In asthma, the airways become hyperresponsive. Researchers from Uppsala University have found a new mechanism that contributes to, and explains, airway hyperresponsiveness. The results are published in the scientific journal Allergy.
Some 10 per cent of Sweden’s population suffer from asthma. In asthmatics, the airways are hyperresponsive (overreactive) to various types of stimuli, such as cold air, physical exertion and chemicals. The airways become constricted, making breathing difficult.
To diagnose asthma, a “methacholine test” is commonly used to determine whether a person is showing signs of airway hyperresponsiveness. Methacholine binds to what are known as muscarinic receptors in the smooth muscle cells lining the inside of the trachea. These muscle cells then begin to contract, causing constriction of the trachea.
In the new study, the scientists show that the airway hyperresponsiveness induced by methacholine is due partly to the body’s mast cells. The research was conducted using a mouse model of asthma, where the mice were made allergic to house dust mites.
Mast cells, which are immune cells of a specific type belonging to the innate immune system, are found mainly in tissues that are in contact with the external environment, such as the airways and the skin. Because of their location and the fact that they have numerous different receptors capable of recognising parts of foreign or pathogenic substances, they react quickly and become activated. In their cytoplasm, mast cells have storage capsules, known as granules, in which some substances are stored in their active form. When the mast cell is activated, these substances can be rapidly released and provoke a physiological reaction. This plays a major part in the body’s defence against pathogens, but in asthma and other diseases where the body starts reacting against harmless substances in the environment, it becomes a problem.
In their study, the researchers were able to demonstrate that the mast cells contribute to airway hyperresponsiveness by having a receptor that recognises methacholine: muscarinic receptor-3 (M3). When methacholine binds M3, the mast cells release serotonin. This then acts on nerve cells, which in turn control the airways. Thereafter, the airways produce acetylcholine, which also acts on M3 in smooth muscle cells and makes the trachea contract even more. A vicious cycle is under way.
The scientists’ discovery also means that drugs like tiotropium, which were previously thought to work solely by blocking M3 in smooth muscle, are probably also efficacious because they prevent activation through M3 in mast cells. Accordingly, the ability of mast cells to rapidly release serotonin in response to various stimuli, thereby contributing to airway hyperresponsiveness, has been underestimated.
Reference: Mendez-Enriquez E, Alvarado-Vazquez PA, Abma W, Simonson OE, Rodin S, Feyerabend TB, Rodewald HR, Malinovschi A, Janson C, Adner M and Hallgren J. Mast cell-derived serotonin enhances methacholine-induced airway hyperresponsiveness in house dust mite-induced experimental asthma. Allergy. 2021 doi: 10.1111/all.14748
Researchers at the University of Tsukuba in Japan find that normal sleep in mice depends on bacteria that help make neurotransmitters such as serotonin in the gut.
With fall and winter holidays coming up, many will be pondering the relationship between food and sleep. Researchers led by Professor Masashi Yanagisawa at the University of Tsukuba in Japan hope they can focus people on the important middlemen in the equation: bacterial microbes in the gut. Their detailed study in mice revealed the extent to which bacteria can change the environment and contents of the intestines, which ultimately impacts behaviors like sleep.
The experiment itself was fairly simple. The researchers gave a group of mice a powerful cocktail of antibiotics for four weeks, which depleted them of intestinal microorganisms. Then, they compared intestinal contents between these mice and control mice who had the same diet. Digestion breaks food down into bits and pieces called metabolites. The research team found significant differences between metabolites in the microbiota-depleted mice and the control mice. As Professor Yanagisawa explains, “we found more than 200 metabolite differences between mouse groups. About 60 normal metabolites were missing in the microbiota-depleted mice, and the others differed in the amount, some more and some less than in the control mice.”
The team next set out to determine what these metabolites normally do. Using metabolome set enrichment analysis, they found that the biological pathways most affected by the antibiotic treatment were those involved in making neurotransmitters, the molecules that cells in the brain use to communicate with each other. For example, the tryptophan–serotonin pathway was almost totally shut down; the microbiota-depleted mice had more tryptophan than controls, but almost zero serotonin. This shows that without important gut microbes, the mice could not make any serotonin from the tryptophan they were eating. The team also found that the mice were deficient in vitamin B6 metabolites, which accelerate production of the neurotransmitters serotonin and dopamine.
The team also analyzed how the mice slept by looking at brain activity in EEGs. They found that compared with the control mice, the microbiota-depleted mice had more REM and non-REM sleep at night—when mice are supposed to be active—and less non-REM sleep during the day—when mice should be mostly sleeping. The number of REM sleep episodes was higher both during the day and at night, whereas the number of non-REM episodes was higher during the day. In other words, the microbiota-depleted mice switched between sleep/wake stages more frequently than the controls.
Professor Yanagisawa speculates that the lack of serotonin was responsible for the sleep abnormalities; however, the exact mechanism still needs to be worked out. “We found that microbe depletion eliminated serotonin in the gut, and we know that serotonin levels in the brain can affect sleep/wake cycles,” he says. “Thus, changing which microbes are in the gut by altering diet has the potential to help those who have trouble sleeping.”
So, this holiday season, when you’re feeling sleepy after eating tryptophan-stuffed turkey, please don’t forget to thank your gut microbes!
References: Yukino Ogawa et al. Gut microbiota depletion by chronic antibiotic treatment alters the sleep/wake architecture and sleep EEG power spectra in mice, Scientific Reports (2020). DOI: 10.1038/s41598-020-76562-9 https://doi.org/10.1038/s41598-020-76562-9.
Serotonin keeps mice waiting longer for food, depending on where in the brain it’s released.
We’ve all been there. Whether we’re stuck in traffic at the end of a long day, or eagerly anticipating the release of a new book, film or album, there are times when we need to be patient. Learning to suppress the impulse for instant gratification is often vital for future success, but how patience is regulated in the brain remains poorly understood.
Now, in a study on mice conducted by the Neural Computation Unit at the Okinawa Institute of Science and Technology Graduate University (OIST), the authors, Dr. Katsuhiko Miyazaki and Dr. Kayoko Miyazaki, pinpoint specific areas of the brain that individually promote patience through the action of serotonin. Their findings were published 27th November in Science Advances.
“Serotonin is one of the most famous neuromodulators of behavior, helping to regulate mood, sleep-wake cycles and appetite,” said Dr. Katsuhiko Miyazaki. “Our research shows that release of this chemical messenger also plays a crucial role in promoting patience, increasing the time that mice are willing to wait for a food reward.”
Their most recent work draws heavily on previous research, where the unit used a powerful technique called optogenetics – using light to stimulate specific neurons in the brain – to establish a causal link between serotonin and patience.
The scientists bred genetically engineered mice which had serotonin-releasing neurons that expressed a light-sensitive protein. This meant that the researchers could stimulate these neurons to release serotonin at precise times by shining light, using an optical fiber implanted in the brain.
The researchers found that stimulating these neurons while the mice were waiting for food increased their waiting time, with the maximum effect seen when the probability of receiving a reward was high but when the timing of the reward was uncertain.
“In other words, for the serotonin to promote patience, the mice had to be confident that a reward would come but uncertain about when it would arrive,” said Dr. Miyazaki.
In the previous study, the scientists focused on an area of the brain called the dorsal raphe nucleus – the central hub of serotonin-releasing neurons. Neurons from the dorsal raphe nucleus reach out into other areas of the forebrain and in their most recent study, the scientists explored specifically which of these other brain areas contributed to regulating patience.
The team focused on three brain areas that had been shown to increase impulsive behaviors when they were damaged – a deep brain structure called the nucleus accumbens, and two parts of the frontal lobe called the orbitofrontal cortex and the medial prefrontal cortex.
“Impulse behaviors are intrinsically linked to patience – the more impulsive an individual is, the less patient – so these brain areas were prime candidates,” explained Dr. Miyazaki.
Good things come to those who wait (or not…)
In the study, the scientists implanted optical fibers into the dorsal raphe nucleus and also one of either the nucleus accumbens, the orbitofrontal cortex, or the medial prefrontal cortex.
The researchers trained mice to perform a waiting task where the mice held with their nose inside a hole, called a “nose poke”, until a food pellet was delivered. The scientists rewarded the mice in 75% of trials. In some test conditions, the timing of the reward was fixed at six or ten seconds after the mice started the nose poke and in other test conditions, the timing of the reward varied.
In the remaining 25% of trials, called the omission trials, the scientists did not provide a food reward to the mice. They measured how long the mice continued performing the nose poke during omission trials – in other words, how patient they were – when serotonin-releasing neurons were and were not stimulated.
When the researchers stimulated serotonin-releasing neural fibers that reached into the nucleus accumbens, they found no increase in waiting time, suggesting that serotonin in this area of the brain has no role in regulating patience.
But when the scientists stimulated serotonin release in the orbitofrontal cortex and the medial prefrontal cortex while the mice were holding the nose poke, they found the mice waited longer, with a few crucial differences.
In the orbitofrontal cortex, release of serotonin promoted patience as effectively as serotonin activation in the dorsal raphe nucleus; both when reward timing was fixed and when reward timing was uncertain, with stronger effects in the latter.
But in the medial prefrontal cortex, the scientists only saw an increase in patience when the timing of the reward was varied, with no effect observed when the timing was fixed.
“The differences seen in how each area of the brain responded to serotonin suggests that each brain area contributes to the overall waiting behavior of the mice in separate ways,” said Dr. Miyazaki.
To investigate this further, the scientists constructed a computational model to explain the waiting behavior of the mice.
The model assumes that the mice have an internal model of the timing of reward delivery and keep estimating the probability that a reward will be delivered. They can therefore judge over time whether they are in a reward or non-reward trial and decide whether or not to keep waiting. The model also assumes that the orbitofrontal cortex and the medial prefrontal cortex use different internal models of reward timing, with the latter being more sensitive to variations in timing, to calculate reward probabilities individually.
The researchers found that the model best fitted the experimental data of waiting time by increasing the expected reward probability from 75% to 94% under serotonin stimulation. Put more simply, serotonin increased the mice’s belief that they were in a reward trial, and so they waited longer.
Importantly, the model showed that stimulation of the dorsal raphe nucleus increased the probability from 75% to 94% in both the orbital frontal cortex and the medial prefrontal cortex, whereas stimulation of the brain areas separately only increased the probability in that particular area.
“This confirmed the idea that these two brain areas are calculating the probability of a reward independently from each other, and that these independent calculations are then combined to ultimately determine how long the mice will wait,” explained Dr. Miyazaki. “This sort of complementary system allows animals to behave more flexibly to changing environments.”
Ultimately, increasing our knowledge of how different areas of the brain are more or less affected by serotonin could have vital implications in future development of drugs. For example, selective serotonin reuptake inhibitors (SSRIs) are drugs that boost levels of serotonin in the brain and are used to treat depression.
“This is an area we are keen to explore in the future, by using depression models of mice,” said Dr. Miyazaki. “We may find under certain genetic or environmental conditions that some of these identified brain areas have altered functions. By pinning down these regions, this could open avenues to provide more targeted treatments that act on specific areas of the brain, rather than the whole brain.”
References: Katsuhiko Miyazaki, Kayoko W. Miyazaki, Gaston Sivori, Akihiro Yamanaka, Kenji F. Tanaka, Kenji Doya, “Serotonergic projections to the orbitofrontal and medial prefrontal cortices differentially modulate waiting for future rewards”, Science Advances 27 Nov 2020: Vol. 6, no. 48, eabc7246 DOI: 10.1126/sciadv.abc7246
The temperatures are dropping, the leaves are changing, and the days are becoming shorter—all of these changes from summer to fall means that winter is just around the corner. Many individuals look forward to winter because of the holidays and the beauty of the snowfall. For others, the change from summer to fall can be trigger depression. The “winter blues” can be just around the corner.
What is SAD?
Seasonal affective disorder (SAD) or seasonal depression is a type of depression that comes with the seasons. Seasonal affective disorder is most common during the winter months, but oddly enough, it also appears in the summer, just not nearly as prevalent. According to research, “A small share of people with SAD show the reverse pattern, being sensitive to summer’s longer days. The very existence of opposite winter-summer patterns suggested to researchers that this mood disorder stems from a problem in adapting to the physical environment”.
Individuals with seasonal affective disorder must meet major depressive disorder criteria with symptoms coinciding with the specific seasons and lasting for at least two years.
Who is at risk for developing SAD?
Researchers believed that SAD’s typical appearance in the winter had a high correlation with the lower exposure to light. The obvious next step was to lengthen exposure to light intensity to mimic the outdoors. By 1998, researchers were studying light treatment variations as a treatment for SAD.
Individuals who live further from the Equator are more at risk for developing seasonal affective disorder than individuals who live closer to the Equator. One percent of individuals who live in Florida have SAD, whereas nine percent of individuals who live in Alaska have SAD. Females are more at risk of developing SAD compared to males, and individuals who have a history of depression or bipolar disorder are also at an increased risk for developing SAD. Individuals who have an increased level of melatonin and decreased serotonin and vitamin D levels are also at a higher risk for developing SAD.
“Sunlight plays a critical role in the decreased serotonin activity, increased melatonin production, disrupted circadian rhythms, and low levels of Vitamin D associated with symptoms of SAD,” according to a study published in Depression Resistant Treatment.
Light therapy to treat seasonal depression
Not any type of bright light is known to treat individuals with SAD. There are certain light therapy boxes, which filter out UV light that are used to treat SAD. Lightboxes that have UV rays are used to treat certain skin disorders. Below are key points to keep in mind when using phototherapy to treat your seasonal affective depression.
• Use a lightbox that is 10,000 lux, which is 20 times the strength of typical indoor lighting. • You can order a lightbox online. • Use a lightbox that blocks out 99% of UV rays. • Position the lightbox above your head to mimic natural outdoor lighting. • Use the lightbox in the morning for 20 to 60 minutes. • Use the lightbox daily from early fall through winter. • Ask your doctor about using your lightbox if you are on certain medications that cause photosensitivity. • Monitor your mood weekly by journaling about your emotions to assess whether light therapy is working. • Phototherapy should also be combined with other therapeutic approaches such as cognitive behavioral therapy and anti-depressants if you do not see an improvement in your mood.
This article is originally written by Kristen Fuller, M.D., is a physician and a clinical mental health writer for Center For Discovery.
Serotonin can act as a growth factor for the stem cells in the fetal human brain that determine brain size.
During human evolution, the size of the brain increased, especially in a particular part called the neocortex. The neocortex enables us to speak, dream and think. In search of the causes underlying neocortex expansion, researchers at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, together with colleagues at the University Hospital Carl Gustav Carus Dresden, previously identified a number of molecular players. These players typically act cell-intrinsically in the so-called basal progenitors, the stem cells in the developing neocortex with a pivotal role in its expansion. The researchers now report an additional, novel role of the happiness neurotransmitter serotonin which is known to function in the brain to mediate satisfaction, self-confidence and optimism – to act cell-extrinsically as a growth factor for basal progenitors in the developing human, but not mouse, neocortex. Due to this new function, placenta-derived serotonin likely contributed to the evolutionary expansion of the human neocortex.
The research team of Wieland Huttner at the Max Planck Institute of Molecular Cell Biology and Genetics, who is one of the institute’s founding directors, has investigated the cause of the evolutionary expansion of the human neocortex in many studies. A new study from his lab focuses on the role of the neurotransmitter serotonin in this process. Serotonin is often called the happiness neurotransmitter because it transmits messages between nerve cells that contribute to well-being and happiness. However, a potential role of such neurotransmitters during brain development has not yet been explored in detail. In the developing embryo, the placenta produces serotonin, which then reaches the brain via the blood circulation. This is true for humans as well as mice. Yet, the function of this placenta-derived serotonin in the developing brain has been unknown.
The postdoctoral researcher Lei Xing in the Huttner group had studied neurotransmitters during his doctoral work in Canada. When he started his research project in Dresden after that, he was curious to investigate their role in the developing brain. Lei Xing says: “I exploited datasets generated by the group in the past and found that the serotonin receptor HTR2A was expressed in fetal human, but not embryonic mouse, neocortex. Serotonin needs to bind to this receptor in order to activate downstream signaling. I asked myself if this receptor could be one of the keys to the question of why humans have a bigger brain.” To explore this, the researchers induced the production of the HTR2A receptor in embryonic mouse neocortex. “Indeed, we found that serotonin, by activating this receptor, caused a chain of reactions that resulted in the production of more basal progenitors in the developing brain. More basal progenitors can then increase the production of cortical neurons, which paves the way to a bigger brain”, continues Lei Xing.
Significance for brain development and evolution
“In conclusion, our study uncovers a novel role of serotonin as a growth factor for basal progenitors in highly developed brains, notably human. Our data implicate serotonin in the expansion of the neocortex during development and human evolution”, summarizes Wieland Huttner, who supervised the study. He continues: “Abnormal signaling of serotonin and a disturbed expression or mutation of its receptor HTR2A have been observed in various neurodevelopmental and psychiatric disorders, such as Down syndrome, attention deficit hyperactivity disorder and autism. Our findings may help explain how malfunctions of serotonin and its receptor during fetal brain development can lead to congenital disorders and may suggest novel approaches for therapeutic avenues.”
Anyone who has experienced “butterflies in the stomach” before giving a big presentation will be unsurprised to learn there is a physical connection between their gut and their brain. Neuroscientists and medical professionals call this connection the “gut-brain axis” (GBA); a better understanding of the GBA could lead to the development of treatments and cures for neurological disorders such as depression and anxiety, as well as for a range of chronic auto-immune inflammatory diseases such as irritable bowel syndrome (IBS) and rheumatoid arthritis.
Right now, these conditions and diseases are primarily diagnosed by patients’ reports of their symptoms. However, neuroscientists and doctors are investigating the GBA in order to find so-called “biomarkers” for these diseases. In the case of the GBA, that biomarker is likely serotonin.
By targeting this complex connection between the gut and the brain, researchers hope they can uncover the role of the gut microbiome in both gut and brain disorders. With an easily identifiable biomarker such as serotonin, there may be some way to measure how dysfunction in the gut microbiome affects the GBA signaling pathways. Having tools that could increase understanding, help with disease diagnosis, and offer insight into how diet and nutrition impacts mental health would be extremely valuable.
With $1 million in National Science Foundation funding, a team of University of Maryland experts from engineering, neuroscience, applied microbiology, and physics has been making headway on building a platform that can monitor and model the real-time processing of gut microbiome serotonin activity. Three new published papers detail the progress of the work, which includes innovations in detecting serotonin, assessing its neurological effects, and sensing minute changes to the gut epithelium.
In “Electrochemical Measurement of Serotonin by Au-CNT Electrodes Fabricated on Porous Cell Culture Membranes” (https://www.nature.com/articles/s41378-020-00184-4), the team developed a platform that provides access to the specific site of serotonin production. The platform included a porous membrane with an integrated serotonin sensor on which a model of the gut lining can be grown. This innovation allowed researchers to access both top and bottom sides of the cell culture–important because serotonin is secreted from the bottoms of cells. The work is the first to demonstrate a feasible method for detection of redox molecules, such as serotonin, directly on a porous and flexible cell culture substrate. It grants superior access to cell-released molecules and creates a controllable model gut environment to perform groundbreaking GBA research without the need to perform invasive procedures on humans or animals.
The team’s second paper, “A Hybrid Biomonitoring System for Gut-Neuron Communication” (https://ieeexplore.ieee.org/document/9123494), builds on the findings of the first: the researchers developed the serotonin measuring platform further so it could assess serotonin’s neurological effects. By adding and integrating a dissected crayfish nerve model with the gut lining model, the team created a gut-neuron interface that can electrophysiologically assess nerve response to the electrochemically detected serotonin. This advance enables the study of molecular signaling between gut and nerve cells, making possible real-time monitoring of both GBA tissues for the first time.
Finally, the concept, design, and use for the entire biomonitoring platform is described in a third paper, “3D Printed Electrochemical Sensor Integrated Transwell Systems” (https://www.nature.com/articles/s41378-020-00208-z). This paper delves into the development of the 3D-printed housing, the maintenance of a healthy lab-on-a-chip gut cell culture, and the evaluation of the two types of sensors integrated on the cell culture membrane. The dual sensors are particularly important because they provide feedback about multiple components of the system–namely, the portions that model the gut lining’s permeability (a strong indicator of disease) and its serotonin release (a measure of communication with the nervous system). Alongside the electrochemical sensor–evaluated using a standard redox molecule ferrocene dimethanol–an impedance sensor was used to monitor cell growth and coverage over the membrane. Using both these sensors would allow monitoring of a gut cell culture under various environmental and dietary conditions. It also would enable researchers to evaluate changes to barrier permeability (a strong indicator of disease), and serotonin release (a measure of communication with the nervous system).
Scientists at Wake Forest School of Medicine have recorded real time changes in dopamine and serotonin levels in the human brain that are involved with perception and decision-making. These same neurochemicals also are critical to movement disorders and psychiatric conditions, including substance abuse and depression.
Their findings are published in the Oct. 12 edition of the journal Neuron.
“This study provides us a unique window into the human brain that has been inaccessible until now,” said principal investigator Kenneth T. Kishida, Ph.D., assistant professor of physiology and pharmacology and neurosurgery at Wake Forest School of Medicine, part of Wake Forest Baptist Health. “Almost everything we have known mechanistically about these neurochemicals was from work done in preclinical animal models, not from direct evidence from humans.”
Having a clearer understanding of how these brain chemicals actually work in people may lead to improved medications or treatments for disorders like Parkinson’s disease, substance use disorder or depression, Kishida said.
In this observational study, the neurotransmitters dopamine and serotonin were tracked in five patients using fast scan cyclic voltammetry, an electrochemical technique used to measure dopamine and serotonin, adapted for use in patients. Dopamine and serotonin are chemical messengers used by the nervous system to regulate countless functions and processes in the body.
Study participants – two with Parkinson’s and three with essential tremor – were patients at Wake Forest Baptist who were scheduled to receive a deep brain stimulating implant to treat their condition. Working closely with neurosurgeons, Stephen B. Tatter, M.D., and Adrian W. Laxton, M.D., Kishida’s team was able to piggyback on the standard surgical mapping process to insert a carbon fiber microelectrode deep into the brain to detect and record serotonin and dopamine released from neurons. The patients with essential tremor were important to the study because, unlike Parkinson’s disease which is caused by loss of dopamine-producing neurons, essential tremor is not believed to be caused by changes in dopamine or serotonin function.
While the patients were awake in the operating room, they performed decision-making tasks similar to playing a simple computer game. As they performed the tasks, measurements of dopamine and serotonin were taken in the striatum, the part of the brain that controls cognition, reward and coordinated movements.
Kishida described the game as a series of dots on a computer screen that moved through a “cross-hair” reference point positioned in the center of the screen. Patients had to decide which way the dots were moving. Sometimes the dots would move in the same direction and at other times the dots would move more chaotically making the decision harder.
The dots then disappeared and the patient had to choose which way the dots had moved – clockwise or counter clockwise – relative to a fixed point. This experimental design, created by Kishida’s collaborators and co-authors Dan Bang and Stephen M. Fleming, at University College London, allowed the team to tease apart different aspects of how the human brain decides what it has perceived.
This sequence was repeated 200 to 300 times per patient, varying how the dots moved and thus how difficult it was for the patient to decide what they saw. Occasionally, the patients had to indicate how confident they were in their choices.
The test was designed to track the patient’s ability to perceive the dots’ movement and the patient’s confidence in correctly identifying the direction of that movement as a way to determine how dopamine and serotonin actually behaved. The trials were randomized so that predictability from one test trial to the next would be minimized, Kishida said.
The findings showed that the more uncertain the patient was about the direction of the dots, the higher the serotonin levels became. When their certainty increased, serotonin levels decreased.
The study also revealed that, prior to the act of choosing, dopamine rose in anticipation of the choice and serotonin levels fell, and when both reached a certain level, the person made their choice. It’s as if dopamine acted like a gas pedal and serotonin acted like a brake and only when both systems were committed was the act of choice (a button press) allowed, Kishida said.
“This study sheds light on the role these neurochemicals play in learning, brain plasticity and how we perceive the environment,” Kishida said. “We now have more detailed insight into how our brains build what we perceive, use those perceptions to make decisions, and interpret the consequences of the choices we make. Dopamine and serotonin appear to be critical in all of these processes.
“Importantly, studies like this will help us and other scientists develop a better understanding of how drugs or medications like serotonin reuptake inhibitors affect cognition, decision-making, and impact psychiatric conditions like depression.”