Gut microbes: a key to normal sleep

November 30, 2020

Science Daily/University of Tsukuba

Researchers used a cocktail of antibiotics to deplete gut microbes in mice. They found that metabolites in the gut differed in these mice compared with controls. In particular, metabolic pathways involved in making important neurotransmitters like serotonin were affected. Additionally, these mice showed abnormal day-night distribution in sleep/wake patterns, particularly the amount of REM sleep, and frequent transitions between REM and non-REM sleep episodes.

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!

https://www.sciencedaily.com/releases/2020/11/201130113532.htm

Everyday activities enhance personal well-being

November 25, 2020

Science Daily/Karlsruher Institut für Technologie (K

Physical activity makes happy and is important to maintain psychic health. Researchers of Karlsruhe Institute of Technology (KIT) and the Central Institute of Mental Health (CIMH) in Mannheim studied the brain regions which play a central role in this process. Their findings reveal that even everyday activities, such as climbing stairs, significantly enhance well-being, in particular of persons susceptible to psychiatric disorders. The study is published in Science Advances.

Exercise enhances physical well-being and mental health. However, impacts of everyday activities, such as climbing stairs, walking, or going to the tram station instead of driving, on a person's mental health have hardly been studied so far. For example, it is not yet clear which brain structures are involved. A team of the Central Institute of Mental Health (CIMH) in Mannheim, KIT's Institute of Sports and Sports Science, and the GIScience / Geoinformatics Research Group of Heidelberg University has now studied everyday activities that make up the highest share of our daily exercise. "Climbing stairs every day may help us feel awake and full of energy. This enhances well-being," the study's first authors explain. These are Dr. Markus Reichert who conducts research at CIMH and KIT and Dr. Urs Braun, Head of the Complex Systems Research Group of the Psychiatry and Psychotherapy Clinic of CIMH.

The research findings are of particular relevance in the current situation with Corona restrictions and the coming winter. "Currently, we are experiencing strong restrictions of public life and social contacts, which may adversely affect our well-being," Professor Heike Tost, Head of the Systems Neuroscience Psychiatry Research Group of the Psychiatry and Psychotherapy Clinic, says. "To feel better, it may help to more often climb stairs."

Everyday Activities Enhance Alertness and Physical Energy 

"For our studies, we newly combined various research methods in everyday life and at the laboratory," says Professor Ulrich Ebner-Priemer, Head of the mHealth Methods in Psychiatry Research Group, Deputy Head of IfSS, and Head of the Mental mHealth Lab of KIT. Among the methods used were ambulant assessments with movement sensors as well as smartphone surveys on the well-being that were triggered by geolocation data as soon as the subjects moved.

67 persons were subjected to ambulant assessments to determine the impact of everyday activity on alertness for seven days. It was found that the persons felt more alert and were bursting with even more energy directly after the activity. Alertness and energy were proved to be important components of well-being and psychic health of the participants.

Brain Regions for Everyday Activities and Well-being Identified

These analyses were combined with magnetic resonance tomography at CIMH for another group of 83 persons. The volume of gray brain matter was measured to find out which brain areas play a role in these everyday processes. It was found that the subgenual cingulate cortex, a section of the cerebral cortex, is important to the interaction between everyday activity and affective well-being. It is in this brain region where emotions and resistance to psychiatric disorders are regulated. The authors identified this brain region to be a decisive neural correlate that mediates the relationship between physical activity and subjective energy. "Persons with a smaller volume of gray brain matter in this region and a higher risk of psychiatric disorders felt less full of energy when they were physically inactive," Heike Tost describes the results. "After everyday activity, however, these persons felt even more filled with energy than persons with a larger brain volume."

Specific Use of Physical Activity in Everyday Life

Professor Andreas Meyer-Lindenberg, Director of CIMH and Medical Director of the Psychiatry and Psychotherapy Clinic, concludes that "the results suggest that physical activity in everyday life is beneficial to well-being, in particular in persons susceptible to psychiatric disorders." In future, the findings of the study might be used in a smartphone app that will motivate users to be active to enhance their well-being in case of decreasing energy." It remains to be studied whether everyday activities may change the well-being and the brain volume and how these results may help prevent and treat psychiatric disorders," Urs Braun says.

https://www.sciencedaily.com/releases/2020/11/201125104348.htm

High blood pressure in midlife is linked to increased brain damage in later life

November 25, 2020

Science Daily/European Society of Cardiology

Higher than normal blood pressure is linked to more extensive brain damage in the elderly, according to a new study published today (Thursday) in the European Heart Journal.

In particular, the study found that there was a strong association between diastolic blood pressure (the blood pressure between heart beats) before the age of 50 and brain damage in later life, even if the diastolic blood pressure was within what is normally considered to be a healthy range.

The findings come from a study of 37,041 participants enrolled in UK Biobank, a large group of people recruited from the general population aged between 40 and 69 years, and for whom medical information, including MRI brain scans was available.

The research, carried out by Dr Karolina Wartolowska, a clinical research fellow at the Centre for Prevention of Stroke and Dementia, University of Oxford, UK, looked for damage in the brain called "white matter hyperintensities" (WMH). These show up on MRI brain scans as brighter regions and they indicate damage to the small blood vessels in the brain that increases with age and blood pressure. WMH are associated with an increased risk of stroke, dementia, physical disabilities, depression and a decline in thinking abilities.

Dr Wartolowska said: "Not all people develop these changes as they age, but they are present in more than 50% of patients over the age of 65 and most people over the age of 80 even without high blood pressure, but it is more likely to develop with higher blood pressure and more likely to become severe."

Information on the participants was collected when they enrolled in UK Biobank between March 2006 and October 2010, and follow-up data, including MRI scans, were acquired between August 2014 and October 2019. The researchers adjusted the information to take account of factors such as age, sex, risk factors such as smoking and diabetes, and diastolic as well as systolic blood pressure. Systolic blood pressure is the maximum blood pressure reached each time the heart beats and is the top number in blood pressure measurements.

"To compare the volume of white matter hyperintensities between people and to adjust the analysis for the fact that people's brains vary slightly in size, we divided the volume of WMH by the total volume of white matter in the brain. In that way, we could analyse the WMH load, which is the proportion of the WMH volume to the total volume of white matter," said Dr Wartolowska.

The researchers found that a higher load of WMH was strongly associated with current systolic blood pressure, but the strongest association was for past diastolic blood pressure, particularly when under the age of 50. Any increase in blood pressure, even below the usual treatment threshold of 140 mmHg for systolic and below 90 mmHg for diastolic, was linked to increased WMH, especially when people were taking medication to treat high blood pressure.*

For every 10mmHg increase in systolic blood pressure above the normal range, the proportion of WMH load increased by an average (median) of 1.126-fold and by 1.106-fold for every 5mmHg increase in diastolic blood pressure. Among the top 10% of people with the greatest WMH load, 24% of the load could be attributed to having a systolic blood pressure above 120mmHg, and 7% could be attributed to having diastolic blood pressure above 70mmHg, which reflects the fact that there is a greater incidence of elevated systolic rather than diastolic blood pressure in older patients.

Dr Wartolowska said: "We made two important findings. Firstly, the study showed that diastolic blood pressure in people in their 40s and 50s is associated with more extensive brain damage years later. This means that it is not just the systolic blood pressure, the first, higher number, but the diastolic blood pressure, the second, lower number, that is important to prevent brain tissue damage. Many people may think of hypertension and stroke as diseases of older people, but our results suggest that if we would like to keep a healthy brain well into our 60s and 70s, we may have to make sure our blood pressure, including the diastolic blood pressure, stays within a healthy range when we are in our 40s and 50s.

"The second important finding is that any increase in blood pressure beyond the normal range is associated with a higher amount of white matter hyperintensities. This suggests that even slightly elevated blood pressure before it meets the criteria for treating hypertension has a damaging effect on brain tissue.

"Our results suggest that to ensure the best prevention of white matter hyperintensities in later life, control of diastolic blood pressure, in particular, may be required in early midlife, even for diastolic blood pressure below 90mmHg, whilst control of systolic blood pressure may be more important in late life. The long time interval between the effects of blood pressure in midlife and the harms in late life emphasises how important it is to control blood pressure long-term, and that research has to adapt to consider the very long-term effects of often asymptomatic problems in midlife."

Potential mechanisms for the development of WMH include damage to the delicate blood vessels in the brain through sustained elevated pressures over time that directly cause damage to the blood vessels; this leads to the lining of the vessels becoming leaky and results in WMH. Alternatively, diastolic pressure might cause large blood vessels to become stiffer with time, which increases pulsations of blood pressure to the brain; this causes high blood pressure with each heart beat, rapid changes in blood pressure, and blood flow that is too low between heart beats, resulting in damage to white matter.

As MRI scans were only available at one time point, the researchers could not quantify the progression of WMH directly. Other limitations include that further analysis is needed to identify differences in different regions of white matter, and that although the researchers showed associations with smoking and diabetes, the potential complex interaction between risk factors, which also include high cholesterol levels, obesity and kidney problems, require further investigation.

Notes: 

* Patients with a 'low normal' blood pressure of 120/70mmHg were used as the 'reference group' with whom the researchers compared the other groups of patient in this analysis. Consistent with most guidelines, the researchers referred to people with blood pressure over 140/90 mmHg as 'hypertensive' and requiring treatment, and those between 140/90 and 130/80 mmHg as 'pre-hypertensive'. People with blood pressure below the pre-hypertensive values were referred to as 'high normotensive' and those with values below 120/70 as 'low normotensive'.

https://www.sciencedaily.com/releases/2020/11/201125190737.htm

Social isolation during COVID-19 pandemic linked with high blood pressure

November 19, 2020

Science Daily/European Society of Cardiology

Lockdown due to the COVID-19 pandemic is associated with an increase in high blood pressure among patients admitted to emergency. That's the finding of a study presented at the 46th Argentine Congress of Cardiology (SAC).

SAC 2020 is a virtual meeting during 19 to 21 November. Faculty from the European Society of Cardiology (ESC) will participate in joint scientific sessions with the Argentine Society of Cardiology as part of the ESC Global Activities programme.

"Admission to the emergency department during the mandatory social isolation period was linked with a 37% increase in the odds of having high blood pressure -- even after taking into account age, gender, month, day and time of consultation, and whether or not the patient arrived by ambulance," said study author Dr. Matías Fosco of Favaloro Foundation University Hospital, Buenos Aires.

Mandatory social isolation due to COVID-19 was implemented on 20 March in Argentina as a part of a general lockdown. People were told to stay at home, except for essential workers (e.g. doctors and nurses). The general public were permitted to leave home only to buy food, medicine and cleaning supplies. Schools and universities were closed, and public events were suspended.

"After social isolation began, we observed that more patients coming to emergency had high blood pressure," said Dr. Fosco. "We conducted this study to confirm or reject this impression."

The study was conducted in the emergency department of Favaloro Foundation University Hospital. The frequency of high blood pressure1 among patients aged 21 and above during the three-month social isolation (20 March to 25 June 2020) was compared to two previous time periods: the same three months in 2019 (21 March to 27 June 2019) and the three months immediately before social isolation (13 December 2019 to 19 March 2020).

Blood pressure is a standard measurement on admission to the emergency department and almost every patient (98.2%) admitted between 21 March 2019 and 25 June 2020 was included in the study. The most common reasons for admission were chest pain, shortness of breath, dizziness, abdominal pain, fever, cough, and hypertension.

The study included 12,241 patients. The average age was 57 years and 45.6% were women. During the three-month isolation period 1,643 patients were admitted to the emergency department. This was 56.9% less than during the same three months in 2019 (3,810 patients) and 53.9% lower than during the three months immediately before social isolation (3,563 patients).

During the social isolation period, 391 (23.8%) patients admitted to emergency had high blood pressure. This proportion was significantly higher compared to the same period in 2019, when it was 17.5%, and compared to the three months before social isolation, when it was 15.4% (p<0.01).

Dr. Fosco said: "There are several possible reasons for the connection between social isolation and high blood pressure. For example, increased stress because of the pandemic, with limited personal contact and the onset or exacerbation of financial or family difficulties. Changed behaviours may have played a role, with higher intake of food and alcohol, sedentary lifestyles and weight gain."

Dr. Fosco noted that the reasons for admission were similar between the periods studied, so were not responsible for the increase in high blood pressure. But he said: "Patients may have felt more psychological tension during transportation to the hospital because of travel restrictions and police controls and a fear of becoming infected with coronavirus after leaving home. In addition, patients being treated for high blood pressure may have stopped taking their medicine due to preliminary warnings about possible adverse effects on COVID-19 outcomes (which were later dismissed)."

He concluded: "Blood pressure control helps prevent heart attacks and strokes and serious illness from COVID-19, so it's essential to maintain healthy lifestyle habits, even under social isolation and lockdown conditions. Many regulations related to the pandemic have now relaxed and we are investigating if this is reflected in the blood pressure of patients admitted to emergency."

Dr. Héctor Deschle, Scientific Programme Chair of SAC 2020, said: "This study illustrates the collateral damage generated by isolation. There has been a significant decrease in heart disease consultations, which inevitably leads to avoidable complications. But I would like to emphasise the psychological damage pointed out by the authors, which we perceive daily in consultations and which is expressed as fear, hopelessness, irritability, and difficulty concentrating. This affects interpersonal relationships and physical health. This study puts the spotlight on the concomitant consequences of the outbreak and the restrictions used to struggle against it."

Professor Jose Luis Zamorano, ESC regional Ambassador for Argentina at SAC 2020, said: "This very interesting study simply highlights that we as cardiologists must keep a watchful eye on our cardiology patients beyond the pandemic. If we do not treat and carefully follow our cardiac patients during the pandemic, we will see an increase of adverse outcomes in the future."

https://www.sciencedaily.com/releases/2020/11/201119083923.htm

Worms reveal why melatonin promotes sleep

Research in C. elegans shows how melatonin activates the BK channel in the brain

November 16, 2020

Science Daily/University of Connecticut

Melatonin is used as a dietary supplement to promote sleep and get over jet lag, but nobody really understands how it works in the brain. Now, researchers at UConn Health show that melatonin helps worms sleep, too, and they suspect they've identified what it does in us.

Our bodies produce melatonin in darkness. It's technically a hormone, but you can readily buy melatonin as a supplement in pharmacies, nutrition stores, and other retail shops. It's widely used by adults and often in children as well.

Melatonin binds to melatonin receptors in the brain to produce its sleep-promoting effects. Think of a receptor as a keyhole, and melatonin as the key. The two keyholes for melatonin are called MT1 and MT2 in human brain cells. But scientists didn't really know what happens when the keyhole is unlocked. Now UConn Health School of Medicine neuroscientists Zhao-Wen Wang and Bojun Chen and their colleagues have identified that process through their work with C. elegans worms, as reported in PNASon Sept. 21. When melatonin fits into the MT1 receptor in the worm's brain, it opens a potassium channel known as the BK channel.

A major function of the BK channel in neurons is to limit the release of neurotransmitters, which are chemical substances used by neurons to talk to each other. In their search for factors related to the BK channel, the Wang and Chen labs found that a melatonin receptor is needed for the BK channel to limit neurotransmitter release. They subsequently found that melatonin promotes sleep in worms by activating the BK channel through the melatonin receptor. Worms that lack either melatonin secretion, the melatonin receptor, or the BK channel spend less time in sleep.

But wait -- worms sleep?

Indeed they do, says Chen. There's actually been quite a lot of research on worm sleep, and researchers found that sleep is similar between worms and mammals like humans and mice.

Wang and Chen next plan to see if the melatonin-MT1-BK relationship holds in mice. The BK channel is involved in all kinds of bodily happenings, from epilepsy to high blood pressure. By learning more about the relationships between the BK channel, sleep, and behavioral changes, the researchers hope both to understand melatonin better and also help people who suffer from other diseases related to the BK channel.

https://www.sciencedaily.com/releases/2020/11/201116092251.htm

Chronic alcohol use reshapes the brain's immune landscape, driving anxiety and addiction

November 16, 2020

Science Daily/Scripps Research Institute

Deep within the brain, a small almond-shaped region called the amygdala plays a vital role in how we exhibit emotion, behavior and motivation. Understandably, it's also strongly implicated in alcohol abuse, making it a long-running focus of Marisa Roberto, PhD, professor in Scripps Research's Department of Molecular Medicine.

Now, for the first time, Roberto and her team have identified important changes to anti-inflammatory mechanisms and cellular activity in the amygdala that drive alcohol addiction. By countering this process in mice, they were able to stop excessive alcohol consumption -- revealing a potential treatment path for alcohol use disorder. The study is published in Progress in Neurobiology.

"We found that chronic alcohol exposure compromises brain immune cells, which are important for maintaining healthy neurons," says Reesha Patel, PhD, a postdoctoral fellow in Roberto's lab and first author of the study. "The resulting damage fuels anxiety and alcohol drinking that may lead to alcohol use disorder."

Roberto's study looked specifically at an immune protein called Interleukin 10, or IL-10, which is prevalent in the brain. IL-10 is known to have potent anti-inflammatory properties, which ensures that the immune system doesn't respond too powerfully to disease threats. In the brain, IL-10 helps to limit inflammation from injury or disease, such as stroke or Alzheimer's. But it also appears to influence key behaviors associated with chronic alcohol use.

In mice with chronic alcohol use, IL-10 was significantly reduced in the amygdala and didn't signal properly to neurons, contributing to increased alcohol intake. By boosting IL-10 signaling in the brain, however, the scientists could reverse the aberrant effects. Notably, they observed a stark reduction in anxiety-like behaviors and motivation to drink alcohol.

"We've shown that inflammatory immune responses in the brain are very much at play in the development and maintenance of alcohol use disorder," Roberto says. "But perhaps more importantly, we provided a new framework for therapeutic intervention, pointing to anti-inflammatory mechanisms."

Alcohol use disorder is widespread, affecting some 15 million people in the United States, and few effective treatments exist. By examining how brain cells change with prolonged exposure to alcohol, Roberto's lab has uncovered many possible new therapeutic approaches for those with alcohol addiction.

In the latest study, Roberto's lab collaborated with Silke Paust, PhD, associate professor in the Department of Immunology and Microbiology. Paust and her team determined the precise immune cells throughout the whole brain that are affected by chronic alcohol use. The findings revealed a large shift in the brain immune landscape, with increased levels of immune cells known as microglia and T-regulatory cells, which produce IL-10.

Despite a higher number of IL-10-producing cells in the whole brain of mice with prolonged alcohol use, the amygdala told a different story. In that region, levels of IL-10 were lower and their signaling function was compromised -- suggesting that the immune system in the amygdala responds uniquely to chronic alcohol use.

This study complements recent findings by the Roberto lab demonstrating a casual role for microglia in the development of alcohol dependence.

Future studies will build on these findings to identify exactly how and when IL-10 signals to neurons in the amygdala and other addition-related brain circuits to alter behavior.

https://www.sciencedaily.com/releases/2020/11/201116132248.htm

Healthy sleep habits help lower risk of heart failure

November 16, 2020

Science Daily/American Heart Association

Adults with the healthiest sleep patterns had a 42% lower risk of heart failure regardless of other risk factors compared to adults with unhealthy sleep patterns, according to new research published today in the American Heart Association's flagship journal Circulation. Healthy sleep patterns are rising in the morning, sleeping 7-8 hours a day and having no frequent insomnia, snoring or excessive daytime sleepiness.

Heart failure affects more than 26 million people, and emerging evidence indicates sleep problems may play a role in the development of heart failure.

This observational study examined the relationship between healthy sleep patterns and heart failure and included data on 408,802 UK Biobank participants, ages 37 to 73 at the time of recruitment (2006-2010). Incidence of heart failure was collected until April 1, 2019. Researchers recorded 5,221 cases of heart failure during a median follow-up of 10 years.

Researchers analyzed sleep quality as well as overall sleep patterns. The measures of sleep quality included sleep duration, insomnia and snoring and other sleep-related features, such as whether the participant was an early bird or night owl and if they had any daytime sleepiness (likely to unintentionally doze off or fall asleep during the daytime).

"The healthy sleep score we created was based on the scoring of these five sleep behaviors," said Lu Qi, M.D., Ph.D., corresponding author and professor of epidemiology and director of the Obesity Research Center at Tulane University in New Orleans. "Our findings highlight the importance of improving overall sleep patterns to help prevent heart failure."

Sleep behaviors were collected through touchscreen questionnaires. Sleep duration was defined into three groups: short, or less than 7 hours a day; recommended, or 7 to 8 hours a day; and prolonged, or 9 hours or more a day.

After adjusting for diabetes, hypertension, medication use, genetic variations and other covariates, participants with the healthiest sleep pattern had a 42% reduction in the risk of heart failure compared to people with an unhealthy sleep pattern.

They also found the risk of heart failure was independently associated and:

• 8% lower in early risers;

• 12% lower in those who slept 7 to 8 hours daily;

• 17% lower in those who did not have frequent insomnia; and

• 34% lower in those reporting no daytime sleepiness.

Participant sleep behaviors were self-reported, and the information on changes in sleep behaviors during follow-up were not available. The researchers noted other unmeasured or unknown adjustments may have also influenced the findings.

Qi also noted that the study's strengths include its novelty, prospective study design and large sample size.

https://www.sciencedaily.com/releases/2020/11/201116075728.htm

Sleep loss hijacks brain's activity during learning

Disruption could increase risks for sleepless workers

November 11, 2020

Science Daily/Elsevier

Sleep is crucial for consolidating our memories, and sleep deprivation has long been known to interfere with learning and memory. Now a new study shows that getting only half a night's sleep -- as many medical workers and military personnel often do -- hijacks the brain's ability to unlearn fear-related memories. That might put people at greater risk of conditions such as anxiety or posttraumatic stress disorder.

The study appears in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, published by Elsevier.

"This study provides us with new insights into how sleep deprivation affects brain function to disrupt fear extinction," said Cameron Carter, MD, Editor of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging.

The researchers, led by Anne Germain, PhD, at the University of Pittsburgh and Edward Pace-Schott, PhD, at Harvard Medical School and Massachusetts General Hospital, studied 150 healthy adults in the sleep laboratory. One third of subjects got normal sleep, one third were sleep restricted, so they slept only the first half the night, and one third were sleep deprived, so they got no sleep at all. In the morning, all the subjects underwent fear conditioning.

"Our team used a three-phase experimental model for the acquisition and overcoming of fearful memories while their brains were scanned using functional magnetic resonance imaging," said Dr. Pace-Schott. In the conditioning paradigm, subjects were presented with three colors, two of which were paired with a mild electric shock. Following this fear conditioning, the subjects underwent fear extinction, in which one of the colors was presented without any shocks to learn that it was now "safe." That evening, subjects were tested for their reactivity to the three colors, a measure of their fear extinction recall, or how well they had "unlearned" the threat.

Brain imaging recorded during the tasks showed activation in brain areas associated with emotional regulation, such as the prefrontal cortex, in people who got normal sleep. But the brain activity looked very different in people with restricted sleep, said Dr. Pace-Schott. "We found that among the three groups, those who had only gotten half a night's sleep showed the most activity in brain regions associated with fear and the least activity in areas associated with control of emotion."

Surprisingly, people who got no sleep lacked the brain activation in fear-related areas during fear conditioning and extinction. During the extinction recall 12 hours later, their brain activity looked more similar to those with normal sleep, suggesting that a limited night of sleep may be worse than none at all.

The researchers hypothesize that sleeping only half the night results in a loss of rapid eye movement (REM) sleep, which has been shown to be important for memory consolidation and usually happens toward the end of a normal sleep period.

Dr. Carter said the study used "noninvasive brain imaging to give us a novel window into how sleep deprivation disrupts the normal fear extinction mechanisms and potentially increases vulnerability to posttraumatic stress symptoms."

"Medical workers and soldiers often have curtailed or interrupted sleep rather than missing an entire night's sleep," Dr. Pace-Schott said. "Our findings suggest that such partially sleep-deprived individuals might be especially vulnerable to fear-related conditions such as posttraumatic stress disorder."

https://www.sciencedaily.com/releases/2020/11/201111092924.htm

Green prescriptions could undermine the benefits of spending time in nature

November 6, 2020

Science Daily/University of Exeter

Spending time in nature is believed to benefit people's mental health. However, new research suggests that giving people with existing mental health conditions formal 'green prescriptions', may undermine some of the benefits.

An international research team led by the University of Exeter and published in the journal Scientific Reports, investigated whether contact with nature has the potential to help people with mental health issues, such as depression and anxiety, to manage their symptoms. They found that nature is associated with a number of benefits for these individuals, but only if they chose to visit these places themselves.

The research team collected data from more than 18,000 people in 18 different countries, as part of the EU Horizons 2020 funded BlueHealth project. A key aim was to understand why people feel motivated to spend time in nature, how often they visit, and how social pressure influences their emotional experiences during visits.

The findings suggest that whilst pressure to spend time outdoors can encourage visits, it can also undermine the potential emotional and wellbeing benefits of contact with nature.

Common mental health issues are the leading cause of disability worldwide, affecting approximately 17% of the world's population each year. Although there is evidence that some people with these issues are using nature as part of their own symptom self-management, there was still much we didn't not know about how widespread this was, or whether more formal 'Green prescriptions' from medical professional to spend time in nature could aid management and potentially recovery.

The research team were surprised to find that people with depression were already visiting nature as frequently as people with no mental health issues, while people with anxiety were visiting significantly more often. On the whole, both groups also tended to feel happy and reported low anxiety during these visits.

However, the benefits of nature seem to be undermined when visits were not by choice. The more pressure people felt to visit nature by presumably well-meaning others, the less motivated people were and the more anxious they felt.

The research was led by Dr Michelle Tester-Jones, of the University of Exeter. She said: "These findings are consistent with wider research that suggests that urban natural environments provide spaces for people to relax and recover from stress. However, they also demonstrate that healthcare practitioners and loved ones should be sensitive when recommending time in nature for people who have depression and anxiety. It could be helpful to encourage them to spend more time in places that people already enjoy visiting; so they feel comfortable and can make the most of the experience."

The authors believe their paper provides evidence that careful techniques to discuss accessing nature as a means of self- or supported-management for people with mental health issues need to be integrated into these programmes if they are to offer clients the best support.

Dr Mathew White, of the University of Exeter and University of Vienna, who co-ordinated the international research team, added: "We had no idea just how much people with depression and anxiety were already using natural settings to help alleviate symptoms and manage their conditions. Our results provide even greater clarity about the value of these places to communities around the world, but also remind us that nature is no silver bullet and needs to be carefully integrated with existing treatment options."

Dr Ann Ojala, a research team member from the Natural Resources Institute Finland (Luke) said: "The results encourage further research in clinical settings. We need more information on this delicate balance between the intrinsic motivation and sometimes necessary encouragement from outside, as well as how nature visits could be integrated to mental health treatment."

Co-author Dr Greg Bratman, of the University of Washington, said: "The results highlighted the importance of taking intrinsic motivation into account when it comes to the benefits of nature visits -- and the relevance of integrating this consideration into effective green prescriptions."

Matilda van den Bosch, Assistant Professor at The University of British Columbia, said: "For green prescriptions, like with any intervention, it is important to avoid pressure to achieve compliance with the treatment. Nature cannot be forced on anyone, but must be provided at the individual's own pace and will."

https://www.sciencedaily.com/releases/2020/11/201106093024.htm

Scientists discover how a common mutation leads to 'night owl' sleep disorder

October 27, 2020

Science Daily/University of California - Santa Cruz

A new study by researchers at UC Santa Cruz shows how a genetic mutation throws off the timing of the biological clock, causing a common sleep syndrome called delayed sleep phase disorder.

People with this condition are unable to fall asleep until late at night (often after 2 a.m.) and have difficulty getting up in the morning. In 2017, scientists discovered a surprisingly common mutation that causes this sleep disorder by altering a key component of the biological clock that maintains the body's daily rhythms. The new findings, published October 26 in Proceedings of the National Academy of Sciences, reveal the molecular mechanisms involved and point the way toward potential treatments.

"This mutation has dramatic effects on people's sleep patterns, so it's exciting to identify a concrete mechanism in the biological clock that links the biochemistry of this protein to the control of human sleep behavior," said corresponding author Carrie Partch, professor of chemistry and biochemistry at UC Santa Cruz.

Daily cycles in virtually every aspect of our physiology are driven by cyclical interactions of clock proteins in our cells. Genetic variations that change the clock proteins can alter the timing of the clock and cause sleep phase disorders. A shortened clock cycle causes people to go to sleep and wake up earlier than normal (the "morning lark" effect), while a longer clock cycle makes people stay up late and sleep in (the "night owl" effect).

Most of the mutations known to alter the clock are very rare, Partch said. They are important to scientists as clues to understanding the mechanisms of the clock, but a given mutation may only affect one in a million people. The genetic variant identified in the 2017 study, however, was found in around one in 75 people of European descent.

How often this particular mutation is involved in delayed sleep phase disorder remains unclear, Partch said. Sleep behavior is complex -- people stay up late for many different reasons -- and disorders can be hard to diagnose. So the discovery of a relatively common genetic variation associated with a sleep phase disorder was a striking development.

"This genetic marker is really widespread," Partch said. "We still have a lot to understand about the role of lengthened clock timing in delayed sleep onset, but this one mutation is clearly an important cause of late night behavior in humans."

The mutation affects a protein called cryptochrome, one of four main clock proteins. Two of the clock proteins (CLOCK and BMAL1) form a complex that turns on the genes for the other two (period and cryptochrome), which then combine to repress the activity of the first pair, thus turning themselves off and starting the cycle again. This feedback loop is the central mechanism of the biological clock, driving daily fluctuations in gene activity and protein levels throughout the body.

The cryptochrome mutation causes a small segment on the "tail" of the protein to get left out, and Partch's lab found that this changes how tightly cryptochrome binds to the CLOCK:BMAL1 complex.

"The region that gets snipped out actually controls the activity of cryptochrome in a way that leads to a 24-hour clock," Partch explained. "Without it, cryptochrome binds more tightly and stretches out the length of the clock each day."

The binding of these protein complexes involves a pocket where the missing tail segment normally competes and interferes with the binding of the rest of the complex.

"How tightly the complex partners bind to this pocket determines how quickly the clock runs," Partch explained. "This tells us we should be looking for drugs that bind to that pocket and can serve the same purpose as the cryptochrome tail."

Partch's lab is currently doing just that, conducting screening assays to identify molecules that bind to the pocket in the clock's molecular complex. "We know now that we need to target that pocket to develop therapeutics that could shorten the clock for people with delayed sleep phase disorder," she said.

Partch has been studying the molecular structures and interactions of the clock proteins for years. In a study published earlier this year, her lab showed how certain mutations can shorten clock timing by affecting a molecular switch mechanism, making some people extreme morning larks.

She said the new study was inspired by the 2017 paper on the cryptochrome mutation from the lab of Nobel Laureate Michael Young at Rockefeller University. The paper had just come out when first author Gian Carlo Parico joined Partch's lab as a graduate student, and he was determined to discover the molecular mechanisms responsible for the mutation's effects.

https://www.sciencedaily.com/releases/2020/10/201027105354.htm

How exercise stalls cancer growth through the immune system

October 26, 2020

Science Daily/Karolinska Institutet

People with cancer who exercise generally have a better prognosis than inactive patients. Now, researchers at Karolinska Institutet in Sweden have found a likely explanation of why exercise helps slow down cancer growth in mice: Physical activity changes the metabolism of the immune system's cytotoxic T cells and thereby improves their ability to attack cancer cells. The study is published in the journal eLife.

"The biology behind the positive effects of exercise can provide new insights into how the body maintains health as well as help us design and improve treatments against cancer," says Randall Johnson, professor at the Department of Cell and Molecular Biology, Karolinska Institutet, and the study's corresponding author.

Prior research has shown that physical activity can prevent unhealth as well as improve the prognosis of several diseases including various forms of cancer. Exactly how exercise exerts its protective effects against cancer is, however, still unknown, especially when it comes to the biological mechanisms. One plausible explanation is that physical activity activates the immune system and thereby bolsters the body's ability to prevent and inhibit cancer growth.

In this study, researchers at Karolinska Institutet expanded on this hypothesis by examining how the immune system's cytotoxic T cells, that is white blood cells specialized in killing cancer cells, respond to exercise.

They divided mice with cancer into two groups and let one group exercise regularly in a spinning wheel while the other remained inactive. The result showed that cancer growth slowed and mortality decreased in the trained animals compared with the untrained.

Next, the researchers examined the importance of cytotoxic T cells by injecting antibodies that remove these T cells in both trained and untrained mice. The antibodies knocked out the positive effect of exercise on both cancer growth and survival, which according to the researchers demonstrates the significance of these T cells for exercise-induced suppression of cancer.

The researchers also transferred cytotoxic T cells from trained to untrained mice with tumors, which improved their prospects compared with those who got cells from untrained animals.

To examine how exercise influenced cancer growth, the researchers isolated T cells, blood and tissue samples after a training sessions and measured levels of common metabolites that are produced in muscle and excreted into plasma at high levels during exertion. Some of these metabolites, such as lactate, altered the metabolism of the T cells and increased their activity. The researchers also found that T cells isolated from an exercised animal showed an altered metabolism compared to T cells from resting animals.

In addition, the researchers examined how these metabolites change in response to exercise in humans. They took blood samples from eight healthy men after 30 minutes of intense cycling and noticed that the same training-induced metabolites were released in humans.

"Our research shows that exercise affects the production of several molecules and metabolites that activate cancer-fighting immune cells and thereby inhibit cancer growth," says Helene Rundqvist, senior researcher at the Department of Laboratory Medicine, Karolinska Institutet, and the study's first author. "We hope these results may contribute to a deeper understanding of how our lifestyle impacts our immune system and inform the development of new immunotherapies against cancer."

The researchers have received financing from the Knut and Alice Wallenberg Foundation, the Swedish Research Council, the Swedish Cancer Society, the Swedish Childhood Cancer Foundation, the Swedish Society of Medicine, Cancer Research UK and the Wellcome Trust.

https://www.sciencedaily.com/releases/2020/10/201026114229.htm