtime with a new and stimulating event like a rock concert or video game.
Researchers kept the second group awake as gently as possible, usually by waving a hand in front of the cage or tapping it lightly whenever the mice appeared to be settling down to sleep. That test group would more resemble parents reluctantly staying awake awaiting a child’s return from a concert.
Both test groups experienced the same amount of sleep deprivation, but their reactions to the different forms of alertness were striking, Dr. Yanagisawa said. In one test, the cage-changing group took longer to fall asleep than the gentle-handling group even though an analysis of their brain waves indicated equal amounts of sleep need in both test groups.
“The need to sleep is as high in the cage-changing group as in the gentle-handling group, but the cage-changers didn’t feel sleepy at all. Their time to fall asleep was nearly the same as the free-sleeping, well-rested control group,” he said.
The researchers identified two proteins that affected these responses, each linked to different aspects of sleep: phosphorylated dynamin 1 levels were linked to how long it took to fall asleep, while phosphorylated N-myc downstream regulated gene 2 protein levels tracked the amount of sleep deprivation and corresponded to the well-known brain-wave measure of sleep need, they report.
“The two situations are different biochemically, which is a novel finding,” Dr. Yanagisawa said, adding, “These proteins are completely new to sleep research and have never before been linked to sleep need and wakefulness.”
From an evolutionary perspective, an arousal mechanism that adapts to environmental stimuli is crucial because sleeping on a rigid schedule could be dangerous. “Animals, including humans, must be able to keep themselves at least temporarily alert, say during a natural disaster,” he said.
(Image: Robert Manella / Getty Images)
Decoding Rett syndrome: New pieces to the puzzle
Rett Syndrome is a neurological disorder that affects about 1 in 10,000 girls. Back in 1992, University of Edinburgh researcher Adrian Bird discovered that the protein, MeCP2, plays a major role in the disease. The story of MeCP2 is in many ways a microcosm of human genetics. It has become the showcase gene for many complex epi-genetic phenomena including X-linked inactivation, DNA methylation, and genomic imprinting. These gender-specific bargaining chips provide compatibility in an evolutionary system where sex-chromosome provisioning is inherently assymetric. In two new papers, one in Nature and the the other in Nature Neuroscience, Bird and collaborator Michael Greenberg, show how mutations found in Rett Syndrome affect the interaction of MeCP2 with a key regulatory protein known as NCoR.
Nearly all cases of Rett Syndrome are caused by mutations at various postions in the MeCP2 gene. Bird and Greenberg analyzed the locations of these mutations using the RettBase MeCp2 database, and found they cluster to two primary locations—the well-known methyl-CpG binding domain, and a new hotspot within a transcriptional repressor domain (TRD). When they compared these locations with mutations found in the general population by using the Exome Variant Server, they found no overlap. This suggests the that the MeCP2 and TRD regions are the primary regions involved in Rett’s.
The researchers hypothesized that the newly found TRD region must act through a unknown regulator of MeCP2 function. Using mass spectrometry, they were able to identify several factors which they had purified from Mecp2-EGFP “knock-in” mice. Most of these factors turned out to be subunits of the co-repressor, NCoR, which was previously known to interact with MeCP2. This is the first identified example of a protein-protein interaction known to be disrupted in Rett’s.
In the Nature paper, the researchers further report that activity-dependent phosphorylation of MeCP2 mediates its interaction with NCoR. They used a technique known as phosphotryptic mapping to identify three sites that are directly phosphorylated in MeCP2 as a result of elevation in cAMP or BDNF. More generally, they showed that membrane depolarization, and therefore activity, results in the phosporylation.
One confounding factor in trying to pinpoint the mechanisms underlying Rett Syndrome is that both loss of MeCP2, and overexpression of MeCP2, can lead to the disease. In mouse models of the disease, this could be accounted for by the observation that both loss of NCoR binding, and constitutive binding of NCoR can lead to disease symptoms. While not a complete explanation of the role of MeCP2 in the disease, it provides some clues to help dissect the involvement of the many different kinds of mutations involved.
Despite the rarity of Rett’s syndrome, its impact on our understanding of human genetics and neural development should not be underestimated. As one of the autistic spectrum disorders, research on Rett’s helps connect molecular mechanics to behavior. For example, when MeCP2 is bound to DNA it can cause condensation of the chromatin structure, and also form complexes with histone deacetylaces. In demostrating that neural activity, and subsequent signal tranduction pathways, lead to modifications of MeCP2, the researchers have revealed a path from the environment directly to the genes.
The X-linked inactivation of one copy of the MeCP2 gene in females adds another layer of complexity to the disease. The celluar mosiac formed by the pattern of inactivation, particularly in the brain, needs more study to be undersatood. The fact that Rett’s symptoms can be “rescued” in mice by the expression of MeCP2 in postmitotic neurons is encouraging. In humans, Rett’s is frequently not observed untill the first or second year of life. As MeCP2 activation correlates with this period of rapid neural maturation, Rett’s is generally considered to be neurodevelopmental disease, as opposed to a neurodegenerative disease.
Rett’s is hardly ever observed in males for the simple reason that they fail to thrive long before birth. In those rare cases that a presumably XXY male child is rescued by the additional X chromsome, as in Klinefelder’s disease, rare opportunity to study the disease etiology is afforded. The efforts of these researchers, and the larger Rett’s community, together with the insights afforded by massive data collation have turned a rare disease into a primary source of knowledge about how evolution proceeds through the interplay of the sexes at the genetic and epigenetic levels.
(Source: medicalxpress.com)
Voices may not trigger brain’s reward centers in children with autism
In autism, brain regions tailored to respond to voices are poorly connected to reward-processing circuits, according to a new study by scientists at the Stanford University School of Medicine.
The research could help explain why children with autism struggle to grasp the social and emotional aspects of human speech. “Weak brain connectivity may impede children with autism from experiencing speech as pleasurable,” said Vinod Menon, PhD, senior author of the study, published online June 17 in Proceedings of the National Academy of Sciences. Menon is a professor of psychiatry and behavioral sciences at Stanford and a member of the Child Health Research Institute at Lucile Packard Children’s Hospital.
"The human voice is a very important sound; it not only conveys meaning but also provides critical emotional information to a child," said Daniel Abrams, PhD, a postdoctoral scholar in psychiatry and behavioral sciences who was the study’s lead author. Insensitivity to the human voice is a hallmark of autism, Abrams said, adding, "We are the first to show that this insensitivity may originate from impaired reward circuitry in the brain."
The study focused on children with a high-functioning form of autism. They had IQ scores in the normal range and could speak and read, but had difficulty holding a back-and-forth conversation or understanding emotional cues in another person’s voice.
The scientists compared functional magnetic resonance imaging brain scans from 20 of these children with scans from 19 typically developing children, paying particular attention to a portion of the brain that responds selectively to the sound of human voices. Prior research has shown that adults with autism had low voice-selective cortex activity in response to speech. But until this study by Menon and his colleagues, no one had looked at connections between the voice-selective cortex and other brain regions in individuals with autism.
The new study found that in children with a high-functioning form of autism, the voice-selective cortex on the left side of the brain was weakly connected to the nucleus accumbens and the ventral tegmental area — brain structures that release dopamine in response to rewards. The voice-selective cortex on the right side of the brain, which specializes in detecting vocal cues such as intonation and pitch, was weakly connected to the amygdala, which processes emotional cues.
The weaker these connections in children with autism, the worse their communication deficits, the study showed. The researchers were able to predict the children’s scores on the verbal portion of a standard test of autism severity by looking at the degree of impairment in these brain connections.
The findings may help to validate some autism therapies already in use, said co-author Jennifer Phillips, PhD, a clinical associate professor of psychiatry and behavioral sciences at Stanford who also treats children with autism at Packard Children’s. For instance, pivotal-response training aims to increase social use of language in children who can speak some words but who usually do not talk to others.
"Pivotal-response training goes after ways to naturally motivate kids to start using language and other forms of social interaction," Phillips said. Future studies could test whether brain connections leading from voice to reward centers are strengthened by autism therapies, she added.
The findings also help resolve a long-standing debate about why individuals with autism show less-than-normal interest in human voices. The team investigated two competing theories to explain the phenomenon: that individuals with autism have a deficit in their social motivation, or, alternatively, that they have sensory-processing deficits which impair their ability to fully hear human voices. The new study found normal connections between voice-selective cortex and primary auditory brain regions in children with high-functioning autism, suggesting that these children do not have sensory-processing deficits.
The next steps for researchers include studying the consequences of the weak voice-to-reward circuit in autism. “It is likely that children with autism don’t attend to voices because they are not rewarding or emotionally interesting, impacting the development of their language and social communication skills,” Menon said. “We have discovered an aberrant brain circuit underlying a core deficit in autism; our findings may aid the development of new treatments for this disorder.”
(Image: Getty Images)
Artificial Sweetener a Potential Treatment for Parkinson’s Disease
TAU researcher says mannitol could prevent aggregation of toxic proteins in the brain
Mannitol, a sugar alcohol produced by fungi, bacteria, and algae, is a common component of sugar-free gum and candy. The sweetener is also used in the medical field — it’s approved by the FDA as a diuretic to flush out excess fluids and used during surgery as a substance that opens the blood/brain barrier to ease the passage of other drugs.
Now Profs. Ehud Gazit and Daniel Segal of Tel Aviv University’s Department of Molecular Microbiology and Biotechnology and the Sagol School of Neuroscience, along with their colleague Dr. Ronit Shaltiel-Karyo and PhD candidate Moran Frenkel-Pinter, have found that mannitol also prevents clumps of the protein α-synuclein from forming in the brain — a process that is characteristic of Parkinson’s disease.
These results, published in the Journal of Biological Chemistry and presented at the Drosophila Conference in Washington, DC in April, suggest that this artificial sweetener could be a novel therapy for the treatment of Parkinson’s and other neurodegenerative diseases. The research was funded by a grant from the Parkinson’s Disease Foundation and supported in part by the Lord Alliance Family Trust.
Seeing a significant difference
After identifying the structural characteristics that facilitate the development of clumps of α-synuclein, the researchers began to hunt for a compound that could inhibit the proteins’ ability to bind together. In the lab, they found that mannitol was among the most effective agents in preventing aggregation of the protein in test tubes. The benefit of this substance is that it is already approved for use in a variety of clinical interventions, Prof. Segal says.
Next, to test the capabilities of mannitol in the living brain, the researchers turned to transgenic fruit flies engineered to carry the human gene for α-synuclein. To study fly movement, they used a test called the “climbing assay,” in which the ability of flies to climb the walls of a test tube indicates their locomotive capability. In the initial experimental period, 72 percent of normal flies were able to climb up the test tube, compared to only 38 percent of the genetically-altered flies.
The researchers then added mannitol to the food of the genetically-altered flies for a period of 27 days and repeated the experiment. This time, 70 percent of the mutated flies could climb up the test tube. In addition, the researchers observed a 70 percent reduction in aggregates of α-synuclein in mutated flies that had been fed mannitol, compared to those that had not.
These findings were confirmed by a second study which measured the impact of mannitol on mice engineered to produce human α-synuclein, developed by Dr. Eliezer Masliah of the University of San Diego. After four months, the researchers found that the mice injected with mannitol also showed a dramatic reduction of α-synuclein in the brain.
Delivering therapeutic compounds to the brain
The researchers now plan to re-examine the structure of the mannitol compound and introduce modifications to optimize its effectiveness. Further experiments on animal models, including behavioral testing, whose disease development mimics more closely the development of Parkinson’s in humans is needed, Prof. Segal says.
For the time being, mannitol may be used in combination with other medications that have been developed to treat Parkinson’s but which have proven ineffective in breaking through the blood/brain barrier, says Prof. Segal. These medications may be able to “piggy-back” on mannitol’s ability to open this barrier into the brain.
Although the results look promising, it is still not advisable for Parkinson’s patients to begin ingesting mannitol in large quantities, Prof. Segal cautions. More testing must be done to determine dosages that would be both effective and safe.
(Source: aftau.org)
Researchers Develop Novel Drug That Reverses Loss of Brain Connections in Models of Alzheimer’s
The first experimental drug to boost brain synapses lost in Alzheimer’s disease has been developed by researchers at Sanford-Burnham Medical Research Institute. The drug, called NitroMemantine, combines two FDA-approved medicines to stop the destructive cascade of changes in the brain that destroys the connections between neurons, leading to memory loss and cognitive decline.
The decade-long study, led by Stuart A. Lipton, M.D., Ph.D., professor and director of the Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, who is also a practicing clinical neurologist, shows that NitroMemantine can restore synapses, representing the connections between nerve cells (neurons) that have been lost during the progression of Alzheimer’s in the brain. The research findings are described in a paper published June 17 by the Proceedings of the National Academy of Sciences of the United States of America (PNAS).
The focus on a downstream target to treat Alzheimer’s, rather than on amyloid beta plaques and neurofibrillary tangles—approaches which have shown little success—“is very exciting because everyone is now looking for an earlier treatment of the disease,” Lipton said. “These findings actually mean that you might be able to intercede not only early but also a bit later.” And that means that an Alzheimer’s patient may be able to have synaptic connections restored even with plaques and tangles already in his or her brain.
Targeting lost synapses
In their study, conducted in animal models as well as brain cells derived from human stem cells, Lipton and his team mapped the pathway that leads to synaptic damage in Alzheimer’s. They found that amyloid beta peptides, which were once thought to injure synapses directly, actually induce the release of excessive amounts of the neurotransmitter glutamate from brain cells called astrocytes that are located adjacent to the nerve cells.
Normal levels of glutamate promote memory and learning, but excessive levels are harmful. In patients suffering from Alzheimer’s disease, excessive glutamate activates extrasynaptic receptors, designated eNMDA receptors (NMDA stands for N-methyl-D-aspartate), which get hyperactivated and in turn lead to synaptic loss.
How NitroMemantine works
Lipton’s lab had previously discovered how a drug called memantine can be targeted to eNMDA receptors to slow the hyperactivity seen in Alzheimer’s. This patented work contributed to the FDA approval of memantine in 2003 for the treatment of moderate to severe Alzheimer’s disease. However, memantine’s effectiveness has been limited. The reason, the researchers found, was that memantine—a positively charged molecule—is repelled by a similar charge inside diseased neurons; therefore, memantine gets repelled from its intended eNMDA receptor target on the neuronal surface.
In their study, the researchers found that a fragment of the molecule nitroglycerin—a second FDA-approved drug commonly used to treat episodes of chest pain or angina in people with coronary heart disease—could bind to another site that the Lipton group discovered on NMDA receptors. The new drug represents a novel synthesis connecting this fragment of nitroglycerin to memantine, thus representing two FDA-approved drugs connected together. Because memantine rather selectively binds to eNMDA receptors, it also functions to target nitroglycerin to the receptor. Therefore, by combining the two, Lipton’s lab created a new, dual-function drug. The researchers developed 37 derivatives of the combined drug before they found one that worked, Lipton said.
By shutting down hyperactive eNMDA receptors on diseased neurons, NitroMemantine restores synapses between those neurons. “We show in this paper that memantine’s ability to protect synapses is limited,” Lipton said, “but NitroMemantine brings the number of synapses all the way back to normal within a few months of treatment in mouse models of Alzheimer’s disease. In fact, the new drug really starts to work within hours.”
To date, therapies that attack amyloid plaques and neurofibrillary tangles have failed. “It’s quite disappointing because I see really sick patients with dementia. However, I’m now optimistic that NitroMemantine will be effective as we advance to human trials, bringing new hope to both early and later-stage Alzheimer’s patients,” Lipton said.
Study of Dietary Intervention Examines Proteins in Brain
The lipidation states (or modifications) in certain proteins in the brain that are related to the development of Alzheimer disease appear to differ depending on genotype and cognitive diseases, and levels of these protein and peptides appear to be influenced by diet, according to a report published Online First by JAMA Neurology, a JAMA Network publication.
Sporadic Alzheimer disease (AD) is caused in part by the accumulation of β-amyloid (Αβ) peptides in the brain. These peptides can be bound to lipids or lipid carrier proteins, such as apolipoprotein E (ApoE), or be free in solution (lipid-depleted [LD] Αβ). Levels of LD Αβ are higher in the plasma of adults with AD, but less is known about these peptides in the cerebrospinal fluid (CSF), the authors write in the study background.
Angela J. Hanson, M.D., Veterans Affairs Puget Sound Health Care System and the University of Washington, Seattle, and colleagues studied 20 older adults with normal cognition (average age 69 years) and 27 older adults with amnestic mild cognitive impairment (average age 67 years).
The patients were randomized to a diet high in saturated fat content (45 percent energy from fat, greater than 25 percent saturated fat) with a high glycemic index or a diet low in saturated fat content (25 percent of energy from fat, less than 7 percent saturated fat) with a low glycemic index. The main outcomes the researchers measured were lipid depleted (LD) Αβ42 and Αβ40 and ApoE in cerebrospinal fluid.
Study results indicate that baseline levels of LD Αβ were greater for adults with mild cognitive impairment compared with adults with normal cognition. The authors also note that these findings were more apparent in adults with mild cognitive impairment and the Ɛ4 allele (a risk factor for AD), who had higher LD apolipoprotein E levels irrespective of cognitive diagnosis. Study results indicate that the diet low in saturated fat tended to decrease LD Αβ levels, whereas the diet high in saturated fat increased these fractions.
The authors note the data from their small pilot study need to be replicated in a larger sample before any firm conclusions can be drawn.
“Overall, these results suggest that the lipidation states of apolipoproteins and amyloid peptides might play a role in AD pathological processes and are influenced by APOE genotype and diet,” the study concludes.
Editorial: Food for Thought
In an editorial, Deborah Blacker, M.D., Sc.D., of the Massachusetts General Hospital/Harvard Medical School, Boston, writes: “The article by Hanson and colleagues makes a serious effort to understand whether dietary factors can affect the biology of Alzheimer disease (AD).”
“Hanson et al argue that the changes observed after their two dietary interventions may underlie some of the epidemiologic findings regarding diabetes and other cardiovascular risk factors and risk for AD. The specifics of their model may not capture the real underlying biological effect of these diets, and it is unclear whether the observed changes in the intermediate outcomes would lead to beneficial changes in oligomers or plaque burden, much less to decreased brain atrophy or improved cognition,” she continues.
“At some level, however, the details of the biological model are not critical; the important lesson from the study is that dietary intervention can change brain amyloid chemistry in largely consistent and apparently meaningful ways – in a short period of time. Does this change clinical practice for those advising patients who want to avoid dementia? Probably not, but it adds another small piece to the growing evidence that taking good care of your heart is probably good for your brain too,” Blacker concludes.
(Source: media.jamanetwork.com)
Rare genomic mutations found in 10 families with early-onset, familial Alzheimer’s disease
Although a family history of Alzheimer’s disease is a primary risk factor for the devastating neurological disorder, mutations in only three genes – the amyloid precursor protein and presenilins 1 and 2 – have been established as causative for inherited, early-onset Alzheimer’s, accounting for about half of such cases. Now Massachusetts General Hospital (MGH) researchers have discovered a type of mutation known as copy-number variants (CNVs) – deletions, duplications, or rearrangements of human genomic DNA – in affected members of 10 families with early-onset Alzheimer’s. Notably, different genomic changes were identified in the Alzheimer’s patients in each family.
The study was conducted as part of the Alzheimer’s Genome Project – directed by Rudolph Tanzi, PhD, director of the Genetics and Aging Research Unit at Massachusetts General Hospital (MGH) and a co-discoverer of the first three early-onset genes – and was supported by the Cure Alzheimer’s Fund and the National Institute of Mental Health (NIMH).
"We found that the Alzheimer’s-afflicted members of these families had duplications or deletions in genes with important roles in brain function, while their unaffected siblings had unaltered copies of those genes," says Basavaraj Hooli, PhD, of the Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, lead author of a report that has been published online in Molecular Psychiatry. “Since our preliminary review of the affected genes has provided strong clues to a range of pathways associated with Alzheimer’s disease and other forms of dementia, we believe that further research into the functional effects of these CNVs will provide new insights into Alzheimer’s pathogenesis.” Hooli is a research fellow in Neurology at Harvard Medical School.
Most studies searching for genes contributing to Alzheimer’s risk have looked for variants in a single nucleotide, and while thousands of such changes have been identified, each appears to have a very small impact on disease risk. Recently research has found that CNVs – in which DNA segments of varying lengths are deleted or duplicated – have a greater impact on genomic diversity than do single-nucleotide changes. This led Tanzi and his team to search for large CNVs in affected members of families with inherited Alzheimer’s disease. “These are the first new early-onset familial Alzheimer’s disease gene mutations to be reported since 1995, when we co-discovered the presenilins. As with those original genes, we hope to use the information gained from studies of the new Alzheimer’s mutations to guide the development of novel therapies aimed at preventing and treating this devastating disease.” Tanzi explains.
The investigators reviewed genomic data from two sources – the NIMH Alzheimer’s Disease Genetics Initiative and the National Cell Repository for Alzheimer’s Disease – and focused on 261 families with at least one member who developed Alzheimer’s before the age of 65. Using a novel algorithm they had developed for analyzing CNVs, the researchers identified deletions or duplications that appeared only in affected members of these families. Two of these families had CNVs that included the well-established amyloid precursor protein gene, but 10 others were found to have novel Alzheimer’s-associated CNVs, with different gene segments being affected in each family.
While none of the novel variants have previously been associated with Alzheimer’s disease, most of them affect genes believed to be essential to normal neuronal function, and several have been previously associated with other forms of dementia. For example, one of the identified CNVs involves deletion of a gene called CHMP2B, mutations of which can cause ALS. In another family, affected members had three copies of the gene MAPT, which encodes the tau protein found in the neurofibrillary tangles characteristic of Alzheimer’s. Mutations in MAPT also cause frontotemporal dementia.
Hooli explains, “Potential clinical application of the findings of this study are not yet clear and require two additional pieces of information: similar studies in larger groups of families with inherited Alzheimer’s to establish the prevalence of these CNVs and whether the presence of one ensures development of the disease, and a better understanding of how these variants affect neuronal pathways leading to the early-onset form of Alzheimer’s disease.”
"In a broader sense," Tanzi adds, "the advent of affordable, advanced whole-genome sequencing will lead to the identification of novel, rare mutations that lead to many human disorders. In the future, diagnosis and prognosis may rely more on disease genetics than on traditional laboratory results and behavioral effects. If knowing the exact genetic causes of these disorders leads to more effective and efficient treatment strategies targeted to specific defects, the consequences of this approach would be enormous."
Psychiatric disorders linked to a protein involved in the formation of long-term memories
Researchers have discovered a pathway by which the brain controls a molecule critical to forming long-term memories and connected with bipolar disorder and schizophrenia.
The discovery was made by a team of scientists led by Alexei Morozov, an assistant professor at the Virginia Tech Carilion Research Institute.
The mechanism – a protein called Rap1 – controls L-type calcium channels, which participate in the formation of long-term memories. Previous studies have also linked alterations in these ion channels to certain psychiatric disorders. The discovery of the channels’ regulation by Rap1 could help scientists understand the physiological genesis of bipolar disorder and schizophrenia.
"People with genetic mutations affecting L-type calcium channels have higher rates of bipolar disorder and schizophrenia," said Morozov. "This suggests that there might be a relationship between the activation of L-type calcium channels and these psychiatric disorders. Understanding how these ion channels are controlled is the first step to determining how their functioning or malfunctioning affects mental health."
A single neuron in the brain can have thousands of synapses, each of which can grow, strengthen, weaken, and change structurally in response to learning new information. Electric signals traveling from neuron to neuron jump across these synapses through chemical neurotransmitters. The release of these chemicals is caused by the flow of electrically charged atoms through a particular subset of ion channels known as voltage-gated calcium channels.
Previous studies have shown that blocking these ion channels inhibits the formation of long-term memories. Although it was known that L-type calcium channels are activated in response to learning, how they are controlled was a mystery.
In the experiment, Morozov and colleagues knocked out the gene responsible for coding the enzyme Rap1, which he suspected played a role in activating L-type calcium channels. The researchers then used live imaging techniques to monitor the release of neurotransmitters and electron microscopy to visualize L-type channels at synapses. They discovered that, without Rap1, the L-type calcium channels were more active and more abundant at synapses all the time, increasing the release of neurotransmitters. The results showed that Rap1 is responsible for suppressing L-type calcium channels, allowing them to activate only at the proper moments, possibly during long-term memory formation.
"Our next step is to determine whether this new signaling pathway is altered in cases of mental disease," said Morozov. "If so, it could help us gain a better understanding of the molecular underpinnings of channel-related psychiatric disorders, such as bipolar disorder and schizophrenia. Such knowledge would go a long way toward developing new therapeutic methods."
(Source: eurekalert.org)
Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects.
When Head Meets Soccer Ball, How Does Your Brain Fare?
Soccer players who frequently head-butt the ball—a commonly used tactic for passing or scoring in a game—may be risking brain injury, memory loss, and impaired cognitive ability, according to a study published in the journal Radiology.
Brain injury and the lasting effects of concussion in sport have become a major health issue in recent years, especially in such hard-hitting sports as American football. Although the thump of a soccer ball on a forehead seems fairly innocuous, compared with a crashing tackle on the three-yard line, a soccer player may “head” the ball hundreds or even thousands of times during the course of the season. The cumulative effect of many “sub-concussive” blows to the brain has been unknown and unstudied until now.
"We chose to study soccer because it is the world’s most popular sport," says the report’s lead author Michael Lipton, associate director of the Gruss Magnetic Resonance Research Center at the Albert Einstein College of Medicine in New York. "It is widely played by millions of people of all ages, including children, and there is concern that heading the ball, an essential part of the game, might cause damage to the brain."
Lipton and his colleagues examined 37 amateur players, all adults, who had played soccer for an average of 22 years each and had played regularly over the previous year. They filled out questionnaires about their playing style and how frequently they headed the ball on the field and in training drills. Then they were given memory tests and highly sophisticated brain scans, using a type of MRI called diffusion-tensor imaging that looks at microscopic changes in the white matter in the brain. White matter is the tissue that conveys messages from one region of the brain to another.
The researchers found that players had to head the ball a certain number of times in a season before white matter abnormalities started to appear on imaging. The threshold varied from player to player but was generally in the range of 900 to 1,500 headers in a season. Beyond this threshold, the brain abnormalities quickly became more apparent. Those who headed the ball more than 1,800 times in a season scored measurably worse on memory tests than those who had headed the ball less frequently. The difference in scores was in the range of 10 to 20 percent.
"To put this into perspective I should make it clear that all of these players’ functions were still within norms," said Lipton. "These are all basically functional young professionals and students."
So, should soccer players—and parents of young soccer players—be worried?
"All we have at this point is some evidence that shows an association between heading and what looks like brain injury. However, we do not yet have the type of data that permits us to prove a causal role for heading or to generalize our findings to other specific individuals. In the meantime, controlling the amount of heading that people do may provide an approach for preventing brain injury as a consequence of heading."
"I should emphasize that we very much see soccer as an excellent source of beneficial physical activity. This should not be curtailed. Our message is to understand the role of heading in the game and look at how we can enhance the safety of soccer play and facilitate its expansion."