Eyes send an unexpected signal to the brain

A subset of retinal neurons communicates differently from the rest of the eye

April 30, 2020

Science Daily/Northwestern University

For decades, biology textbooks have stated that eyes communicate with the brain exclusively through one type of signaling pathway. But a new discovery shows that some retinal neurons take a road less traveled.

New research, led by Northwestern University, has found that a subset of retinal neurons sends inhibitory signals to the brain. Before, researchers believed the eye only sends excitatory signals. (Simply put: Excitatory signaling makes neurons to fire more; inhibitory signaling makes neurons to fire less.)

The Northwestern researchers also found that this subset of retinal neurons is involved in subconscious behaviors, such as synchronization of circadian rhythms to light/dark cycles and pupil constriction to intense bright lights. By better understanding how these neurons function, researchers can explore new pathways by which light influences our behavior.

"These inhibitory signals prevent our circadian clock from resetting to dim light and prevent pupil constriction in low light, both of which are adaptive for proper vision and daily function," said Northwestern's Tiffany Schmidt, who led the research. "We think that our results provide a mechanism for understanding why our eye is so exquisitely sensitive to light, but our subconscious behaviors are comparatively insensitive to light."

The research will be published in the May 1 issue of the journal Science.

Schmidt is an assistant professor of neurobiology at Northwestern's Weinberg College of Arts and Sciences. Takuma Sonoda, a former Ph.D. student in the Northwestern University Interdepartmental Neuroscience program, is the paper's first author.

To conduct the study, Schmidt and her team blocked the retinal neurons responsible for inhibitory signaling in a mouse model. When this signal was blocked, dim light was more effective at shifting the mice's circadian rhythms.

"This suggests that there is a signal from the eye that actively inhibits circadian rhythms realignment when environmental light changes, which was unexpected," Schmidt said. "This makes some sense, however, because you do not want to adjust your body's entire clock for minor perturbations in the environmental light/dark cycle, you only want this massive adjustment to take place if the change in lighting is robust."

Schmidt's team also found that, when the inhibitory signals from the eye were blocked, mice's pupils were much more sensitive to light.

"Our working hypothesis is that this mechanism keeps pupils from constricting in very low light," Sonoda said. "This increases the amount of light hitting your retina, and makes it easier to see in low light conditions. This mechanism explains, in least part, why your pupils avoid constricting until bright light intensifies."

https://www.sciencedaily.com/releases/2020/04/200430150201.htm

Time of day affects global brain fluctuations

February 18, 2020

Science Daily/PLOS

As the day progresses, the strength of the brain's global signal fluctuation shows an unexpected decrease, according to a study published on February 18 in the open-access journal PLOS Biology by Csaba Orban and a multi-disciplinary team of scientists from the Faculty of Engineering, Yong Loo Lin School of Medicine and N.1 Institute of Health at the National University of Singapore.

Circadian rhythms govern diverse aspects of physiology including sleep/wake cycles, cognition, gene expression, temperature regulation, and endocrine signaling. But despite the clear influence of circadian rhythms on physiology, most studies of brain function do not report or consider the impact of time of day on their findings.

To address this gap in knowledge, the team analysed functional magnetic resonance imaging (fMRI) data of approximately 900 subjects who were scanned between 8 am and 10 pm on two different days as part of the Human Connectome Project. Multiple studies have shown that the brain's global signal fluctuates more strongly when one is drowsy (e.g. after insufficient sleep), and fluctuates less when one is more alert (e.g. after coffee). Based on known circadian variation in sleepiness, the authors hypothesized that global signal fluctuation would be lowest in the morning, increase in the mid-afternoon and dip in the early evening.

Instead, they observed a cumulative decrease in global signal fluctuation as the day progressed. This global decrease was most prominent in visual and somatosensory brain regions, which are known for expressing dynamic fluctuations within individuals over time. Across the whole brain, time of day was also associated with marked decreases in resting-state functional connectivity -- the correlated activity between different brain regions when no explicit task is being performed.

"We were surprised by the size of the overall time-of-day effects, since the global fMRI signal is affected by many factors and there is substantial variation across individuals. At the present moment we don't have a good explanation of the directionality of our findings. However, the fact that we also observed slight time-of-day-associated variation in the breathing patterns of participants suggests that we may also need to consider clues outside of the brain to fully understand these effects," said Csaba Orban, first author of the study.

Based on the findings, the authors recommend that researchers explicitly report the time of day of fMRI scans and other experimental protocols and measurements, as this could help account for between-study variation in results and potentially even failure to replicate findings.

"We hope these findings will motivate fellow neuroscientists to give more consideration to potential effects of time of day on measures of brain activity, especially in other large-scale studies where subjects are often scanned throughout the day for logistical reasons," said Thomas Yeo, the study's senior author.

https://www.sciencedaily.com/releases/2020/02/200218143717.htm

Parents aren't powerless when it comes to sleep-deprived teenagers

January 9, 2020

Science Daily/University of Rochester

Teenagers in the US simply don't get enough shut eye. The consequences of this epidemic of sleep deprivation are extensive and include increasing rates of anxiety and depression among adolescents, as well as suicidal thoughts and actions. Sleep-deprived teens are more likely to be involved in car crashes, and run a higher risk of injury during sports-related activities.

Experts have pointed to various reasons for the chronic teenage sleep deficit: growing homework loads, too many extra-curricular activities, caffeine consumption, school start times that run counter to middle and high schoolers' natural circadian rhythms, and the use of electronic devices and backlit screens, which may disrupt sleep patterns, before bedtime.

But researchers at the University of Rochester have found that a simple and timeworn solution yields solid results: a clear bedtime that parents consistently adhere to.

"Greater enforcement of parent-set bedtimes for teenagers aged 14-to-17 are associated with longer sleep duration," says Jack Peltz, lead author of a recent study, which was published in the academic journal Sleep. Peltz, now an assistant professor of psychology at Daemen College, earned his PhD in psychology at Rochester in 2013 and conducted the study as part of a research appointment at the University of Rochester Medical Center's Department of Psychiatry.

Study participants included teenagers and their parents. The team asked their teenage participants to keep twice-daily sleep diary entries over seven days, collecting reports of sleep duration, daytime energy levels, and depressive symptoms. Parents, meanwhile, provided information about their enforcement of sleep-related rules and bedtimes.

Among the key findings:

• Parent-enforced bedtimes -- along with later school start times -- are the greatest predictors of sleep duration, daytime energy level, and depressive symptoms.

• More than 50 percent of parent respondents reported no specific or enforced bedtime rules, consistent with rates measured in previous research across families in the US.

• Evening screen time and caffeine consumption did not, contrary to the researchers' hypotheses, significantly affect teenagers' sleep duration over the course of the study.

In 2014, the American Academy of Pediatrics responded to the sleep deprivation epidemic by urging school districts to start classes no earlier than 8:30 am, especially for middle and high schoolers. But to date, only about 14 percent of US high schools have heeded the recommendation, which makes the rule-setting role of parents all the more important.

The researchers acknowledge that setting a bedtime for teenagers might be difficult; but their results suggest that even with pre-bedtime conflict, parents' enforcement of bedtimes yielded better mental health outcomes for their offspring. That said -- "ideally parents should be able to work collaboratively with their teenagers to develop bedtimes that still support the child's autonomy," says Peltz.

The bottom line, according to coauthor Ronald Rogge, an associate professor of psychology at Rochester, is that "even though adolescents start gaining self-sufficiency and independence, they still need sleep and might not prioritize that if left to their own devices."

Absent an iron-clad rule, there are nevertheless healthy ranges, says Heidi Connolly, a professor of pediatrics and chief of the Division of Pediatric Sleep Medicine at Rochester, who is also a coauthor of the study. Most teenagers need 8.5 to 9.5 hours of sleep each night, she says, mirroring recommendations made by the American Academy of Sleep Medicine and endorsed by the American Academy of Pediatrics.

As for an appropriate bedtime, that of course depends on the wake-up time. "It's inherently more difficult for teenagers to fall asleep earlier than later because of their circadian rhythm," says Connolly. "That's why it's so important for high school start times to be later, as the American Academy of Pediatrics has recommended across the board."

The ideal is to feel well rested during the daytime, and spontaneously awaken at around your scheduled wake-up time even when allowed to sleep in.

The team notes that future studies may be necessary to determine if their findings hold true across a range of populations; they caution that their sample was predominantly white, well-educated, and economically advantaged.

https://www.sciencedaily.com/releases/2020/01/200109130203.htm

Let there be 'circadian' light

New study describes science behind best lights to affect sleep, mood and learning

February 20, 2020

Science Daily/University of Washington Health Sciences/UW Medicine

Researchers said the wavelengths at sunrise and sunset have the biggest impact to brain centers that regulate our circadian clock and our mood and alertness.

Their study, "A color vision circuit for non-image-forming vision in the primate retina," published in Current Biology Feb. 20, identifies a cell in the retina, which plays an important role in signaling our brain centers that regulate circadian rhythms, boost alertness, help memory and cognitive function, and elevate mood.

These effects have been attributed to a pigment in the eye called melanopsin, which is sensitive to blue light, but researchers say cone photoreceptors are a thousand times more sensitive to light than melanopsin. The cone photoreceptor inputs to the circadian circuity respond to short wavelength blue light, but they also respond strongly to long wavelength oranges and yellows and contrasting light -- the colors at sunrise and sunset. What makes good lighting, researchers discovered, is lighting capable of stimulating the cone photoreceptor inputs to specific neurons in the eye that regulate circadian rhythms.

Lead author Sara Patterson, a graduate student in neuroscience at the University of Washington School of Medicine, said how we set our internal clocks to the external light-dark cycle has been studied a lot. But how the changes in the color of light affect our brain has not.

"Color vision used for something other than color perception was the most exciting part for me," she said.

In the study, Patterson and colleagues identified a cell known as an inhibitory interneuron or amacrine cell in the retina, which signals to photosensitive ganglion cells that affect our circadian brain centers. The researchers said these amacrine cells provide "the missing component of an evolutionary ancient color vision circuit capable of setting the circadian clock by encoding the spectral content of light."

Patterson said so little is known about rare retinal circuitry that it was possible to find a new blue cone cell. She said there is a lot more to be discovered about how blue cone cells are projecting to other areas of the brain.

While sunrise lights, blue lights and seasonal affective disorder (SAD) lights have all tried to capture benefits of natural light, they haven't been that effective because they are missing key science data, said corresponding author Jay Neitz, professor of ophthalmology at the UW School of Medicine, a scientist at the UW Medicine Eye Institute, and a well-known color vision researcher. He said the science behind SAD lights, for example, is to make lights hundreds of times brighter than normal lights to stimulate melanopsin.

"This research all started because of our interest in the health benefits of having natural light that occurs at the right time of day that helps regulate our circadian clock and our mood and alertness," Neitz said.

The University of Washington has licensed technology based on this discovery to TUO (https://www.thetuolife.com/), a lighting technology company that will be selling white LED lightbulbs that will incorporate undetectable sunrise and sunset wavelengths for commercial use.

The work was supported by the National Eye Institute and Research to Prevent Blindness. Other collaborators include James A. Kuchenbecker, research scientist/biomedical engineer with the Department of Ophthalmology at the University of Washington School of Medicine; James R. Anderson, research scientist/software architect with the John A. Moran Eye Center at the University of Utah School of Medicine, and Maureen Neitz, professor of ophthalmology at the University of Washington School of Medicine.

https://www.sciencedaily.com/releases/2020/02/200220141731.htm

Biological clock influences immune response efficiency

September 24, 2019

Science Daily/McGill University

The biological clock influences immune response efficacy. Indeed, CD8 T cells, which are essential to fight infections and cancers, function very differently according to the time of day.

According to a recent study published in Proceedings of the National Academy of Sciences, the biological clock influences immune response efficacy. Indeed, CD8 T cells, which are essential to fight infections and cancers, function very differently according to the time of day. The study was carried out by a team of researchers led by Nicolas Cermakian, PhD, of the Douglas Research Centre, and Nathalie Labrecque, PhD, of the Maisonneuve-Rosemont Hospital Research Centre.

We know that circadian rhythms are generated by "clock genes," which influence most organs and cells -- including those of the immune system, whose function varies according to the time of day. Accordingly, circadian rhythms are found for various aspects of physiology, including sleep, nutrition, hormonal activity, and body temperature. These daily rhythms help the body adapt to cyclical changes in the environment, such as seasons and the day and night cycle.

In earlier research, the team had demonstrated that T cells react more or less strongly to a foreign body according to the time of day, but the role of the biological clock in this phenomenon remained unknown. "Using a mouse vaccine model, we observed that after vaccination, the strength of the CD8 T cell response varied according to the time of day. Conversely, in mice whose CD8 T cells were deficient for the clock gene, this circadian rhythm was abolished, and response to the vaccine was diminished in the daytime," explains Dr. Cermakian, who is also Professor at the McGill University Department of Psychiatry.

"Our study shows that T cells are more prone to be activated at certain times of the day. Identifying the mechanisms through which the biological clock modulates the T cell response will help us better understand the processes that regulate optimal T cell responses. This knowledge will contribute to improving vaccination strategies and cancer immune therapies," states Nathalie Labrecque, Professor at the Departments of Medicine and Microbiology, Infectious Diseases and Immunology at Université de Montréal.

https://www.sciencedaily.com/releases/2019/09/190924125015.htm

Circadian clock plays unexpected role in neurodegenerative diseases

Seemingly counterintuitive evidence shows that disrupted sleep protects the brain

April 2, 2019

Science Daily/Northwestern University

Researchers induced jet lag in a fruit fly model of Huntington disease and found that jet lag protected the flies' neurons.

While your body might bemoan the many uncomfortable effects of jet lag, your brain may be thanking you for that cross-time zone travel.

In a new study, Northwestern University researchers induced jet lag in a fruit fly model of Huntington disease and found that jet lag protected the flies' neurons. The team then identified and tested a circadian clock-controlled gene that, when knocked down, also protected the brain from the disease.

The findings reveal potential new treatment pathways to slow the progression of or prevent neurodegenerative diseases.

"It seems counterintuitive, but we showed that a little bit of stress is good," said Northwestern's Dr. Ravi Allada, a circadian rhythms expert who led the research. "We subtly manipulated the circadian clock, and that stress appears to be neuroprotective."

The study will be published April 2 in the journal Cell Reports. Allada is the Edward C. Stuntz Distinguished Professor and chair of the department of neurobiology in Northwestern's Weinberg College of Arts and Sciences.

Patients with neurodegenerative diseases often experience profound disruptions in their circadian rhythms, or sleep-wake cycles. They may sleep more than usual or lose the ability to stay asleep. This can lead to nighttime wandering, increased agitation, general stress and a decreased quality of life.

"We have long known that a disrupted clock is an early indicator of neurodegenerative disease," Allada said. "In many cases, sleep disruption precedes any other symptom. But we didn't know whether the circadian disruption is a cause of the disease or a consequence of the disease."

To probe this question, Allada employed the fruit fly model of Huntington disease, a well-studied model organism for both circadian rhythms and neurodegenerative diseases. Although fruit flies might seem completely different from humans, the neurons that govern flies' sleep-wake cycles are strikingly similar to humans'. Fruit flies that have the mutant Huntington gene also demonstrate similar symptoms as humans with the disease: reduced lifespan, motor deficits, neurodegeneration, disrupted circadian rhythms and an accumulation of diseased proteins in the brain, which aggregate and cause neurons to die.

"Normally, fruit flies wake up, get very active, then go to sleep and become inactive," Allada explained. "It's a 24-hour pattern. In the Huntington model, there is no rhythm. The flies wake up and fall asleep all the time."

Allada's team altered the flies' circadian rhythms two different ways. For one group of flies, the researchers altered the flies' environment by changing the daily timing of light-dark cycles. This manipulation caused the flies to live a 20-hour day instead of a 24-hour day. And for another group of flies, the researchers mutated a gene that is well known for controlling the internal circadian clock.

"We essentially gave the flies jet lag for every day of their lives," Allada said. "It's like traveling four hours east every day."

In both cases, the mutant Huntington disease proteins aggregated less and fewer neurons died. Allada, who expected jet lag to inflict even more damage on the brain, was surprised. "We had wondered if the clock played a role in the disease," he said. "It turned out that the clock was important -- but in a manner that we did not predict."

Allada and his team were so fascinated by the result that they took the study one step further. They decided to screen through dozens of clock-controlled genes to pinpoint one that also might similarly protect the brain against neurodegenerative diseases.

The team zeroed in on a gene that encodes the "heat shock organizing protein," or "hop" for short. Not only is hop controlled by the body's circadian clock, the gene is also responsible for protein folding. Because misfolded proteins can result in many different neurodegenerative diseases, Allada thought hop made an interesting target. He and his team knocked down the hop gene in flies with the protein that causes Huntington disease and -- again -- were surprised. Knocking down the gene restored the flies' arrhythmic circadian clocks, reduced the aggregation of diseased proteins in the brain and reduced the number of neurons killed by those proteins.

"We thought that inhibiting this gene that helps your proteins fold properly would make things worse, but they got better," Allada said. "It again shows that a little bit of stress is probably good."

Next, Allada plans to test this method in a fruit fly model of Alzheimer's disease. He believes that targeting and knocking down the hop gene could potentially be an early intervention for slowing the progression of various neurodegenerative diseases.

https://www.sciencedaily.com/releases/2019/04/190402113220.htm

Postnatal depression could be linked to fewer daylight hours during late pregnancy

Shortening days during third trimester of pregnancy may add to risk of postpartum depression

September 27, 2018

Science Daily/Springer

Women in late pregnancy during darker months of the year may have a greater risk of developing postpartum depression once their babies are born. This is consistent with what is known about the relationship between exposure to natural light and depression among adults in the general population.

Although reduced exposure to natural light has been associated with depression among adults in the general population, there is not yet a consensus about whether light exposure or seasonality influences the development of depression during and after pregnancy.

In this study, Goyal and her colleagues at the University of California San Francisco analysed available information from 293 women who participated in one of two randomized controlled clinical trials about sleep before and after pregnancy. The participants were all first-time mothers from the US state of California. Data included the amount of daylight during the final trimester of their pregnancy, along with information about known risk factors such as a history of depression, the woman's age, her socioeconomic status and how much she slept.

Overall, the participants had a 30 per cent risk of depression. The analysis suggested that the number of daylight hours a woman was exposed to during her final month of pregnancy and just after birth had a major influence on the likelihood that she developed depressive symptoms.

The lowest risk for depression (26 per cent) occurred among women whose final trimester coincided with seasons with longer daylight hours. Depression scores were highest (35 per cent) among women whose final trimester coincided with "short" days and the symptoms continued to be more severe following the birth of their babies in this group of women. In the northern hemisphere, this timeframe refers to the months of August to the first four days of November (late summer to early autumn).

"Among first-time mothers, the length of day in the third trimester, specifically day lengths that are shortening compared to day lengths that are short, long or lengthening, were associated with concurrent depressive symptom severity," Goyal explains.

The findings suggest that using light treatment in the late third trimester when seasonal day length is shortening could minimize postpartum depressive symptoms in high-risk mothers during the first three months of their children's lives. Goyal says that women with a history of mental health problems and those who are already experiencing depressive symptoms in the third trimester might further benefit from being outdoors when possible, or using devices such as light boxes that provide light therapy.

"Women should be encouraged to get frequent exposure to daylight throughout their pregnancies to enhance their vitamin D levels and to suppress the hormone melatonin," adds Goyal, who says that clinicians should also advise their patients to get more exercise outdoors when weather and safety permit. "Daily walks during daylight hours may be more effective in improving mood than walking inside a shopping mall or using a treadmill in a gym. Likewise, early morning or late evening walks may be relaxing but would be less effective in increasing vitamin D exposure or suppressing melatonin."

https://www.sciencedaily.com/releases/2018/09/180927105733.htm

Fish-rich diets in pregnancy may boost babies' brain development

September 20, 2018

Science Daily/Springer

Women could enhance the development of their unborn child's eyesight and brain function by regularly eating fatty fish during pregnancy. This is the suggestion from a small-scale study. The research supports previous findings that show how important a prospective mother's diet and lifestyle choices are for the development of her baby.

According to Laitinen, a mother's diet during pregnancy and breastfeeding is the main way that valuable long-chain polyunsaturated fatty acids become available to a fetus and infant brain during the period of maximum brain growth during the first years of a child's life. Such fatty acids help to shape the nerve cells that are relevant to eyesight and particularly the retina. They are also important in forming the synapses that are vital in the transport of messages between neurons in the nervous system.

In this study, Laitinen and her colleagues analysed the results of 56 mothers and their children drawn from a larger study. The mothers had to keep a regular food diary during the course of their pregnancy. Fluctuations in their weight before and during pregnancy were taken into account, along with their blood sugar level and blood pressure. Aspects such as whether they smoked or developed diabetes related to pregnancy were also noted.

The team recorded the levels of nutritional long-chain polyunsaturated fatty acid sources in the mother's diet and blood serum, and the levels in the blood of their children by the age of one month. Their children were further tested around their second birthday using pattern reversal visual evoked potentials (pVEP). This sensitive and accurate, non-invasive method is used to detect visual functioning and maturational changes occurring within a young child's visual system.

The subsequent analyses of the visual test results revealed that infants whose mothers ate fish three or more times a week during the last trimester of their pregnancy fared better than those whose mothers ate no fish or only up to two portions per week. These observations were further substantiated when the serum phospholipid fatty acid status was evaluated.

"The results of our study suggest that frequent fish consumption by pregnant women is of benefit for their unborn child's development. This may be attributable to long-chain polyunsaturated fatty acids within fish, but also due to other nutrients like vitamin D and E, which are also important for development," explains Laitinen.

"Our study therefore highlights the potential importance of subtle changes in the diet of healthy women with uncompromised pregnancies, beyond prematurity or nutritional deficiencies, in regulating infantile neurodevelopment," adds Laitinen, who believes that their results should be incorporated into counselling given to pregnant women about their diets.

https://www.sciencedaily.com/releases/2018/09/180920102207.htm

Removing digital devices from the bedroom can improve sleep for children, teens

November 2, 2017

Science Daily/Penn State

Removing electronic media from the bedroom and encouraging a calming bedtime routine are among recommendations researchers outline in a recent manuscript on digital media and sleep in childhood and adolescence.

The manuscript appears in the first-ever special supplement on this topic in Pediatrics and is based on previous studies that suggest the use of digital devices before bedtime leads to insufficient sleep.

The recommendations, for clinicians and parents, are:

1. Make sleep a priority by talking with family members about the importance of sleep and healthy sleep expectations;

2. Encourage a bedtime routine that includes calming activities and avoids electronic media use;

3. Encourage families to remove all electronic devices from their child or teen's bedroom, including TVs, video games, computers, tablets and cell phones;

4. Talk with family members about the negative consequences of bright light in the evening on sleep; and

5. If a child or adolescent is exhibiting mood or behavioral problems, consider insufficient sleep as a contributing factor.

"Recent reviews of scientific literature reveal that the vast majority of studies find evidence for an adverse association between screen-based media consumption and sleep health, primarily delayed bedtimes and reduced total sleep duration," said Orfeu Buxton, associate professor of biobehavioral health at Penn State and an author on the manuscript.

The reasons behind this adverse association likely include time spent on screens replacing time spent sleeping; mental stimulation from media content; and the effects of light interrupting sleep cycles, according to the researchers.

Buxton and other researchers are further exploring this topic. They are working to understand if media use affects the timing and duration of sleep among children and adolescents; the role of parenting and family practices; the links between screen time and sleep quality and tiredness; and the influence of light on circadian physiology and sleep health among children and adolescents.

https://www.sciencedaily.com/releases/2017/11/171102121003.htm

Smell sensitivity varies with circadian rhythm

October 26, 2017

Science Daily/Brown University

A person's ability to smell may vary throughout the day in accordance with their circadian rhythm, according to new evidence in a small study by researchers who are looking at how sleep may influence eating patterns in teens.

It has always been apparent that some individuals have a better sense of smell than others, but a new study of 37 teens provides the first direct evidence that within each person, smell sensitivity varies over the course of each day. The pattern, according to the data, tracks with the body's internal day-night cycle, or circadian rhythm.

"This finding is very important for olfactory perception science," said Rachel Herz, lead author of the study in Chemical Senses and an adjunct assistant professor of psychiatry and human behavior at the Warren Alpert Medical School of Brown University. "This hadn't been known before and this is the first clear, direct evidence."

As one of the five senses, smell is an important ability, Herz noted, not only for experiencing and enjoying the world, but also for receiving information about danger, such as nearby fire or spoiled food, and for basic functions like eating. Changes in the sense during the day can affect all these capabilities.

Indeed Herz, an expert in the sense of smell, made the findings in collaboration with sleep expert Mary Carskadon, a Brown professor of psychiatry and human behavior. Carskadon is conducting a larger study with a hypothesis that circadian timing and sleep habits may affect the eating habits of teens, potentially contributing to obesity. Smell is associated with food consumption, notes Herz -- who has authored the upcoming book "Why You Eat What You Eat" -- so the researchers devised an experiment to determine whether smell varies with circadian rhythm.

28-hour 'days'

To conduct the study, the researchers asked the 21 boys and 16 girls, all between ages 12 and 15, to sleep on a fixed schedule for two weeks before reporting to the Bradley Hospital sleep lab. After an adaptation night in the lab, the teens began a week of 28-hour days where their sleep was shifted four hours later each "night."

All along, they lived indoors in dim light, socializing and participating in fun activities with each other and staff members. The goal was to separate them temporarily from typical sleep disruptions and from external cues of circadian timing. In this way, Carskadon said, their inherent, internal circadian rhythms could be measured, as could the sensitivity of their sense of smell at all times throughout their rhythms (in addition to other measures, such as food intake).

The team measured circadian rhythm by detecting levels of the sleep-cueing hormone melatonin in their saliva. Melatonin secretion begins about an hour before the urge to sleep hits. They assessed smell sensitivity using "Sniffin' Sticks," a common test for measuring odor detection thresholds. Each time they used the sticks, the researchers could determine the threshold concentration of the odor that the teens could detect. Smell was assessed every three hours while teens were awake.

The rhythm of smell

Individuals varied substantially in how much their smell sensitivity varied over a circadian cycle and in when it peaked. But there were clear patterns individually and overall. One was that the variance showed a circadian rhythm, and the other was that smell sensitivity was never strongest well into the "biological night," or the period well after melatonin onset when people are most likely to be asleep and least likely to be eating. In clock terms, it's from about 3 to 9 a.m.

"So we have 84 tests done on each child, and each one has a circadian phase associated with it," Carskadon said. "There is a rhythm here, and it's not flat or that you smell the same all the time. Your sense of smell changes in a predictable manner, though it's not the same for every child."

Carskadon said the findings should be of note to clinicians and researchers who seek to assess a patient's sense of smell. The study suggests that sensitivity might be inherently higher at an afternoon appointment than in the early morning.

Herz noted that there could be implications for fire safety as well. A decade ago she and Carskadon had found that the sense of smell all but shuts down during sleep. Now there is evidence that the sense of smell is relatively weak during a quarter of the circadian cycle. This emphasizes, Herz said, the value of audible smoke alarms, since smell may be a poor indicator of that danger at least in the early morning hours.

On average, the peak of smell sensitivity was at the beginning of biological night, or about 9 p.m. for the teens.

Herz said she can only speculate about why smell sensitivity might peak, on average, in the late evening. From an evolutionary standpoint, it might be to ensure the greatest sense of satiety during the important end of day meal, it might be a way of increasing mating desire, or perhaps a way of scanning for nearby threats before bedding down for the evening.

For each individual, she said, knowing when during the day smell their sensitivity might peak could be a way of identifying the time when sensory experiences could be most pleasant.

For less ancient health concerns, however, Carskadon says more data from the experiments is coming to help the team determine whether the circadian fluctuations of smell sensitivity helps determine food choices and eating behaviors among teens.

"The sense of smell changes across the 24 hours of the day," Carskadon said. "We don't know if that difference will affect what or how people eat. There is more to come."

https://www.sciencedaily.com/releases/2017/10/171026103130.htm

Living against the clock; Does loss of daily rhythms cause obesity?

August 29, 2012

Science Daily/Wiley

When Thomas Edison tested the first light bulb in 1879, he could never have imagined that this invention could one day contribute to a global obesity epidemic. Electric light allows us to work, rest and play at all hours of the day, and a new article suggests that this might have serious consequences for our health and for our waistlines.

Daily or "circadian" rhythms including the sleep wake cycle, and rhythms in hormone release are controlled by a molecular clock that is present in every cell of the human body. This human clock has its own inbuilt, default rhythm of almost exactly 24 hours that allows it to stay finely tuned to the daily cycle generated by the rotation of Earth. This beautiful symmetry between the human clock and the daily cycle of Earth's rotation is disrupted by exposure to artificial light cycles, and by irregular meal, work and sleep times. This mismatch between the natural circadian rhythms of our bodies and the environment is called "circadian desynchrony."

The paper, by Dr. Cathy Wyse, working in the chronobiology research group at the University of Aberdeen, focuses on how the human clock struggles to stay in tune with the irregular meal, sleep and work schedules of the developed world, and how this might influence health and even cause obesity.

"Electric light allowed humans to override an ancient synchronization between the rhythm of the human clock and the environment, and over the last century, daily rhythms in meal, sleep and working times have gradually disappeared from our lives," said Wyse. "The human clock struggles to remain tuned to our highly irregular lifestyles, and I believe that this causes metabolic and other health problems, and makes us more likely to become obese."

"Studies in microbes, plants and animals have shown that synchronization of the internal clock with environmental rhythms is important for health and survival, and it is highly likely that this is true in humans as well."

The human clock is controlled by our genes, and the research also suggests that some people may be more at risk of the effects of circadian desynchrony than others. For example, humans originating from Equatorial regions may have clocks that are very regular, which might be more sensitive to the effects of circadian desynchrony.

Shiftwork, artificial light and the 24-hour lifestyle of the developed world mean that circadian desynchrony is now an inevitable part of 21st century life. Nevertheless, we can help to maintain healthy circadian rhythms by keeping regular meal times, uninterrupted night-time sleep in complete darkness, and by getting plenty of sunlight during daylight hours.

Dr. Wyse believes that circadian desynchrony affects human health by disrupting the systems in the brain that regulate metabolism, leading to an increased likelihood of developing obesity and diabetes.

"The reason for the relatively sudden increase in global obesity in the developed world seems to be more complicated than simply just diet and physical activity. There are other factors involved, and circadian desynchrony is one that deserves further attention."

"Our 24-hour society has come at the high price of circadian desynchrony," concluded Wyse. "There are many factors driving mankind towards obesity but disrupted circadian rhythms should be considered alongside the usual suspects of diet and exercise."

http://www.sciencedaily.com/releases/2012/08/120829195119.htm

Obesity and the Biological Clock: When Times Are out of Joint

May 10, 2012

Science Daily/Ludwig-Maximilians-Universitaet Muenchen (LMU)

Urgent appointments, tight work timetables and hectic social schedules structure modern life, and they very often clash with our intrinsic biological rhythms. The discrepancy results in so-called social jetlag, which can damage one's health. Among other effects, it can contribute to the development of obesity, as a new LMU study shows.

"Our surveys suggest that in Western societies two thirds of the population are burdened with a significant discrepancy between their internal time and the demands imposed by school and work schedules and leisure stress," says LMU chronobiologist Professor Till Roenneberg, who coined the term "social jetlag" to describe the phenomenon. If the rhythms dictated by our lifestyles are persistently out of phase with our biological clock, the risk of illness, such as high blood pressure and even cancer, rises.

Tired -- around the clock A team of researchers led by Roenneberg has now shown that social jetlag also contributes to another growing health problem, particularly in countries with a Western lifestyle -- obesity. Individuals who are overweight are at increased risk for serious metabolic diseases, such as diabetes. Many factors, in addition to excessive consumption of energy-rich foods, play a role in the development of obesity, and one of them is a lack of sleep. In persons who get too little sleep, the perception of hunger is perturbed, often leading to overeating.

And it is not just sleep duration that is important here. The LMU team has also found that social jetlag shows a significant association with increased body-mass index (BMI). The BMI, which is based on a quantitative relationship between weight and height, is used as a measure of body fat, and varies depending on age and sex.

Individuals with BMIs above the normal range are regarded as being overweight or obese. The results of the new study strongly indicate that a lifestyle that conflicts with our internal physiological rhythms can promote the development of obesity.

Moreover, it appears that the incidence of social jetlag is itself increasing, perhaps as a consequence of a general reduction in sleep duration."The ongoing debate on the usefulness of daylight-saving time (DST) should take note of our findings," remarks Roenneberg. "Just like conventional school and work schedules, DST disrupts our biological clock and subjects us to more social jetlag with all its consequences."

http://www.sciencedaily.com/releases/2012/05/120510132637.htm

Disrupted Circadian Rhythm May Cause Triglycerides to Rise

August 4, 2010

Science Daily/Cell Press

When the circadian rhythm gets thrown off, it could come with an unexpected side effect: high triglycerides. The discovery, based on studies in mice with a "broken clock," helps to explain the normal rise and fall in triglycerides, which happens at about the same time each day, according to researchers who report their findings in the August issue of Cell Metabolism, a Cell Press publication.

"We show that the normal up and down [of triglycerides] is lost in clock mutants," said M. Mahmood Hussain of SUNY Downstate Medical Center. "They have high triglycerides all the time." An elevated triglyceride level is a risk factor for atherosclerosis and heart disease.

Several biological, physiological, and behavioral activities show a characteristic recurrence with 24-hour intervals attuned to sunrise and sunset, the researchers explained. That circadian rhythm is driven by the interaction of so-called clock genes.

In normal mice, plasma triglycerides double or triple over the course of the day, reaching their lowest point at night when the nocturnal animals eat and are most active, the new report shows. In clock mutants, triglyceride levels don't change; rather, they stay high all the time.

The researchers delved further into the mechanism linking the animal's internal clocks to triglycerides. They found that a core component of the circadian circuitry -- a protein known as CLOCK -- controls levels of another protein (called microsomal triglyceride transfer protein, or MTP) that helps to ferry triglycerides through the bloodstream. That control takes place via yet another transcription factor.

"Metabolic syndrome and obesity are major metabolic disorders characterized by high plasma lipid concentrations," the researchers conclude. "Plasma lipids are tightly controlled by mechanisms regulating their production and clearance. Here, we show that light-entrained mechanisms involving clock genes also play a role in regulating plasma triglyceride."

If the findings in mice can be extrapolated to humans, it suggests that the effects of drugs designed to lower triglyceride levels by acting on MTP might depend on when they are taken each day, the researchers said.

"The dose needed may vary depending on the time of day," Hussain said. "Now we can start to think about [the role of] drug timing in controlling disease states."

The findings also suggest that activities that disrupt the circadian rhythm -- staying up until 2:00 a.m. or traveling overseas -- might come with real consequences for lipid metabolism, he added.

http://www.sciencedaily.com/releases/2010/08/100803132736.htm

That Late-Night Snack: Worse Than You Think

September 7, 2009

Science Daily/Northwestern University

Eat less, exercise more. Now there is new evidence to support adding another "must" to the weight-loss mantra: eat at the right time of day.

A Northwestern University study has found that eating at irregular times -- the equivalent of the middle of the night for humans, when the body wants to sleep -- influences weight gain. The regulation of energy by the body's circadian rhythms may play a significant role. The study is the first causal evidence linking meal timing and increased weight gain.

"One of our research interests is shift workers, who tend to be overweight," said lead author Deanna M. Arble, a doctoral student in Turek's lab. "Their schedules force them to eat at times that conflict with their natural body rhythms. This was one piece of evidence that got us thinking -- eating at the wrong time of day might be contributing to weight gain. So we started our investigation with this experiment."

Simply modifying the time of feeding alone can greatly affect body weight, the researchers found. Mice that were fed a high-fat diet during normal sleeping hours gained significantly more weight (a 48 percent weight increase over their baseline) than mice eating the same type and amount of food during naturally wakeful hours (a 20 percent increase over their baseline). There was no statistical difference between the two groups regarding caloric intake or the amount of activity.

http://www.sciencedaily.com/releases/2009/09/090903110800.htm

Another Reason to Avoid High-Fat Diet: It Can Disrupt Our Biological Clock

December 31, 2008

Science Daily/Hebrew University of Jerusalem

Indulgence in a high-fat diet can not only lead to overweight because of excessive calorie intake, but also can affect the balance of circadian rhythms – everyone’s 24-hour biological clock, Hebrew University of Jerusalem researchers have shown.

The biological clock regulates the expression and/or activity of enzymes and hormones involved in metabolism, and disturbance of the clock can lead to such phenomena as hormone imbalance, obesity, psychological and sleep disorders and cancer.

While light is the strongest factor affecting the circadian clock, Dr. Oren Froy and his colleagues of the Institute of Biochemistry, Food Science and Nutrition at the Hebrew University’s Robert H. Smith Faculty of Agriculture, Food and Environment in Rehovot, have demonstrated in their experiments with laboratory mice that there is a cause-and-effect relation between diet and biological clock imbalance.

To examine this thesis, Froy and his colleagues, Ph.D. student Maayan Barnea and Zecharia Madar, the Karl Bach Professor of Agricultural Biochemistry, tested whether the clock controls the adiponectin signaling pathway in the liver and, if so, how fasting and a high-fat diet affect this control. Adiponectin is secreted from differentiated adipocytes (fat tissue) and is involved in glucose and lipid metabolism. It increases fatty acid oxidation and promotes insulin sensitivity, two highly important factors in maintaining proper metabolism.

The researchers fed mice either a low-fat or a high-fat diet, followed by a fasting day, then measured components of the adiponectin metabolic pathway at various levels of activity. In mice on the low-fat diet, the adiponectin signaling pathway components exhibited normal circadian rhythmicity. Fasting resulted in a phase advance. The high-fat diet resulted in a phase delay. Fasting raised and the high-fat diet reduced adenosine monophosphate-activated protein kinase (AMPK) levels. This protein is involved in fatty acid metabolism, which could be disrupted by the lower levels.

In an article soon to be published by the journal Endocrinology, the researchers suggest that this high-fat diet could contribute to obesity, not only through its high caloric content, but also by disrupting the phases and daily rhythm of clock genes. They contend also that high fat-induced changes in the clock and the adiponectin signaling pathway may help explain the disruption of other clock-controlled systems associated with metabolic disorders, such as blood pressure levels and the sleep/wake cycle.

http://www.sciencedaily.com/releases/2008/12/081228191054.htm

Body Clocks May Hold Key for Treatment of Bipolar Disorder

March 13, 2012

Science Daily/Manchester University

Scientists have gained insight into why lithium salts are effective at treating bipolar disorder in what could lead to more targeted therapies with fewer side-effects.

Bipolar disorder is characterised by alternating states of elevated mood, or mania, and depression. It affects between 1% and 3% of the general population.

The extreme 'mood swings' in bipolar disorder have been strongly associated with disruptions in circadian rhythms -- the 24-hourly rhythms controlled by our body clocks that govern our day and night activity.

"Our findings are important for two reasons: firstly, they offer a novel explanation as to how lithium may be able to stabilise mood swings in bipolar patients; secondly, they open up opportunities to develop new drugs for bipolar disorder that mimic and even enhance the effect lithium has on GSK3 without the side-effects lithium salts can cause."

These side-effects include nausea, acne, thirstiness, muscle weakness, tremor, sedation and/or confusion. Promisingly, GSK3 inhibiting drugs are already in development, as they have been shown to be important in other diseases, including diabetes and Alzheimer's disease.

Dr Meng added: "Lithium salt has a wide spectrum of targets within cells, in addition to GSK3; drugs which only block the actions of GSK3 would therefore have the major advantage of reduced 'off-target' effects of lithium.

"Our study has identified the robust rhythm-enhancing effect of GSK3 inhibition, which has potential to be developed as a new pharmacological approach to regulate body clocks. The implications of our study are that there may also be beneficial effects leading to new treatments for bipolar disorder, and this now needs to be tested."

http://www.sciencedaily.com/releases/2012/03/120313103922.htm

Social media use in young adults linked to sleep disturbance

January 26, 2016

Science Daily/University of Pittsburgh Schools of the Health Sciences

Young adults who spend a lot of time on social media during the day or check it frequently throughout the week are more likely to suffer sleep disturbance than their peers who use social media less, according to new research.

Published online and scheduled for the April issue of the journal Preventive Medicine, the study indicates that physicians should consider asking young adult patients about social media habits when assessing sleep issues. The research was supported by the National Institutes of Health (NIH).

"This is one of the first pieces of evidence that social media use really can impact your sleep," said lead author Jessica C. Levenson, Ph.D., a postdoctoral researcher in Pitt's Department of Psychiatry. "And it uniquely examines the association between social media use and sleep among young adults who are, arguably, the first generation to grow up with social media."

In 2014, Dr. Levenson and her colleagues sampled 1,788 U.S. adults ages 19 through 32, using questionnaires to determine social media use and an established measurement system to assess sleep disturbances.

The questionnaires asked about the 11 most popular social media platforms at the time: Facebook, YouTube, Twitter, Google Plus, Instagram, Snapchat, Reddit, Tumblr, Pinterest, Vine and LinkedIn.

On average, the participants used social media a total of 61 minutes per day and visited various social media accounts 30 times per week. The assessment showed that nearly 30 percent of the participants had high levels of sleep disturbance.

The participants who reported most frequently checking social media throughout the week had three times the likelihood of sleep disturbances, compared with those who checked least frequently. And participants who spent the most total time on social media throughout the day had twice the risk of sleep disturbance, compared to peers who spent less time on social media.

"This may indicate that frequency of social media visits is a better predictor of sleep difficulty than overall time spent on social media," Dr. Levenson explained. "If this is the case, then interventions that counter obsessive 'checking' behavior may be most effective."

Senior author Brian A. Primack, M.D., Ph.D., assistant vice chancellor for health and society in Pitt's Schools of the Health Sciences, emphasized that more study is needed, particularly to determine whether social media use contributes to sleep disturbance, whether sleep disturbance contributes to social media use -- or both.

For example, social media may disturb sleep if it is:

·      Displacing sleep, such as when a user stays up late posting photos on Instagram.

·      Promoting emotional, cognitive or physiological arousal, such as when engaging in a contentious discussion on Facebook.

·      Disrupting circadian rhythms through the bright light emitted by the devices used to access social media accounts.

·      Alternatively, young adults who have difficulty sleeping may subsequently use social media as a pleasurable way to pass the time when they can't fall asleep or return to sleep.

"It also may be that both of these hypotheses are true," said Dr. Primack, also director of Pitt's Center for Research on Media, Technology and Health. "Difficulty sleeping may lead to increased use of social media, which may in turn lead to more problems sleeping. This cycle may be particularly problematic with social media because many forms involve interactive screen time that is stimulating and rewarding and, therefore, potentially detrimental to sleep."

http://www.sciencedaily.com/releases/2016/01/160126110759.htm