Posts tagged science
Articles and news from the latest research reports.
Pain curbs sex drive in female mice, but not in males
“Not tonight, dear, I have a headache.” Generally speaking, that line is attributed to the wife in a couple, implying that women’s sexual desire is more affected by pain than men’s.
Now, researchers from McGill University and Concordia University in Montreal have investigated, possibly for the first time in any species, the direct impact of pain on sexual behaviour in mice. Their study, published in the April 23 issue of The Journal of Neuroscience, found that pain from inflammation greatly reduced sexual motivation in female mice in heat — but had no such effect on male mice.
“We know from other studies that women’s sexual desire is far more dependent on context than men’s – but whether this is due to biological or social/cultural factors, such as upbringing and media influence, isn’t known,” says Jeffrey Mogil, a psychology professor at McGill and corresponding author of the new study. “Our finding that female mice, too, show pain-inhibited sexual desire suggests there may be an evolutionary biology explanation for these effects in humans – and not simply a sociocultural one.”
To conduct the study, the researchers placed mice in a mating chamber divided by a barrier with openings too small for male mice to squeeze through. This enabled the females to decide whether, and for how long, to spend time with a male partner. Female mice in pain spent less time on the “male side” of the testing chamber, and as a result less sexual behaviour occurred. The researchers found that the sexual motivation of the female mice could be revived, however with a pain-relieving drug (pregabalin) or with either of two known desire-enhancing drugs.
Male mice, for their part, were tested in an undivided chamber in which they had free access to a female partner in heat. Their sexual behaviour was entirely unaffected by the same inflammatory pain. There were no differences in pain perception between the sexes, the researchers determined.
“Chronic pain is very often accompanied by sexual problems in humans,” says Prof. Yitzchak Binik, a professor of psychology at McGill and Director of the Sex and Couple Therapy Service at the McGill University Health Center. “This research provides an animal model of pain-inhibited sexual desire that will help scientists study this important symptom of chronic pain.”
Melissa Farmer, now a postdoctoral fellow at Northwestern University, led the study as a doctoral student at McGill under the supervision of Prof. Mogil, a pain researcher, and Prof. Binik, a human sexual-disorder researcher.
Prof. James Pfaus of Concordia University’s Centre for Studies in Behavioral Neurobiology, an expert on rodent sexual behaviour, also co-authored the study. “The sex differences in pain reactivity open new doors to understanding how sexual responses are organized in the brain,” Prof. Pfaus said. “In fact, the growing trend towards personalized medicine requires us to understand how particular ailments, along with their treatments, might impact the sexual lives of women and men.“
Know your enemy: Oligomers’ role in the development of Parkinson’s disease
Researchers at Aarhus University, Denmark, have drawn up the most detailed ‘image of the enemy’ to date of one of the body’s most important players in the development of Parkinson’s disease. This provides much greater understanding of the battle taking place when the disease occurs – knowledge that is necessary if we are to understand and treat Parkinsonism. However, it also raises an existential question because part of the conclusion is that we do not live forever!
Parkinson’s disease is one of the most common neurological disorders, with about 7000 people suffering from the disease in Denmark alone. There is no cure, and the symptoms continue to get worse. The disease occurs because different nerves in the brain die. These include the nerve cells that form dopamine, which is known as the brain’s ‘reward substance’ and which also helps control our fine motor skills.
A group of researchers from Aarhus University, the University of Southern Denmark (SDU) and the University of Cambridge has just published two studies in the prestigious Journal of the American Chemical Society (JACS) and Angewandte Chemie. These studies provide the best insight to date into the behaviour of a particular protein state that plays an important role in Parkinson’s disease. In other words, they have created a detailed image of what is presumed to be the arch enemy we are up against in our understanding of Parkinsonism. It is an advanced antagonist, and one that functions with a considerable degree of unpredictability. “Fighting the enemy is by no means a Sunday outing,” say the main authors of the results – Professor Daniel Otzen, Aarhus University, and his colleagues Nikolai Lorenzen and Wojciech Paslawski, who recently defended their PhD dissertations on this subject at Aarhus University’s Interdisciplinary Nanoscience Centre (iNANO).
(Source: eurekalert.org)
Scientists Find Connection Between Gene Mutation, Key Symptoms of Autism
Scientists have known that abnormal brain growth is associated with autism spectrum disorder. However, the relationship between the two has not been well understood.
(Image: Thinkstock)
Now, scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown that mutations in a specific gene that is disrupted in some individuals with autism results in too much growth throughout the brain, and yet surprisingly specific problems in social interactions, at least in mouse models that mimic this risk factor in humans.
“What was striking is that these were basically normal animals in terms of behavior, but there were consistent deficits in tests of social interaction and recognition—which approximate a major symptom of autism,” said Damon Page, a TSRI biologist who led the study. “This suggests that when most parts of the brain are overgrown, the brain somehow adapts to it with minimal effects on behavior in general. However, brain circuits relevant to social behavior are more vulnerable or less able to tolerate this overgrowth.”
The study, which focuses on the gene phosphatase and tensin homolog (PTEN), was recently published online ahead of print by the journal Human Molecular Genetics.
Autism spectrum disorder is a neurodevelopmental disorder involving a range of symptoms and disabilities involving social deficits and communication difficulties, repetitive behaviors and interests, and sometimes cognitive delays. The disorder affects in approximately one percent of the population; some 80 percent of those diagnosed are male.
In a previous study, Page and colleagues found that mutations in Pten causes increased brain size and social deficits, with both symptoms being exacerbated by a second “hit” to a gene that regulates levels of the neurotransmitter serotonin in the brain. In the new study, the TSRI team set out to explore whether mutations in Pten result in widespread or localized overgrowth within the brain, and whether changes in brain growth are associated with broad or selective deficits in tests of autism-relevant behaviors in genetically altered mice. The team tested mice for autism spectrum disorder-related behaviors including mood, anxiety, intellectual, and circadian rhythm and/or sleep abnormalities.
The researchers found that Pten mutant mice showed altered social behavior, but few other changes—a more subtle change than would have been predicted given broad expression and critical cellular function of the gene.
Intriguingly, some of the more subtle impairments were sex-specific. In addition to social impairments, males with the mutated gene showed abnormalities related to repetitive behavior and mood/anxiety, while females exhibited additional circadian activity and emotional learning problems.
The results raise the question of how mutations in PTEN, a general regulator of growth, can have relatively selective effects on behavior and cognitive development. One idea is that PTEN mutations may desynchronize the normal pattern of growth in key cell types—the study points to dopamine neurons—that are relevant for social behavior.
“Timing is everything,” Page said. “Connections have to form in the right place at the right time for circuits to develop normally. Circuitry involved in social behavior may turn out to be particularly vulnerable to the effects of poorly coordinated growth.”
(Source: scripps.edu)
Seeking the Causes of Hyperactivity
The 60 trillion cells that comprise our bodies communicate constantly. Information travels when chemical compounds released by some cells are received by receptors in the membrane of another cell. In a paper published in the Journal of Neuroscience, the OIST Cell Signal Unit, led by Professor Tadashi Yamamoto, reported that mice lacking an intracellular trafficking protein called LMTK3, are hyperactive. Hyperactivity is a behavioral disorder that shows symptoms including restlessness, lack of coordination, and aggressive behavior. Identifying the genetic factors that contribute to such behaviors may help to explain the pathological mechanisms underlying autism and Attention Deficit Hyperactivity Disorder, ADHD, in humans.
LMTK3 is abundant in two brain regions: the cerebral cortex, which coordinates perception, movement, and thought, and the hippocampus, which governs memory and learning. In the brain, neurons communicate via connections called synapses. To send a message, a nerve terminus in the pre-synapse releases neurotransmitters to be received by the post-synaptic receptors. Yamamoto’s team discovered that LMTK3 regulates trafficking of neurotransmitter receptors at synapses. In neurons of mice deficient in LMTK3, internalization of receptors are augmented in the post-synapse, suggesting that synaptic communication is impaired. The LMTK3-deficient mice exhibited various hyperactive behaviors such as restlessness and hypersensitivity to sound. Interestingly, their dopamine levels were elevated. Dopamine is a neurotransmitter known to be involved in regulation of movement and hormone levels, motivation, learning, and expression of emotion. Excessive dopamine secretion results in schizophrenia, causing a loss of integrity of neuronal activity, and abnormal thoughts and emotions. The relationships between regulation of neurotransmitter receptor expression by LMTK3, dopamine turnover, and the biochemical pathways that induce hyperactivity, remain unknown.
Functions of many human proteins are still not understood. The Cell Signal Unit continues genetic studies of intracellular proteins that maintain and regulate complex functions such as behaviors, through their activities inside cells. “We hope to advance our research in order to elucidate genetic defects that result in behavioral abnormalities,” Yamamoto said.
Study Suggests Targeting B Cells May Help with MS
A new study suggests that targeting B cells, which are a type of white blood cell in the immune system, may be associated with reduced disease activity for people with multiple sclerosis (MS). The study is released today and will be presented at the American Academy of Neurology’s 66th Annual Meeting in Philadelphia, April 26 to May 3, 2014.
For the study, 231 people with relapsing-remitting MS received either a placebo or one of several low dosages of the drug ofatumumab, which is an anti-B cell antibody, for 24 weeks, with the first 12 weeks making up the placebo-controlled period. The main objective was to determine the effects of ofatumumab dosing regimens compared to placebo on the total number of new brain lesions assessed every four weeks over a 12-week period.
All dose groups including placebo showed lesion activity in the first four weeks with lesion suppression in all ofatumumab dose groups from weeks four to12. Researchers measured the amount of B cells in participants and compared that to the total number of new brain lesions that appeared on brain scans, which is a marker of disease activity.
The researchers found that when B cells were reduced to below a threshold of 64 cells per microliter, disease activity, as measured by appearance of new brain lesions, was significantly reduced. On average, participants had an annualized rate of less than one new brain lesion per year when B cells were maintained below a threshold of 32 to 64 cells per microliter, compared with 16 lesions without treatment.
The most common side effects, defined as those occurring in at least five percent of participants and at a rate twice that of placebo for weeks zero to12, were injection-related reaction, dizziness, anxiety, fever, respiratory tract infection and nerve pain.
Study author Daren Austin, PhD, of GlaxoSmithKline in Uxbridge, United Kingdom, and a member of the American Academy of Neurology, said the study results also suggest that peripheral, rather than central, B cells may be the most relevant target for anti-B cell therapy.
“These results need to be validated, of course, but the findings are interesting,” Austin said. “They provide new insight into the mechanism of B cells in MS and present a possible new target threshold for exploring the potential benefit of anti-B cell therapy.” Ofatumumab is not approved anywhere in the world for use in the treatment of multiple sclerosis.
Biologists discover a key regulator in the pacemakers of our brain and heart
Biologists have discovered how an outer shield over T-type channels change the electrochemical signaling of heart and brain cells. Understanding how these shields work will help researchers eventually develop a new class of drugs for treating epilepsy, cardiovascular disease and cancer.
The study from the University of Waterloo is published in the Journal of Biological Chemistry today and is featured as the “Paper of the Week” for its significance.
The researchers discovered T-type channels in the pond snail, Lymnaea stagnalis, can shift from using calcium ions to using sodium ions to generate the electrical signal because of an outer shield of amino acids called a turret situated above the channel’s entrance.
Low voltage T-type channels generate tiny pulses of current at regular intervals by selectively passing positively charged cations across the cell’s membrane through a gate-like channel. The channels are normally extremely selective, allowing just one sodium ion to pass for every 10,000 calcium ions.
The resulting rhythmic signals produced by this transfer of cations are what support the synchronous contraction of our heart muscles and neuronal firing in parts of the brain, like the thalamus, which helps regulate our sleep-wake cycle, or circadian rhythm.
In addition to their published findings, the researchers also found the shield-like turrets in pond snails restrict access of therapeutic drugs to the channel.
T-type channels in pond snails and other invertebrates are similar to those found in humans. Although pond snails reach only 7 cm in length, its simple neural network and physiology make it a popular model organism with neurobiologists.
Over-active T-type channels are linked to epilepsy, cardiac problems, neuropathic pain, as well as the spreading of several kinds of cancer. Drugs that could quench out-of-control T-type channel activity are unable to bind to the channels themselves.
“We wanted to understand the molecular structures of T-type channels,” said Spafford. “How they pass ionic currents to generate electrical activity, and to identify drug binding sites, and the drugs which may block these channels to treat neurological disease or heart complications.”
The group is currently investigating how dismantling this extracellular turret will improve drug access and binding in T-type channels.
Paying closer attention to attention
Ellen’s (not her real name) adoptive parents weren’t surprised when the school counselor suggested that she might have attention deficit hyperactivity disorder (ADHD).
Several professionals had made this suggestion over the years. Given that homework led to one explosion after another, and that at school Ellen, who is eleven, spent her days jiggling up and down in her seat, unable to concentrate for more than ten minutes, it seemed a reasonable assumption. Yet her parents always felt that ADHD didn’t quite capture the extent of Ellen’s issues over the years. Fortunately the school counsellor was familiar with fetal alcohol spectrum disorder (FASD). When she learned that Ellen’s birth mother had consumed alcohol during pregnancy, she raised the possibility that Ellen’s problems could be attributable to FASD and referred her for further assessment.
It’s a familiar story, and most of us reading about Ellen would assume that she did indeed suffer from ADHD.
But now researchers from McGill have suggested that there may be an overreporting of attention problems in children with FASD, simply because parents and teachers are using a misplaced basis for comparison. They are testing and comparing children with FASD with children of the same physical or chronological age, rather than with children of the same mental age, which is often quite a lot younger.
“Because the link between fetal alcohol syndrome and ADHD is so commonly described in the literature, both parents and teachers are more likely to expect these children to have attention problems,” says Prof. Jacob Burack, a professor in McGill’s Dept. of Educational and Counselling Psychology and the senior author on a recent study on the subject. “But what teachers often don’t recognize is that although the child they are dealing with is eleven years old in chronological terms, they are actually functioning at the developmental age of an eight-year old. That’s a pretty big difference. And when you use mental age as the basis of comparison, many of the attention problems that have been described in children with FASD no longer seem of primary importance.”
The researchers recruited children with FASD whose average chronological age was just under twelve years old. But their average mental age, determined by standard tests, was actually closer to nine-and-a-half years old. (The children were recruited through the Asante Centre for Fetal Alcohol Syndrome in British Columbia, and though the number of children studied may appear small, this is a fairly typical size for studies on FASD, given the difficulties of the diagnostic process.)
These children were then compared with children who were developing typically and whose average chronological age was about eight-and-a-half years old and whose average mental age was similar to that of the group of children diagnosed with FASD.
After using tests to measure specific aspects of attention, the researchers then compared the performance of children with FASD on these tests with the results of children of the same mental age. What they found was that while children like Ellen had difficulties with certain kinds of attention skills, notably in terms of shifting attention from one object to another, there were other areas, such as focus, where they had no significant difficulties at all. So, if we were to compare these aspects of attention to a hockey game, typically these children would have no difficulty focusing on the puck in the arena, but would have problems following the puck being passed from one player to another.
This suggests to Dr. Kimberly Lane, the PhD student who conducted the research, that there is a need to develop a more nuanced understanding of attention skills. “We use words like attention loosely, but it’s really an umbrella term that covers various aspects of attending to different people or events or environments,” says Dr. Lane. “By using more complex assessment techniques of various aspects of attention it will be possible to get a better picture of the attention difficulties faced by children with FASD,” she adds.
“But no matter what the tests say, it’s important for teachers and parents to understand that.the difficulties these children have with attention may be less important than their more general problems, and we need to work with them as they are.”
(Source: mcgill.ca)
Controlling Brain Waves to Improve Vision
Have you ever accidently missed a red light or a stop sign? Or have you heard someone mention a visible event that you passed by but totally missed seeing?
“When we have different things competing for our attention, we can only be aware of so much of what we see,” said Kyle Mathewson, Beckman Institute Postdoctoral Fellow. “For example, when you’re driving, you might really be concentrating on obeying traffic signals.”
But say there’s an unexpected event: an emergency vehicle, a pedestrian, or an animal running into the road—will you actually see the unexpected, or will you be so focused on your initial task that you don’t notice?
“In the car, we may see something so brief or so faint, while we’re paying attention to something else, that the event won’t come into our awareness,” says Mathewson. “If you present this scenario hundreds of times to someone, sometimes they will see the unexpected event, and sometimes they won’t because their brain is in a different preparation state.”
By using a novel technique to test brain waves, Mathewson and colleagues are discovering how the brain processes external stimuli that do and don’t reach our awareness. A paper about their results, “Dynamics of Alpha Control: Preparatory Suppression of Posterior Alpha Oscillations by Frontal Modulators Revealed with Combined EEG and Event-related Optical Signal,” published this month in the Journal of Cognitive Neuroscience, reveals how alpha waves, typically thought of as your brain’s electrical activity while it’s at rest, can actually influence what we see or don’t see.
The researchers used both electroencephalography (EEG) and the event-related optical signal (EROS), developed in the Cognitive Neuroimaging Laboratory of Gabriele Gratton and Monica Fabiani, professors of psychology and members of the Beckman Institute’s Cognitive Neuroscience Group, and authors of the study.
While EEG records the electrical activity along the scalp, EROS uses infrared light passed through optical fibers to measure changes in optical properties in the active areas of the cerebral cortex. Because of the hard skull between the EEG sensors and the brain, it can be difficult to find exactly WHERE signals are produced. EROS, which examines how light is scattered, can noninvasively pinpoint activity within the brain.
“EROS is based on near-infrared light,” explained Fabiani and Gratton via email. “It exploits the fact that when neurons are active, they swell a little, becoming slightly more transparent to light: this allows us to determine when a particular part of the cortex is processing information, as well as where the activity occurs.”
This allowed the researchers to not only measure activity in the brain, but also allowed them to map where the alpha oscillations were originating. Their discovery: the alpha waves are produced in the cuneus, located in the part of the brain that processes visual information.
The alpha can inhibit what is processed visually, making it hard for you to see something unexpected.
By focusing your attention and concentrating more fully on what you are experiencing, however, the executive function of the brain can come into play and provide “top-down” control—putting a brake on the alpha waves, thus allowing you to see things that you might have missed in a more relaxed state.
“We found that the same brain regions known to control our attention are involved in suppressing the alpha waves and improving our ability to detect hard-to-see targets,” said Diane Beck, a member of the Beckman’s Cognitive Neuroscience Group, and one of the study’s authors.
“Knowing where the waves originate means we can target that area specifically with electrical stimulation” said Mathewson. “Or we can also give people moment-to-moment feedback, which could be used to alert drivers that they are not paying attention and should increase their focus on the road ahead, or in other situations alert students in a classroom that they need to focus more, or athletes, or pilots and equipment operators.”
The study examined 16 subjects and mapped the electrical and optical data onto individual MRI brain images.
Researchers Pinpoint Protein Crucial For Development Of Biological Rhythms In Mice
Johns Hopkins researchers report that they have identified a protein essential to the formation of the tiny brain region in mice that coordinates sleep-wake cycles and other so-called circadian rhythms.
(Image caption: An illustration of the activity patterns of normal mice (left). An illustration of the activity patterns mice whose “master clock,” or SCN, has been disrupted (right). Credit: Cell Reports, Bedont et al.)
By disabling the gene for that key protein in test animals, the scientists were able to home in on the mechanism by which that brain region, known as the suprachiasmatic nucleus or SCN, becomes the body’s master clock while the embryo is developing.
The results of their experiments, reported in the tk issue of Cell Reports, are an important step toward understanding how to better manage the disruptive effects experienced by shift workers, as well as treatment of people with sleep disorders, the researchers say.
“Shift workers tend to have higher rates of diabetes, obesity, depression and cancer. Many researchers think that’s somehow connected to their irregular circadian rhythms, and thus to the SCN,” says Seth Blackshaw, Ph.D., an associate professor in the Department of Neuroscience and the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. “Our new research will help us and other researchers isolate the specific impacts of the SCN on mammalian health.”
Blackshaw explains that every cell in the body has its own “clock” that regulates aspects such as its rate of energy use. The SCN is the master clock that synchronizes these individual timekeepers so that, for example, people feel sleepy at night and alert during the day, are hungry at mealtimes, and are prepared for the energy influx that hits fat cells after eating. “A unique property of the SCN is that if its cells are grown in a dish, they quickly synchronize their clocks with each another,” Blackshaw says.
But while evidence like this gave researchers an idea of the SCN’s importance, they hadn’t completely teased its role apart from that of the body’s other clocks, or from other parts of the brain.
The Johns Hopkins team looked for ways to knock down SCN function by targeting and disabling certain genes that disrupt only the formation of the SCN clock. They analyzed which genes were active in different areas of developing mouse brains to identify those that were “turned on” only in the SCN. One of the “hits” was Lhx1, a member of a family of genes whose protein products affect development by controlling the activity of other genes. When the researchers turned off Lhx1 in the SCN of mouse embryos, the grown mice lacked distinctive biochemical signatures seen in the SCN of normal mice.
The genetically modified mice behaved differently, too. Some fell into a pattern of two to three separate cycles of sleep and activity per day, in contrast to the single daily cycle found in normal mice, while others’ rhythms were completely disorganized, Blackshaw says. Though an SCN is present in mutant mice, it communicates poorly with clocks elsewhere in the body.
Blackshaw says he expects that the mutant mice will prove a useful tool in finding whether disrupted signaling from the SCN actually leads to the health problems that shift workers experience, and if so, how this might happen. Although mouse models do not correlate fully to human disease, their biochemical and genetic makeup is closely aligned.
Blackshaw’s team also plans to continue studying the biochemical chain of events surrounding the Lhx1 protein to determine which proteins turn the Lhx1 gene on and which genes it, in turn, directly switches on or off. Those genes could be at the root of inherited sleep disorders, Blackshaw says, and the proteins they make could prove useful as starting points for the development of new drugs to treat insomnia and even jet lag.
Fruitfly Study Identifies Brain Circuit that Drives Daily Cycles of Rest, Activity
Amita Sehgal, PhD, a professor of Neuroscience at the Perelman School of Medicine, University of Pennsylvania, describes in Cell a circuit in the brain of fruit flies that controls their daily, rhythmic behavior of rest and activity. The new study also found that the fly version of the human brain protein known as corticotrophin releasing factor (CRF) is a major coordinating molecule in this circuit. Fly CRF, called DH44, is required for rest/activity cycles and is produced in cells that receive input from the clock cells in the fly brain. In mammals, CRF is secreted rhythmically and it drives the expression of glucocorticoids such as cortisol and is associated with stress and anxiety.
Animal models like flies are helping to fill gaps in current knowledge about how the brain works, notes Sehgal. Indeed, she says, the Brain Research through Advancing Innovative Neurotechnologies (BRAIN), initiative, a project of the National Institutes of Health, includes the study of simple animal models, which are expected to provide more detailed insight into brain function.
Though much is known about the cellular and molecular components of the clock, the connections that link clock cells to overt behaviors, such as rest/activity behavior, have not been identified. “This study is essentially a map-of-the-circuitry experiment,” says Sehgal, who is also an investigator with the Howard Hughes Medical Institute (HHMI). Like humans, flies are active during the day — walking, flying, feeding and mating — and spend most of the night asleep.
“We conducted a screen for circadian-relevant neurons in the flybrain and found that cells of the pars intercerebralis — the fly version of the mammalian hypothalamus — comprise an important component of the circadian output pathway for rest/activity rhythms in flies,” Sehgal says. The mammalian hypothalamus is a neuroendocrine structure that regulates sleep, circadian rhythms, feeding and, metabolism.
The Penn team did a random targeting of cells, activating neuronal firing with a transgene designed for this purpose, to see which cells are important in the rest/active behavior. They found that cells in the pars intercerebralis (PI) are essential for rhythmic behavior, and PI cells are connected to the clock cells through a circuit of at least two synapses.
Molecular profiling of PI cells identified the fly version of DH44 as a circadian molecule that is specifically expressed by PI neurons and required for normal rest/activity rhythms in flies. And, when the scientists selectively activated or removed just six PI cells positive for DH44, the fly’s activity cycles became irregular. In other words, the flies no longer restricted their sleep to the dark and their activity to the light, but instead showed more random distribution of these behaviors