Pinpointing the cells that keep the body's master circadian clock ticking
A new mouse model helps researchers study the roles of cell types in keeping time inside the body
August 7, 2020
Science Daily/UT Southwestern Medical Center
UT Southwestern scientists have developed a genetically engineered mouse and imaging system that lets them visualize fluctuations in the circadian clocks of cell types in mice. The method, described online in the journal Neuron, gives new insight into which brain cells are important in maintaining the body's master circadian clock. But they say the approach will also be broadly useful for answering questions about the daily rhythms of cells throughout the body.
"This is a really important technical resource for advancing the study of circadian rhythms," says study leader Joseph Takahashi, Ph.D., chair of the department of neuroscience at UT Southwestern Medical Center, a member of UT Southwestern's Peter O'Donnell Jr. Brain Institute, and an investigator with the Howard Hughes Medical Institute (HHMI). "You can use these mice for many different applications."
Nearly every cell in humans -- and mice -- has an internal circadian clock that fluctuates on a roughly 24-hour cycle. These cells help dictate not only hunger and sleep cycles, but biological functions such as immunity and metabolism. Defects in the circadian clock have been linked to diseases including cancer, diabetes, and Alzheimer's, as well as sleep disorders. Scientists have long known that a small part of the brain -- called the suprachiasmatic nucleus (SCN) -- integrates information from the eyes about environmental light and dark cycles with the body's master clock. In turn, the SCN helps keep the rest of the cells in the body in sync with each other.
"What makes the SCN a very special kind of clock is that it's both robust and flexible," says Takahashi. "It's a very strong pacemaker that doesn't lose track of time, but at the same time can shift to adapt to seasons, changing day lengths, or travel between time zones."
To study the circadian clock in both the SCN and the rest of the body, Takahashi's research group previously developed a mouse that had a bioluminescent version of PER2 -- one of the key circadian proteins whose levels fluctuate over the course of a day. By watching the bioluminescence levels wax and wane, the researchers could see how PER2 cycled throughout the animals' bodies during the day. But the protein is present in nearly every part of the body, sometimes making it difficult to distinguish the difference in circadian cycles between different cell types mixed together in the same tissue.
"If you observe a brain slice, for instance, almost every single cell has a PER2 signal, so you can't really distinguish where any particular PER2 signal is coming from," says Takahashi.
In the new work, the scientists overcame this problem by turning to a new bioluminescence system that changed color -- from red to green -- only in cells that expressed a particular gene known as Cre. Then, the researchers could engineer mice so that Cre, which is not naturally found in mouse cells, was only present in one cell type at a time.
To test the utility of the approach, Takahashi and his colleagues studied two types of cells that make up the brain's SCN -- arginine vasopressin (AVP) and vasoactive intestinal polypeptide (VIP) cells. In the past, scientists have hypothesized that VIP neurons hold the key to keeping the rest of the SCN synchronized.
When the research team looked at VIP neurons -- expressing Cre in just those cells, so that PER2 luminesced green in VIP cells, while red elsewhere -- they found that removing circadian genes from the neurons had little overall effect on the circadian rhythms of the VIP neurons, or the rest of the SCN. "Even when VIP neurons no longer had a functioning clock, the rest of the SCN behaved essentially the same," explains Yongli Shan, Ph.D., a UTSW research scientist and lead author of the study. Nearby cells were able to signal to the VIP neurons to keep them in sync with the rest of the SCN, he says.
When they repeated the same experiment on AVP neurons, however -- removing key clock genes -- not only did AVP neurons themselves show disrupted rhythms, but the entire SCN stopped synchronously cycling on its usual 24-hour rhythm.
"What this showed us was that the clock in AVP neurons is really essential for the synchrony of the whole SCN network," says Shan. "That's a surprising result and somewhat counterintuitive, so we hope it leads to more work on AVP neurons going forward."
Takahashi says other researchers who study circadian rhythms have already requested the mouse line from his lab to study the daily cycles of other cells. The mice might allow scientists to hone in on the differences in circadian rhythms between cell types within a single organ, or how tumor cells cycle differently than healthy cells, he says.
"In all sorts of complex or diseased tissues, this can let you see which cells have rhythms and how they might be similar or different from the rhythms of other cell types."
https://www.sciencedaily.com/releases/2020/08/200807111938.htm
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
1 in 300 thrives on very-early-to-bed, very-early-to-rise routine
Many extreme early birds share genetic trait with family members
August 6, 2019
Science Daily/University of California - San Francisco
A quirk of the body clock that lures some people to sleep at 8 p.m., enabling them to greet the new day as early as 4 a.m., may be significantly more common than previously believed.
So-called advanced sleep phase -- previously believed to be very rare -- may affect at least one in 300 adults, according to a study led by UC San Francisco and publishing in the journal SLEEP on Aug. 6, 2019.
Advanced sleep phase means that the body's clock, or circadian rhythm, operates on a schedule hours earlier than most people's, with a premature release of the sleep hormone melatonin and shift in body temperature. The condition is distinct from the early rising that develops with normal aging, as well as the waking in the wee hours experienced by people with depression.
"While most people struggle with getting out of bed at 4 or 5 a.m., people with advanced sleep phase wake up naturally at this time, rested and ready to take on the day," said the study's senior author, Louis Ptacek, MD, professor of neurology at the UCSF School of Medicine. "These extreme early birds tend to function well in the daytime but may have trouble staying awake for social commitments in the evening."
Advanced Sleepers 'Up and at 'Em' on Weekends too
Additionally, "advanced sleepers" rouse more easily than others, he said, and are satisfied with an average of an extra five-to-10 minutes of sleep on non-work days, versus the 30-to-38 minutes' more sleep of their non-advanced sleeper family members.
Ptacek and his colleagues at the University of Utah and the University of Wisconsin calculated the estimated prevalence of advanced sleepers by evaluating data from patients at a sleep disorder clinic over a nine-year period. In total, 2,422 patients were followed, of which 1,748 presented with symptoms of obstructive sleep apnea, a condition that the authors found was not related to sleep-cycle hours.
Among this group, 12 people met initial screening criteria for advanced sleep phase. Four of the 12 declined enrollment in the study and the remaining eight comprised the 0.03 percent of the total number of patients -- or one out of 300 -- that was extrapolated for the general population.
This is a conservative figure, the researchers noted, since it excluded the four patients who did not want to participate in the study and may have met the criteria for advanced sleep phase, as well as those advanced sleepers who had no need to visit a sleep clinic.
Night Owls More Likely to Struggle with Sleep Deficits
"Generally, we find that it's the people with delayed sleep phase -- those night owls that can't sleep until as late as 7 a.m. -- who are more likely to visit a sleep clinic. They have trouble getting up for work and frequently deal with chronic sleep deprivation," said Ptacek.
Criteria for advanced sleep phase include the ability to fall asleep before 8:30 p.m. and wake before 5:30 a.m. regardless of any occupational or social obligations, and having only one sleep period per day. Other criteria include the establishment of this sleep-wake pattern by the age of 30, no use of stimulants or sedatives, no bright lights to aid early rising and no medical conditions that may impact sleep.
All study participants were personally seen by Christopher R. Jones, MD, a former neurologist at the University of Utah and co-author of the paper. Patients were asked about their medical histories and both past and present sleep habits on work days and work-free days. Researchers also looked at sleep logs and level of melatonin in the participants' saliva, as well as sleep studies, or polysomnography, that record brainwaves, oxygen levels in the blood, heart rate and breathing.
Of note, all eight of the advanced sleepers claimed that they had at least one first-degree relative with the same sleep-wake schedule, indicating so-called familial advanced sleep phase. Of the eight relatives tested, three did not meet the full criteria for advanced sleep phase and the authors calculated that the remaining five represented 0.21 percent of the general population.
The authors believe that the percentage of advanced sleepers who have the familial variant may approach 100 percent. However, some participants may have de novo mutations that may be found in their children, but not in parents or siblings, and some may have family members with "nonpenetrant" carrier mutations. Two of the remaining five were found to have genetic mutations that have been identified with familial advanced sleep phase. Conditions associated with these genes include migraine and seasonal affective disorder.
"We hope the results of this study will not only raise awareness of advanced sleep phase and familial advanced sleep phase," said Ptacek, "but also help identify the circadian clock genes and any medical conditions that they may influence."
https://www.sciencedaily.com/releases/2019/08/190806101552.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
Moving light-dark exposure could reduce disruption faced by night shift workers
March 27, 2018
Science Daily/The Physiological Society
New research shows that our brain clock can be shifted by light exposure, potentially to align it with night shift patterns. It highlights that a 'one size fits all' approach to managing sleep disruption in shift workers may not be appropriate. A personalized approach, with light-dark exposure scheduled and taking into account whether someone is a 'morning' or 'evening' person, could reduce shift workers' risk of health problems.
Our sleep-wake cycle, in part controlled by our brain clock, encompasses physical, mental and behavioural changes that follow a daily cycle. Light is the dominant environmental time cue which results in, for example, sleeping at night and being awake during the day.
Night time shift work disrupts the normal sleep-wake cycle and our internal circadian (24-hour) rhythms, and has been associated with significant health problems, such as a higher risk of heart disease and cancer. Alertness levels are often markedly impaired while working night shifts.
While it has been known that there are considerable differences in how the brain clock of different individuals responds to changing shift cycles, we have known very little about the mechanisms that underlie these differences between people. If someone was able to realign their brain clock to their shift pattern, then it would improve sleep and could lead to health benefits. While such realignment is rare, in some circumstances such as on offshore oil rig platforms, complete adaption has been observed.
This new research aims to understand the relationship between light exposure and how an individual's circadian rhythm is affected across a transition from day to night shift schedules. The researchers found that timing of light exposure is the primary factor in determining how the brain clock responds to night shift work, accounting for 71% of the variability in timing of the clock observed in the study. It also found that the extent to which an individual is a 'morning' or 'evening' type affects how the body responds, which shows that a personalised approach is important.
This study was led by the CRC for Alertness, Safety and Productivity and saw nursing and medical staff recruited from an Intensive Care Unit at a major hospital in Melbourne, Australia. Staff members were enrolled into the study when working a schedule of day or evening shifts, or days off, followed by at least 3 or 4 consecutive night shifts.
To examine how the sleep-wake cycle responds to the shift schedule, the timing of the brain clock was measured on the day schedule, and at the end of the night shifts. It was measured by monitoring urinary concentration of the major metabolite of melatonin, which is a hormone produced in the pineal gland known to be involved in the regulation of sleep cycles. Individual light exposure was measured using wrist actigraphs, worn for the duration of the study.
Prof Shantha Rajaratnam, from Monash University and the CRC for Alertness, Safety and Productivity, corresponding author for the study, said:
"We know that night time shift workers are more likely to suffer health problems due to disruption of their circadian clock, and the mismatch between the timing of the clock and their sleep-wake cycle. This research is important because if we can realign a person's clock to fit their shift pattern, then they will sleep better and this may result in improved health, safety and productivity.
"These results will drive development of personalised approaches to improve sleep-wake cycles of shift workers and other vulnerable people, and could potentially reduce the increased risk of disease due to circadian disruption."
https://www.sciencedaily.com/releases/2018/03/180327203014.htm
Effects of night-time light on internal body clock
April 30, 2018
Science Daily/The Physiological Society
New research published in The Journal of Physiology has illuminated the effects of night-time light exposure on internal body clock processes. This is important for helping those who have poor quality sleep, such as shift workers, and could help improve treatments for depression.
The body has an internal clock that causes various physiological processes to oscillate in 24-h cycles, called circadian rhythms, which includes daily changes in sleepiness. Light is the strongest environmental time cue that resets the body's internal 24-h clock. Melatonin is a hormone produced in the brain at night that regulates this body clock and exposure to light before bedtime may reduce sleep quality by suppressing its production. The research team aimed to explore the link between the physiological process that enables our internal body clock to synchronise to external time cues (i.e. day and night) -- called circadian phase resetting -- and suppression of melatonin.
Melatonin suppression and circadian phase resetting are often correlated such that high levels of melatonin suppression can be associated with large shifts of the body clock. This association between the two responses has often been assumed to represent a functional relationship, resulting in the acceptance that one could be used as a proxy measure for the other. Circadian phase resetting is more difficult to measure than melatonin suppression, meaning the latter has often been used to assess disruption to the body clock caused by light exposure at night. However, this research has found that the magnitude of the shift in internal body clock is functionally independent from melatonin suppression. This casts doubt on the use of melatonin suppression as a proxy for circadian phase resetting. This knowledge may shape future research designed to improve treatments for depression and shift work sleep disorder.
The researchers tested the association between melatonin suppression and circadian phase resetting in participants who received either continuous or intermittent bright light exposure at night. This research procedure involved each participant completing a 9-10 day inpatient study at Brigham and Women's Hospital, Boston, under highly controlled laboratory conditions with strict control over their sleep/wake, activity and light/dark schedules. Intermittent exposure patterns were found to show significant phase shifts with disproportionately less melatonin suppression. Moreover, each and every intermittent bright light pulse induced a similar degree of melatonin suppression, but did not appear to cause an equal magnitude of phase shift.
Despite the results of this study suggesting functional independence in circadian phase resetting and melatonin suppression responses to exposure to light at night, the study's conclusions may be restricted by the limited sample size in each light exposure condition.
Lead author Dr Shadab Rahman is excited by his team's findings, and is looking forward to investigating new avenues of interest they have opened up:
"Overall, our data suggest that melatonin suppression and phase resetting are sometimes correlated, but ultimately are regulated by separate neurophysiological processes. Therefore melatonin suppression is not a reliable surrogate for phase resetting. This is an important consideration for developing light-therapy treatments for people who have poor quality sleep and biological clock disruption, such as shift workers, or disorders such as depression. Additional work is needed to optimize light therapy protocols used as treatment."
https://www.sciencedaily.com/releases/2018/04/180430075635.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
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
New Evidence of Age-Related Decline in the Brain's Master Circadian Clock
July 25, 2011
Science Daily/University of California - Los Angeles
A new study of the brain's master circadian clock -- known as the suprachiasmatic nucleus, or SCN -- reveals that a key pattern of rhythmic neural activity begins to decline by middle age. The study, whose senior author is UCLA Chancellor Gene Block, may have implications for the large number of older people who have difficulty sleeping and adjusting to time changes.
"Aging has a profound effect on circadian timing," said Block, a professor of psychiatry and biobehavioral sciences and of physiological science. "It is very clear that animals' circadian systems begin to deteriorate as they age, and humans have enormous problems with the quality of their sleep as they age, difficulty adjusting to time-zone changes and difficulty performing shift-work, as well as less alertness when awake. There is a real change in the sleep-wake cycle.
"The question is, what changes in the nervous system underlie all of that? This paper suggests a primary cause of at least some of these changes is a reduction in the amplitude of the rhythmic signals from the SCN."
The SCN, located in the hypothalamus, is the central circadian clock in humans and other mammals and controls not only the timing of the sleep-wake cycle but also many other rhythmic and non-rhythmic processes in the body.
The SCN keeps the system of multiple distributed circadian oscillators in synchrony, but disruptions in the SCN lead to disrupted sleep, as well as dysfunction in memory, the cardiovascular system, and the body's immune response and metabolism.
The SCN, Block said, can be imagined as a heavy pendulum that controls many light pendulums (oscillators), with rubber bands between them.
"If the central clock weakens, it's effectively like making those rubber bands thinner and weaker," Block said. "When the SCN ages and those rubber bands become weaker, it becomes hard for the SCN to synchronize all of these other oscillators."
http://www.sciencedaily.com/releases/2011/07/110719093808.htm
Faulty Body Clock May Make Kids Bipolar
November 13, 2009
Science Daily/BioMed Central
Malfunctioning circadian clock genes may be responsible for bipolar disorder in children. Researchers writing in the open access journal BMC Psychiatry found four versions of the regulatory gene RORB that were associated with pediatric bipolar disorder.
Alexander Niculescu from Indiana University School of Medicine, Indianapolis, US, worked with a team of researchers at Harvard, UC San Diego, Massachusetts General Hospital and SUNY Upstate Medical University to study the RORA and RORB genes of 152 children with the condition and 140 control children.
They found four alterations to the RORB gene that were positively associated with being bipolar. Niculescu said, "Our findings suggest that clock genes in general and RORB in particular may be important candidates for further investigation in the search for the molecular basis of bipolar disorder".
http://www.sciencedaily.com/releases/2009/11/091111200213.htm
Light exposure and kids' weight: Is there a link?
World-first study revealing light exposure plays a role in the weight of preschool children
January 7, 2016
Science Daily/Queensland University of Technology
Light exposure plays a role in the weight of preschool children, a world-first study reveals. The researchers studied children aged three to five, from six childcare centers, measuring the children's sleep, activity and light exposure for a two week period, along with height and weight to calculate their BMI, then followed up 12-months later.
https://images.sciencedaily.com/2016/01/160107104820_1_540x360.jpg
Around 42 million children around the globe under the age of five are classified as overweight or obese so this study is a significant breakthrough and a world-first, say the researchers.
Credit: © TuTheLens / Fotolia
PhD student Cassandra Pattinson and colleagues Simon Smith, Alicia Allan, Sally Staton and Karen Thorpe studied children aged three to five, from six Brisbane childcare centres. At time 1, they measured children's sleep, activity and light exposure for a two week period, along with height and weight to calculate their BMI, then followed up 12-months later
"At time 1, we found moderate intensity light exposure earlier in the day was associated with increased body mass index (BMI) while children who received their biggest dose of light -- outdoors and indoors -- in the afternoon were slimmer," said Ms Pattinson of the Environmental Light Exposure is Associated with Increased Body Mass in Children study.
"At follow-up, children who had more total light exposure at Time 1 had higher body mass 12 months later. Light had a significant impact on weight even after we accounted for Time 1 body weight, sleep, and activity.
"Around 42 million children around the globe under the age of five are classified as overweight or obese so this is a significant breakthrough and a world-first.
"Artificial lighting, including light given off by tablets, mobile phones, night lights, and television, means modern children are exposed to more environmental light than any previous generation. This increase in light exposure has paralleled global increases in obesity."
The research team is from QUT's Institute of Health and Biomedical Innovation and the Centre for Children's Health Research
Ms Pattinson said it is known the timing, intensity and duration of exposure to both artificial and natural light have acute biological effects in mammals.
"The circadian clock -- also known as the internal body clock -- is largely driven by our exposure to light and the timing of when that happens. It impacts on sleep patterns, weight gain or loss, hormonal changes and our mood," Ms Pattinson said
"Factors that impact on obesity include calorie intake, decreased physical activity, short sleep duration, and variable sleep timing. Now light can be added to the mix."
Ms Pattinson said the next step was to figure out how the research can be used in the fight against obesity in children.
"We plan to conduct further studies with pre-schoolers and also infants," she said.
"Animal studies have shown that timing and intensity of light exposure is critical for metabolic functioning and weight status. Our findings suggest that the same applies to us.
"This research suggests that exposure to different types of light (both artificial and natural) at different times now needs to be part of the conversation about the weight of children."
http://www.sciencedaily.com/releases/2016/01/160107104820.htm
Light exposure linked to weight gain in children
October 23, 2015
Science Daily/Queensland University of Technology
A world-first study has revealed pre-schoolers exposed to more light earlier in day tend to weigh more. She says the research suggests light exposure, artificial and natural, needs to be part of the conversation about the weight of children, along with calorie intake, decreased physical activity and sleep patterns.
http://images.sciencedaily.com/2015/10/151023105914_1_540x360.jpg
Ms Pattinson said it is known the timing, intensity and duration of exposure to both artificial and natural light have acute biological effects in mammals. (Stock image of normal healthy child)
Credit: © Sabphoto / Fotolia
Cassandra Pattinson, a PhD student and her colleagues studied 48 children aged three to five from six Brisbane childcare centres over a two week period, measuring each child's sleep, activity and light exposure along with their height and weight to calculate their BMI.
"We found moderate intensity light exposure earlier in the day was associated with increased body mass index (BMI) while children who received their biggest dose of light -- outdoors and indoors -- in the afternoon were slimmer," said Ms Pattinson who will present her findings at the ASA Sleep Downunder Conference in Melbourne on 23 October.
"Surprisingly physical activity was not associated with the body mass of the children but sleep timing and light exposure was. This is the first time light has been shown to contribute to weight in children.
"With an estimated 42 million children around the globe under the age of five being classified as overweight or obese, it is a significant breakthrough and a world-first.
"Thanks to artificial lighting, including light given off by tablets, mobile phones, night lights, and television, modern children are exposed to more environmental light than any previous generation. This increase in light exposure has paralleled global increases in obesity."
The research team, from QUT's Institute of Health and Biomedical Innovation, worked with the Centre for Children's Health Research
Ms Pattinson said it is known the timing, intensity and duration of exposure to both artificial and natural light have acute biological effects in mammals.
"The circadian clock -- also known as the internal body clock -- is largely driven by our exposure to light and the timing of when that happens. It impacts on sleep patterns, weight gain or loss, hormonal changes and our mood," Ms Pattinson said
"Recent research in adults suggests exposure to light later in the day is associated with increased body mass, but no studies had investigated these effects in young children and it turns out it has the opposite effect.
"While adults who take in more morning light are slimmer, pre-school children exposed to morning light tend to be heavier.
"Factors that impact on obesity include calorie intake, decreased physical activity, short sleep duration, and variable sleep timing. Now light can be added to the mix."
Ms Pattinson said the next step was to figure out how the research can be used in the fight against obesity in children.
"We plan to conduct further studies with pre-schoolers and also infants," she said.
"Animal studies have shown that timing and intensity of light exposure is critical for metabolic functioning and weight status. Our findings suggest that the same applies to us.
"This research suggests that exposure to different types of light at different times now needs to be part of the conversation about the weight of children."
Jet lag treatment? Blast of thin air can reset circadian clocks
October 20, 2016
Science Daily/Cell Press
We might not think of our circadian clock until we are jetlagged, but scientists continue to puzzle over what drives our biological timepiece. Now, a study has found that variations in surrounding oxygen levels can reset circadian clocks of mice. If confirmed in humans, the research could help inform how airlines moderate cabin air pressure.
Presently, light, food, and temperature are the best known cues that can influence circadian rhythms. But lead author Gad Asher, a senior scientist at the Weizmann Institute of Science in Rehovot, Israel, and his colleagues, including postdoctoral fellows Yaarit Adamovich and Benjamin Ladeuix, wondered if oxygen might also cue circadian rhythms since oxygen absorption in animals varies alongside meals and changing temperatures.
In the paper, the researchers show that changing the concentration of oxygen in cells by just 3%, twice a day, will synchronize mouse cells to a circadian rhythm. They suspected HIF1α was the link between oxygen and the circadian clock because HIF1α plays both a role in oxygen homeostasis in cells. They found that cells with low HIF1α levels won't synchronize in response to oxygen variations.
"It was extremely exciting to see that even small changes in oxygen levels were sufficient to efficiently reset the circadian clock," says Asher. "The study actually raises a lot of important questions; although we show that clock reset by oxygen is dependent on HIF1α, we did not yet fully identify how HIF1α integrates within the core clock circuitry."
The researchers further explored oxygen's effect on circadian rhythms with jetlag experiments. Just like humans, mice are prone to jetlag after a sudden shift in daylight hours. Mice were first left to eat, sleep and run on their wheels in air-controlled environments. Altering oxygen levels alone did not change their circadian rhythms but once mice experienced a 6-hour jump ahead in daylight hours, varying oxygen levels could help them adapt their eating, sleeping and running habits to the new time faster. They also saw that a small drop in oxygen levels 12 hours before the 6-hour daylight shift, or 2 hours afterwards, put the mice back on their circadian schedules faster and this too was dependent on HIF1α levels.
Presently, commercial airliners pressurize cabins to the same air density of a city 6,000-8,000 feet above sea level. This low-pressure saves wear and tear on the airplane, but enough passengers suffer from airsickness in response to this drop in oxygen levels that some airlines are considering ways to increase the pressure on flights. In fact, Boeing designed its new 787 Dreamliner so that it can be pressurized to the equivalent of lower altitudes for this reason. But in light of these findings, the researchers noted passengers may feel better with higher pressurized cabins during flights, but may also lose a potential advantage of recovering from jetlag. And in light of the effects of lower oxygen levels, the researchers now want to see what higher oxygen levels may do to the circadian clock.
"We are very looking forward to seeing the outcome of these experiments -- it will be interesting both from basic science and also from a practical standpoint," said Asher. "I believe passengers might be more enthusiastic to inhale oxygen-enriched air to alleviate jetlag in contrast to low oxygen."
Understanding how oxygen influences the circadian clock goes beyond jetlag. Cardiovascular disease, COPD, shift work sleep disorder, and other common health problems can result in tissues with low oxygen levels. "We show that oxygen works in mammals, specifically rodents, but it will be interesting to test whether oxygen can reset the clock of bacteria, plants, flies and additional organisms," says Asher.
https://www.sciencedaily.com/releases/2016/10/161020142746.htm