Helping SAD Sufferers Sleep Soundly

Lying awake in bed plagues everyone occasionally, but for those with seasonal affective disorder, sleeplessness is routine.University of Pittsburgh researchers report in the Journal of Affective Disorders that individuals with seasonal affective disorder (SAD)—a winter depression that leads to loss of motivation and interest in daily activities—have misconceptions about their sleep habits similar to those of insomniacs. These findings open the door for treating seasonal affective disorder similar to the way doctors treat insomnia.

Kathryn Roecklein, primary investigator and assistant professor in Pitt’s Department of Psychology within the Kenneth P. Dietrich School of Arts and Sciences, along with a team of researchers from Pitt’s School of Medicine and Reyerson University, investigated why, according to a previously published sleep study by the University of California, Berkeley, individuals with seasonal affective disorder incorrectly reported that they slept four more hours a night in the winter. 

“We wondered if this misreporting was a result of depression symptoms like fatigue and low motivation, prompting people to spend more time in bed,” said Roecklein. “And people with seasonal affective disorder have depression approximately five months a year, most years. This puts a significant strain on a person’s work life and home life.”

Roecklein and her team interviewed 147 adults between the ages of 18 and 65 living in the Pittsburgh metropolitan area during the winters of 2011 and 2012. Data was collected through self-reported questionnaires and structured clinical interviews in which participants were asked such questions as: “In the past month, have you been sleeping more than usual?” and “How many hours, on average, have you been sleeping in the past month? How does that compare to your normal sleep duration during the summer?” 

In order to understand participants’ ideas about sleep, Roecklein’s team asked them to respond to questions such as “I need at least 8 hours of sleep to function the next day” and “Insomnia is dangerous for health” on a scale from 0 to 7, where 7 means “strongly agree” and 0 means “disagree completely.”

Roecklein and her team found that SAD participants’ misconceptions about sleep were similar to the “unhelpful beliefs” or personal misconceptions about sleep that insomniacs often hold. Due to depression, individuals with SAD, like those with insomnia, may spend more time resting in bed, but not actually sleeping—leading to misconceptions about how much they sleep. These misconceptions, said Roecklein, play a significant role in sleep cognition for those with seasonal affective disorder.

“We predict that about 750,000 people in the Pittsburgh metro area suffer from seasonal affective disorder, making this an important issue for our community and the economic strength and vitality of our city,” said Roecklein. “If we can properly treat this disorder, we can significantly lower the number of sufferers in our city.”

Roecklein’s research data suggests that addressing, understanding, and managing these “unhelpful beliefs” about sleep by way of psychotherapy could lead to improved treatments for seasonal affective disorder. One of the most effective treatment options for insomnia, said Roecklein, is cognitive behavioral therapy for insomnia (known as CBT-I), which aims to help people take control of their thinking to improve their sleep habits as well as mood, behavior, and emotions.

Roecklein’s next research project aims to improve treatment for seasonal affective disorder by studying light perception and biological clock synchronization. Light from the environment synchronizes internal biological rhythms with the timing of dawn and dusk, which naturally changes with the seasons. This synchronization allows people to be awake and alert during the day and to sleep at night. Roecklein will examine whether people with seasonal affective disorder perceive this light from the environment differently because of changes in the function of neurological pathways from the eye to the brain. This could help uncover reasons why people suffer from seasonal affective disorder and could suggest new treatment options.

(Image: Shutterstock)

Key Protein is Linked to Circadian Clocks, Helps Regulate Metabolism

Inside each of us is our own internal timing device. It drives everything from sleep cycles to metabolism, but the inner-workings of this so-called “circadian clock” are complex, and the molecular processes behind it have long eluded scientists. But now, researchers at the Gladstone Institutes have discovered how one important protein falls under direct instructions from the body’s circadian clock. Furthermore, they uncover how this protein regulates fundamental circadian processes—and how disrupting its normal function can throw this critical system out of sync.

In the latest issue of the Journal of Neuroscience, Gladstone Investigator Katerina Akassoglou, PhD, and her team reveal in animal models how the production of the p75 neurotrophin receptor (p75NTR) protein oscillates in time with the body’s natural circadian clock—and how these rhythmic oscillations help regulate vital metabolic functions. This discovery underscores the widespread importance of p75NTR by offering insight into how the circadian clock helps maintain the body’s overall metabolic health.

Virtually every organism on the planet—from bacteria to humans—has a circadian clock, a biological timing mechanism that oscillates with a period of about 24 hours and is coordinated with the cycle of day and night. And while it runs independent of external cues, it is influenced by the rhythms of light, temperature and food availability. Intriguingly, recent studies have also found a link between circadian clocks and metabolism.

“Important metabolic functions are also heavily influenced by circadian clocks, which is why activities such as chronic night-shift work—which can cause a misalignment of this clock—increase one’s risk for metabolic and autoimmune diseases such as obesity, Type 2 diabetes, cancer and multiple sclerosis,” said Dr. Akassoglou. Dr. Akassoglou is also a professor of neurology at the University of California, San Francisco, (UCSF) with which Gladstone is affiliated. “In this study, we pinpointed p75NTR as an important molecular ‘link’ between circadian clocks and metabolic health.”

Originally, p75NTR was only thought to be active in the nervous system. Later studies found it to be active in many cell types throughout the body, suggesting that it impacts a variety of biological functions. Last year, Gladstone researchers discovered that p75NTR was present in the liver and in fat cells, and that it regulates glucose levels in the blood—an important metabolic process. Since these findings uncovered a link between p75NTR and metabolism, the research team tested—first in a petri dish and then in animal models—whether there was also a link between p75NTR and the circadian clock.

The team focused on two genes called Clock and Bmal1. These so-called “circadian regulator genes,” and others like them, are found throughout the body. Their activity controls the body’s circadian clock. The researchers wanted to see if there was a connection between these circadian genes and p75NTR.

“Our initial experiments revealed such a connection,” recalls Gladstone Postdoctoral Fellow Bernat Baeza-Raja, PhD, the paper’s lead author. “In individual cells, we saw that p75NTR production was controlled by Clock and Bmal1, which bind directly to the gene that codes for the p75NTR and start production of the protein.”

But perhaps even more important than how p75NTR was produced was when. The team found that p75NTR production, like the circadian clock genes themselves, oscillated in a 24-hour cycle—in sync with the cells’ natural circadian rhythm. Experiments in mouse models further supported these findings.

And when the team genetically modified a group of mice so that it lacked the circadian Clock gene, everything else fell out of sync. The circadian oscillation of p75NTR production was disrupted, and p75NTR levels dropped.

However, what was most fascinating, say the researchers, was how a drop in p75NTR levels then affected a variety of circadian clock systems. Specifically, the regular oscillations of other circadian genes in the brain and the liver became disrupted, as well as genes known to regulate glucose and lipid metabolism.

“The finding that a loss of p75NTR affected circadian and metabolic systems is strong evidence that this protein is intricately tied to both,” said Life Sciences Institute Director Alan Saltiel, PhD, who is also a professor at the University of Michigan and was not involved in the study. “It will be fascinating to see what additional insight Dr. Akassoglou and her team will uncover as they continue to examine the role of p75NTR in circadian clocks and metabolic function.”

“While these findings reveal p75NTR to be an important link between circadian clocks and metabolism, the system is complex, and there are likely other factors at play,” said Dr. Akassoglou. “We are currently working to identify the relationship between the circadian clock, metabolism and the immune system, so that one day we could develop therapies to treat diseases influenced by circadian clock disruption—including not only obesity and diabetes, but also potentially multiple sclerosis and even Alzheimer’s disease.”

(Image: Brain Treatment Center)

Scientists map the wiring of the biological clock

The World Health Organization lists shift work as a potential carcinogen, says Erik Herzog, PhD, Professor of Biology in Arts & Sciences at Washington University in St. Louis. And that’s just one example among many of the troubles we cause ourselves when we override the biological clocks in our brains and pay attention instead to the mechanical clocks on our wrists.

In the June 5 issue of Neuron, Herzog and his colleagues report the discovery of a crucial part of the biological clock: the wiring that sets its accuracy to within a few minutes out of the 1440 minutes per day. This wiring uses the neurotransmitter, GABA, to connect the individual cells of the biological clock in a fast network that changes strength with time of day.

Daily rhythms of sleep and metabolism are driven by a biological clock in the suprachiasmatic nucleus (SCN), a structure in the brain made up of 20,000 neurons, all of which can keep daily (circadian) time individually.

If the SCN is to be a robust, but sensitive, timing system, the neurons must synchronize precisely with one another and adjust their rhythms to those of the environment.

Herzog’s lab has discovered a push-pull system in the SCN that does both. In 2005 they reported that the neurons in the clock network communicate by means of a neuropeptide (VIP) that pushes them to synchronize with one another. And, as they now report in Neuron, these neurons also communicate with GABA that pulls on them weakly, so they are not too tightly coupled.

Together these two networks (VIP and GABA) ensure the clock runs as coordinated, precise timepiece but one that can still adjust its timing to synchronize with the environment.

“We think the neurotransmitter network is there to introduce enough jitter into the system to allow the neurons to resynchronize when environmental cues change, as they do with the seasons,” Herzog says. But, he says, since this biological ‘reset button’ evolved long before mechanical clocks, artificial lights, and high-speed travel, it doesn’t introduce enough jitter to allow us to adjust quickly to the extreme time shifts of modern life, such as flying “backward” (east) through several time zones.

Understanding the push-pull system in the SCN has enormous implications for public health, bearing, as it does, on daylight saving times, shift work, school starting times, medical intern schedules, truck driver hours, and many other issues where the clock in the brain is pitted against the clock in the hand.

Synchronizing the cellular clocks
The “clock” inside each SCN neuron depends on the cyclic expression of a family of genes such as the Period (PER) genes. The expression of these genes and the neuron’s firing rate typically peak at mid-day and fall at night. The gene activity is like the cogs in a clock, and the electrical activity like the hands on the clock.

Each neuron in the SCN keeps time, but because they’re different cells, they have slightly different rhythms. Some run a little bit fast and others a bit slow. If the SCN as a whole is to function as a clock, its neurons need to synchronize with one another.

The goal of the recent work in the Herzog lab has been to figure out how the clock cells are connected to each other. “It wasn’t clear, for example, if each neuron communicated with just a few of its neighbors or with all of them,” Herzog says.

Mark Freeman, a graduate student in the lab, developed a method for recording the firing rate of about 100 neurons simultanously on a multi-electrode array. “You float the SCN neurons down gently,” Herzog says, “and the neurons will attach to the electrodes, creating a clock in a dish that will tick away for weeks or months.”

Using these electrode arrays, his lab demonstrated that the neurons in the SCN are synchronized by the exchange of the neuropeptide VIP (vasoactive intestinal polypeptide), which alters the expression of PER to speed up or slow down neurons until they are all in synch.

These synchronized networks are very precise, says Herzog. If you let them free-run in constant darkness they will lose or gain only a few minutes out of the 1,440 minutes in a day. So they’re accurate to within 1 or 2 percent.

But they’re ever so slightly off the 24-hour cycle tied to one turn of the planet on its axis. Over time they would drift far enough off that cycle to be of little use to us, unless they also had some means of synchronizing to local time.

Resetting the cellular clocks
In the article published in Neuron, Herzog and his colleagues report on a second network in the biological clock.

In this network the connections are made by the neurotransmitter GABA (γ-amino-butyric acid). “We proved we had found a GABAergic network by applying drugs that block GABA receptors on the cells,” Herzog says. “All of the connections we had mapped between neurons dropped out.”

Remarkably, when the network drops out, the clock becomes more precise. So the GABAergic network destabilizes the clock; it jiggles it a little.

Herzog points out that the GABAergic network, is sparse, weak and fast (much faster than the VIP network, which relies on the slower action of a neuropeptide), as you might expect a jitter-generator to be.

“We think the GABAergic network is there to let our clocks adjust to environmental cues, such as gradual, seasonal changes in sunrise and sunset,” says Herzog. 

It’s a bit like whacking an old television set that has lost vertical synch to get it to resynch with the broadcast signal.

But there isn’t enough jitter in the clock to allow it to make abrupt adjustments, such as the one-hour forward jump when Daylight Savings Time starts. That “spring forward” has been statistically shown to increase the likelihood of heart attacks and car accidents, Herzog says.

Some sleep aids, such as benzodiazepines, that activate the GABA receptors may make the circadian clock a little more jittery, helping people adjust to big time jumps, such as flying across time zones. “But we don’t yet know whether they can improve jetlag; if they do, we want to know if it is because they help you sleep on the long flight or because they help the biological clock adjust to the new time zone,” Herzog cautions.

In any case, it is clear that if people repeatedly force the clock to reset, they throw off more than sleep. The biological clock regulates metabolism and cell division as well as sleep/wake cycles. So shift work, for example, is associated both with metabolic disorders, such as diabetes, and with the unregulated cell division that characterizes cancer.

Fighting our biological clocks does a lot more than make us crabby coffee drinkers.

Circadian clock linked to obesity, diabetes and heart attacks

Disruption in the body’s circadian rhythm can lead not only to obesity, but can also increase the risk of diabetes and heart disease.

That is the conclusion of the first study to show definitively that insulin activity is controlled by the body’s circadian biological clock. The study, which was published on Feb. 21 in the journal Current Biology, helps explain why not only what you eat, but when you eat, matters.

The research was conducted by a team of Vanderbilt scientists directed by Professor of Biological Sciences Carl Johnson and Professors of Molecular Physiology and Biophysics Owen McGuinness and David Wasserman.

“Our study confirms that it is not only what you eat and how much you eat that is important for a healthy lifestyle, but when you eat is also very important,” said postdoctoral fellow Shu-qun Shi, who performed the experiment with research assistant Tasneem Ansari in the Vanderbilt University Medical Center’s Mouse Metabolic Phenotyping Center.

In recent years, a number of studies in both mice and men have found a variety of links between the operation of the body’s biological clock and various aspects of its metabolism, the physical and chemical processes that provide energy and produce, maintain and destroy tissue. It was generally assumed that these variations were caused in response to insulin, which is one of the most potent metabolic hormones. However, no one had actually determined that insulin action follows a 24-hour cycle or what happens when the body’s circadian clock is disrupted.

Because they are nocturnal, mice have a circadian rhythm that is the mirror image of that of humans: They are active during the night and sleep during the day. Otherwise, scientists have found that the internal timekeeping system of the two species operate in nearly the same way at the molecular level. Most types of cells contain their own molecular clocks, all of which are controlled by a master circadian clock in the suprachiasmatic nucleus in the brain.

“People have suspected that our cells’ response to insulin had a circadian cycle, but we are the first to have actually measured it,” said McGuinness. “The master clock in the central nervous system drives the cycle and insulin response follows.”

Circadian rhythms can be modified for potential treatment of disorders

UC Irvine-led studies have revealed the cellular mechanism by which circadian rhythms – also known as the body clock – modify energy metabolism and also have identified novel compounds that control this action. The findings point to potential treatments for disorders triggered by circadian rhythm dysfunction, ranging from insomnia and obesity to diabetes and cancer.

UC Irvine’s Paolo Sassone-Corsi, one of the world’s leading researchers on the genetics of circadian rhythms, led the studies and worked with international groups of scientists. Their results are detailed in two companion pieces appearing this week in the early online edition of the Proceedings of the National Academy of Science (1 , 2).

“Circadian rhythms of 24 hours govern fundamental physiological functions in almost all organisms,” said Sassone-Corsi, the Donald Bren Professor of Biological Chemistry. “The circadian clocks are intrinsic time-tracking systems in our bodies that anticipate environmental changes and adapt themselves to the appropriate time of day. Disruption of these rhythms can profoundly influence human health.”

He added that up to 15 percent of people’s genes are regulated by the day-night pattern of circadian rhythms.

What Drives Your Daily Biological Clock?

Researchers working with fruit flies say they have discovered one way that the body’s biological clock controls brain-cell activity that influences daily rhythms.

They believe their findings might improve understanding about sleep-wake cycles and lead to new treatments for sleep disorders and jet lag.

"The findings answer a significant question: how biological clocks drive the activity of clock neurons, which, in turn, regulate behavioral rhythms," study senior author Justin Blau, associate professor in New York University’s department of biology, said in a university news release.

Previous research with fruit flies’ “clock genes” led to the discovery of similar genes in humans, according to the news release.

It was known that biological clocks control neuronal activity, but it wasn’t known how information from biological clocks drives rhythms in the electrical activity of pacemaker neurons that control daily rhythms.

The NYU team looked at pacemaker neurons in the central brain of fruit flies that set the timing of the daily transitions between sleep and wake. They isolated these neurons and identified sets of genes with different levels of activity at dawn and dusk.

Follow-up experiments found that the activity of a gene called Ir was much higher at dusk than at dawn and that it was more active in the pacemaker neurons than in the rest of the brain. The researchers also found that increasing or decreasing levels of Ir affected behavioral rhythms and changed the timing and strength of variations in the core clock.

"We were looking for an output of the biological clock that would link the core clock to neuronal activity," Blau said. "Ir seems to do this, but it also, remarkably, feeds back to regulate the core clock itself. Feedback loops seem to be deeply engrained into the biological clock and presumably help these clocks work so well."

The study was published in the October issue of the Journal of Biological Rhythms. Researchers have noted that results from animal studies do not necessarily translate to humans.

NYU researchers find electricity in biological clock

Biologists from New York University have uncovered new ways our biological clock’s neurons use electrical activity to help keep behavioral rhythms in order. The findings, which appear in the journal Current Biology, also point to fresh directions for exploring sleep disorders and related afflictions.

“This process helps explain how our biological clocks keep such amazingly good time,” said Justin Blau, an associate professor of biology at NYU and one of the study’s authors.

Blau added that the findings may offer new pathways for exploring treatments to sleep disorders because the research highlights the parts of our biological clock that “may be particularly responsive to treatment or changes at different times of the day.”

Do Ovaries Continue to Produce Eggs During Adulthood?

A compelling new genetic study tracing the origins of immature egg cells, or ‘oocytes’, from the embryonic period throughout adulthood adds new information to a growing controversy. The notion of a “biological clock” in women arises from the fact that oocytes progressively decline in number as females get older, along with a decades-old dogmatic view that oocytes cannot be renewed in mammals after birth.

After careful assessment of data from a recent study published in PLoS Genetics, scientists from Massachusetts General Hospital and the University of Edinburgh argue that the findings support formation of new eggs during adult life; a topic that has been historically controversial and has sparked considerable debate in recent years.