Posts tagged serotonin
Articles and news from the latest research reports.
New study shows how seals sleep with only half their brain at a time
A new study led by an international team of biologists has identified some of the brain chemicals that allow seals to sleep with half of their brain at a time.
The study was published this month in the Journal of Neuroscience and was headed by scientists at UCLA and the University of Toronto. It identified the chemical cues that allow the seal brain to remain half awake and asleep. Findings from this study may explain the biological mechanisms that enable the brain to remain alert during waking hours and go off-line during sleep.
“Seals do something biologically amazing — they sleep with half their brain at a time. The left side of their brain can sleep while the right side stays awake. Seals sleep this way while they’re in water, but they sleep like humans while on land. Our research may explain how this unique biological phenomenon happens” said Professor John Peever of the University of Toronto.
The study’s first author, University of Toronto PhD student Jennifer Lapierre, made this discovery by measuring how different chemicals change in the sleeping and waking sides of the brain. She found that acetylcholine – an important brain chemical – was at low levels on the sleeping side of the brain but at high levels on the waking side. This finding suggests that acetylcholine may drive brain alertness on the side that is awake.
But, the study also showed that another important brain chemical – serotonin – was present at the equal levels on both sides of the brain whether the seals were awake or asleep. This was a surprising finding because scientist long thought that serotonin was a chemical that causes brain arousal.
These findings have possible human health implications because “about 40% of North Americans suffer from sleep problems and understanding which brain chemicals function to keep us awake or asleep is a major scientific advance. It could help solve the mystery of how and why we sleep” says the study’s senior author Jerome Siegel of UCLA’s Brain Research Institute.
(Image: AFP)
Threat bias interacts with combat, gene to boost PTSD risk
Soldiers preoccupied with threat at the time of enlistment or with avoiding it just before deployment were more likely to develop post-traumatic stress disorder (PTSD), in a study of Israeli infantrymen. Such pre-deployment threat vigilance and avoidance, interacting with combat experience and an emotion-related gene, accounted for more than a third of PTSD symptoms that emerged later, say National Institutes of Health scientists, who conducted the study in collaboration with American and Israeli colleagues.
“Since biased attention predicted future risk for PTSD, computerized training that helps modify such attention biases might help protect soldiers from the disorder,” said Daniel Pine, M.D., of the NIH’s National Institute of Mental Health (NIMH).
Pine, Yair Bar-Haim, Ph.D., of Tel Aviv University, and colleagues, report their findings, Feb. 13, 2013, in the journal JAMA Psychiatry.
An interdisciplinary team of researchers from the University of Texas Medical Branch at Galveston and the University of Houston has found a new way to influence the vital serotonin signaling system — possibly leading to more effective medications with fewer side effects.
Scientists have linked malfunctions in serotonin signaling to a wide range of health issues, everything from depression and addictions to epilepsy and obesity and eating disorders. Much of their attention has focused on complex proteins called serotonin receptors, which are located in the cell membrane. Each receptor has a so-called “active site” specially suited to bond with a serotonin molecule; when that bond is formed, the receptor changes shape, transmitting a signal to the cell’s interior.
Traditional drug discovery efforts target interactions that take place at such active sites. But a receptor’s behavior can also be changed by additional proteins that bind to the receptor at locations quite distant (in molecular terms) from the active site, in a process called “allosteric regulation” — the mechanism examined by the UTMB-UH team for one specific and highly significant kind of serotonin receptor, designated the 5-HT2C.
“This is a whole new way of thinking about this system, targeting these interactions,” said UTMB professor Kathryn Cunningham, senior author of a paper on the research now online in the Journal of Neuroscience. “Basically, we’ve created a new series of molecules and validated that we can use them to change the way the receptor functions both in vitro and in vivo, through an allosteric effect.”
(Image: thedea.org)
Some Autism Behaviors Linked to Altered Gene
Scientists at Washington University School of Medicine in St. Louis have identified a genetic mutation that may underlie common behaviors seen in some people with autism, such as difficulty communicating and resistance to change.
An error in the gene, CELF6, leads to disturbances in serotonin, a chemical that relays messages in the brain and has long been suspected to be involved in autism.
The researchers identified the error in a child with autism and then, working in mice, showed that the same genetic alteration results in autism-related behaviors and a sharp drop in the level of serotonin circulating in the brain.
While the newly discovered mutation appears to be rare, it provides some of the first clues to the biological basis of the disease, the scientists report Feb. 13 in the Journal of Neuroscience.
“Genetically, autism looks very complicated, with many different genetic routes that lead to the disease,” says lead author Joseph D. Dougherty, PhD, an assistant professor of genetics at Washington University. “But it’s not possible to design a different drug for every child. The real key is to find the common biological pathways that link these different genetic routes and target those pathways for treatment.”
Autism is known to have a strong genetic component, but the handful of genes implicated in the condition so far explain only a small number of cases or make a small contribution to symptoms.
This led Dougherty and senior author Nathaniel Heintz, PhD, a Howard Hughes Medical Institute investigator at Rockefeller University, to speculate that some of the most common behavioral symptoms of autism may be caused by disruptions in a common biological pathway, like the one involved in serotonin signaling.
In the brain, broken down ‘motors’ cause anxiety
When motors break down, getting where you want to go becomes a struggle. Problems arise in much the same way for critical brain receptors when the molecular motors they depend on fail to operate. Now, researchers reporting in Cell Reports, a Cell Press publication, on February 7, have shown these broken motors induce stress and anxiety in mice. The discovery may point the way to new kinds of drugs to treat anxiety and other disorders.
The study in mice focuses on one motor in particular, known as KIF13A, which, according to the new evidence, is responsible for ferrying serotonin receptors. Without proper transportation, those receptors fail to reach the surface of neurons and, as a result, animals show signs of heightened anxiety.
In addition to their implications for understanding anxiety, the findings also suggest that defective molecular motors may be a more common and underappreciated cause of disease.
"Most proteins are transported in vesicles or as protein complexes by molecular motors," said Nobutaka Hirokawa of the University of Tokyo. "As shown in this study, defective motors could cause many diseases."
Scientists know that serotonin and serotonin receptors are involved in anxiety, aggression, and mood. But not much is known about how those players get around within cells. When Hirokawa’s team discovered KIF13A at high levels in the brain, they wondered what it did.
The researchers discovered that mice lacking KIF13A show greater anxiety in both open-field and maze tests and suggest that this anxious behavior may stem from an underlying loss of serotonin receptor transport, which leads to a lower level of expression of those receptors in critical parts of the brain.
"Collectively, our results suggest a role for this molecular motor in anxiety control," the researchers wrote. Hirokawa says the search should now be on for anti-anxiety drug candidates aimed at restoring the brain’s serotonin receptor transport service.
Lightning May Trigger Migraine Headaches
Migraine sufferers know that a variety of influences—everything from stress to hunger to a shift in the weather—can trigger a dreaded headache. A new study published in the journal Cephalalgia, though, suggests that another migraine trigger could be an unexpected atmospheric condition—a bolt of lightning.
As part of the study, Geoffrey Martin of the University of Cincinnati and colleagues from elsewhere asked 90 chronic migraine sufferers in Ohio and Missouri to keep detailed daily diaries documenting when they experienced headaches for three to six months. Afterward, they looked back over this period and analyzed how well the occurrence of headaches correlated with lightning strikes within 25 miles of the participants’ houses, along with other weather factors such as temperature and barometric pressure.
Their analysis found that there was a 28 precent increased chance of a migraine and a 31 precent chance of a non-migraine (i.e. less severe) headache on days when lightning struck nearby. Since lightning usually occurs during thunderstorms, which bring a host of other weather events—notable changes in barometric pressure—they used mathematical models to parse the related factors and found that even in the absence of other thunderstorm-related elements, lightning alone caused a 19 percent increased chance of headaches.
Despite these results, it’s probably a bit premature to argue that lightning is a definitive trigger of migraines. For one, a number of previous studies have explored the links between weather and migraine headaches, and the results have been unclear. Some have suggested that high pressure increases the risk of headaches, while others have indicated that low pressure increases the risk as well. Other previous studies, in fact, have failed to find a link between migraines and lightening, in particular.
Understanding the Chemical Mechanism Behind Antidepressants
Millions of Americans take antidepressants such as Prozac, Effexor, and Paxil, but the explanations for how they work never satisfied René Hen, a professor of psychiatry, neuroscience and pharmacology.
So the French-born researcher began a series of experiments a decade ago that are now helping to overturn conventional wisdom about the class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs) and providing new insights into the biological mechanisms in the brain that affect mood and cognition.
Adult-born neurons in the hippocampus have been engineered to express channelrhodopsin (red), a protein that allows the activation of these neurons and the study of their impact on pattern separation and mood. (Image credit: Mazen Kheirbek and René Hen)
SSRIs, it has long been thought, work by inhibiting brain cells from reabsorbing serotonin, a signaling agent in the brain associated with positive mood. Yet unlike with psychoactive substances, the effects of the drugs take weeks to be felt—even though the increase in serotonin circulating in the brain begins almost immediately. Something more, Hen concluded, must be happening after that to create such a profound effect in depressed patients.
In 2003, Hen demonstrated an important finding in mice: The change in mood—measured by the amount of time it took the animals to overcome anxiety and feed in new environments—appeared to be due in part to the production of new brain cells in the hippocampus, an area of the brain associated with learning and memory. And those new brain cells, Hen thinks, are the result of growth-stimulating chemicals released in the brain, in response to the increased serotonin.
Last year, Hen published another groundbreaking study, suggesting how these new brain cells might affect mood. The new brain cells are located in the dentate gyrus, an area of the hippocampus involved in pattern separation, a cognitive process that helps us to recognize that something is new and different from similar experiences and stimuli. This information is then sent to other brain regions where the new stimulus is assigned a positive or negative emotional value.
Using genetic manipulations that block or enhance the production of brain cells in the dentate gyrus, Hen demonstrated that the new brain cells led to a marked improvement not just in the cognitive abilities of mice, but also in their mood. “What we think, even though it hasn’t been proven yet, is that some depressed human patients also have a problem with pattern separation,” Hen says. “What we are hoping is, if we can boost production of new neurons in their hippocampus, maybe we can improve pattern separation in patients and decrease general symptoms.”
Hen sees numerous ways that a disruption in pattern separation might lead to negative emotions such as anxiety and depression. The hippocampus is located next to, and is strongly linked with, another brain structure, the almond-shaped amygdala, thought to be the seat of our emotions.
If wrong judgments were assigned to novel stimuli in the amygdala, that could easily trigger the brain’s fight-or-flight instinct or, at the very least, produce fear. That might help explain features of anxiety disorders—why survivors of the 9/11 terrorist attacks suffering from post-traumatic stress disorder, for instance, might be hit with a panic attack whenever they see an airplane fly over a skyscraper, Hen says.
A deficit in pattern separation might also help explain why depressed patients often are unable to experience pleasure, exhibit a lack of interest in novel experiences, and feel profound malaise. Perhaps they are simply unable to register an experience as novel or pleasurable because they are unable to recognize it as sufficiently different from prior experiences.
Hen is quick to point out that new brain cell production in the hippocampus is just one effect of a cascade of neurochemical changes unleashed by SSRIs. Other researchers have demonstrated, among other things, that the drugs also have a strong impact on the prefrontal cortex, the area of the brain associated with executive functions such as decision-making and restraint.
Even so, Hen hopes his findings will have significant implications for some depressed patients—and perhaps even reveal why certain antidepressants work for some people and not others. Over the next several years, he plans to explore his hypotheses further by evaluating the pattern-separation abilities of depressed patients before and after they are treated with SSRIs.
“There is still a long way to go, but we are at least starting to provide a theoretical framework,” Hen says. “With complex disorders such as anxiety and depression, you are dealing with many parts of the brain. We think we have identified the biological basis for one of the symptoms present in a subgroup of patients, and maybe by targeting it, we will be able to help them.”
(Source: news.columbia.edu)
Probing the roots of depression by tracking serotonin regulation at a new level
June 28, 2012
In a process akin to belling an infinitesimal cat, scientists have managed to tag a protein that regulates the neurotransmitter serotonin with tiny fluorescent beads, allowing them to track the movements of single molecules for the first time.
This is a microphotograph of neurons with their serotonin transporter protein labeled with red quantum dots. Credit: Jerry Chang, Vanderbilt University
The capability, which took nearly a decade to achieve, makes it possible to study the dynamics of serotonin regulation at a new level of detail, which is important because of the key role that serotonin plays in the regulation of mood, appetite and sleep.
The achievement was reported by an interdisciplinary team of Vanderbilt scientists in the June 27 issue of the Journal of Neuroscience.
The regulatory protein that the scientists successfully tagged is known as the serotonin transporter. This is a protein that extends through the membrane that forms the nerve’s outer surface and acts like a nano-sized vacuum cleaner that sucks serotonin molecules into the cell body and away from serotonin target receptors on other cells. In this fashion it helps regulate the concentration of serotonin in the area around the cell. Serotonin transporters are an important research subject because they are the target for the most common drugs used to treat depression, including Prozac, Paxil and Lexapro.
"If you are interested in mental health, then serotonin transporters are an ideal subject," said Sandra Rosenthal, the Jack and Pamela Egan Chair of Chemistry, who directed the study with Randy Blakely, the Allan D. Bass Professor of Pharmacology and Psychiatry.
Problems with serotonin transporter regulation have also been implicated in autism. Two years ago, Blakely and geneticist James Sutcliffe, associate professor of molecular physiology and biophysics, reported the discovery of multiple changes in the serotonin transporter protein that cause the transporter to become “overactive” in subjects with autism. Recently, Blakely and Assistant Professor of Psychiatry Jeremy Veenstra-VanderWeele reported that mice expressing one of these high-functioning transporters exhibit multiple behavioral changes that resemble changes seen in kids with autism.
The brain’s other key neurotransmitters have their own transporter proteins, so scientists can use the capability to track the motion of individual transporter molecules to determine how they are regulated as well.
Attempts to understand how these transporters work have been limited by the difficulty of studying their dynamic behavior. “In the past, we have been limited to snapshots that show the location of transporter molecules at a specific time,” said chemistry graduate student Jerry Chang, who developed the tagging technique. “Now we can follow their motion on the surface of cells in real time and see how their movements relate to serotonin uptake activity.”
The fluorescent tags that the researchers used are nanoscale beads called quantum dots made from a mixture of cadmium and selenium. These beads are only slightly bigger than the proteins they are tagging: You would have to string 10,000 together to span the width of a human hair.
Quantum dots emit colored light when illuminated and have the useful property that small changes in their size cause them to glow in different colors. Team member Ian D. Tomlinson, assistant research professor of chemistry, developed a special molecular string that attaches to the quantum dot at one end and, on the other end, attaches to a drug derivative that binds exclusively with the serotonin transporter. When a mixture that contains these quantum dots is incubated with cultured nerve cells, the drug attaches to the transporter. As the protein moves around, it drags the quantum dot behind it like a child holding a balloon on a string. When the area is illuminated, the quantum dots show up in a microscope as colored points of light.
"Until now, neurobiologists have had to rely on extremely low resolution approaches where it takes the signals coming from thousands to millions of molecules to be detected," said Blakely, "We really had no idea exactly what we were going to see."
Putting their new procedure to use, the researchers looked at extensions of the nerve cell that are involved in secreting serotonin on the presumption that transporters would be localized there as well. From previous research, the investigators suspected that the transporters would be concentrated in cholesterol-rich parts of these extensions, termed rafts, although the level of resolution with standard approaches was inadequate to provide any clues as to what they were doing there.
The quantum dot studies demonstrated that there were two distinct populations of transporters in these areas: Those that can travel freely around the membrane and those that act as if they are unable to move. They found that the immobile transporters were located in the rafts. When they stimulated the cell to increase transporter activity, they were surprised at what happened. “We found that the transporters in the rafts began to move much faster whereas the motion of the other population didn’t change at all,” Rosenthal reported. Since the mobilized transporters do not leave the rafts, they appear to whizz around inside a confined compartment, as if released from chains that normally keep them subdued. These observations suggest it is likely that the two populations are controlled by different regulatory pathways.
"Now that we can watch transporter regulation actually happening, we should be able to figure out the identity of the anchoring proteins and the signals these proteins respond to that permit transporters to switch back and forth between low and high activity levels," said Blakely.
"Currently, antidepressant drugs must fully shut down the brain’s serotonin transporters to achieve a clinical benefit," the pharmacologist said. Such a manipulation can produce a number of unpleasant side-effects, such as nausea, weight gain, sexual problems, fatigue and drowsiness.
"By understanding the basic mechanisms that naturally turn serotonin transporter activity up and down, maybe we can develop medications that produce milder side-effects and have even greater efficacy," he said. "Our sights are also focused on transferring what we have learned with normal serotonin transporters to an understanding of the hyperactive transporters we have found in kids with autism.”
Provided by Vanderbilt University
Source: medicalxpress.com
Early Gut Bacteria Regulate Happiness
ScienceDaily (June 12, 2012) — UCC scientists have shown that brain levels of serotonin, the ‘happy hormone’ are regulated by the amount of bacteria in the gut during early life. Their research is being published June 12 in the international psychiatry journal, Molecular Psychiatry.
Happy children. UCC scientists have shown that brain levels of serotonin, the ‘happy hormone’ are regulated by the amount of bacteria in the gut during early life. (Credit: © Marzanna Syncerz / Fotolia)
This research shows that normal adult brain function depends on the presence of gut microbes during development. Serotonin, the major chemical involved in the regulation of mood and emotion, is altered in times of stress, anxiety and depression and most clinically effective antidepressant drugs work by targeting this neurochemical.
Scientists at the Alimentary Pharmabiotic Centre in UCC used a germ-free mouse model to show that the absence of bacteria during early life significantly affected serotonin concentrations in the brain in adulthood. The research also highlighted that the influence is sex dependent, with more marked effects in male compared with female animals. Finally, when the scientists colonized the animals with bacteria prior to adulthood, they found that many of the central nervous system changes, especially those related to serotonin, could not be reversed indicating a permanent imprinting of the effects of absence of gut flora on brain function.
This builds on earlier work, from the Cork group and others, showing that a microbiome-gut-brain axis exists that is essential for maintaining normal health which can affect brain and behavior. The research was carried out by Dr Gerard Clarke, Professor Fergus Shanahan, Professor Ted Dinan and Professor John F Cryan and colleagues at the Alimentary Pharmabiotic Centre in UCC.
"As a neuroscientist these findings are fascinating as they highlight the important role that gut bacteria play in the bidirectional communication between the gut and the brain, and opens up the intriguing opportunity of developing unique microbial-based strategies for treatment for brain disorders," said Professor John F Cryan, senior author on the publication and Head of the Department of Anatomy & Neuroscience at UCC.
This research has multiple health implications as it shows that manipulations of the microbiota (e.g. by antibiotics, diet, or infection) can have profound knock-on effects on brain function. “We’re really excited by these findings” said lead author Dr Gerard Clarke. “Although we always believed that the microbiota was essential for our general health, our results also highlight how important our tiny friends are for our mental wellbeing.”
Source: Science Daily