Monday, February 27, 2006

Lunar Rhythms in the Antlion

[Note: People who have read my other blog about a year ago are familiar with this story]

When I was a kid I absolutely loved a book called "Il Ciondolino" by Ricardo Vamba - a book in two slim volumes for kids (how times change - try to publish a 200+ page book of dense text for children today!). I later found out that it was translated into English under the title The Prince And His Ants in 1910 (Luigi BERTELLI (M: 1858 or 1860 - 1920) (&ps: VAMBA) The Prince And His Ants [It-?]. Holt.(tr S F WOODRUFF) [1910] * Il Giornalino Di Gran Burrasca [It-?] (tr ?) [?] ) and was even The Nation's Book of the Week on June 2nd 1910.

["Vamba" is the pseudonym of Italian fantasist Luigi
Bertelli. The Prince and His Ants (1910) tells the tale of a boy who becomes an
ant, and a girl who becomes a butterfly. The English translation by one Miss
Woodruff was edited by Vernon Kellogg, an insect authority at Stanford
University. Ninety interior illustrations are scientifically accurate.]

This book is hard to find - don't even bother with Amazon - but my brother was persistent and after several weeks of patient searching he got a copy from Alibris and sent it to me. It is a story of a boy who wakes up one morning transformed into an ant. The book describes his travels and adventures in the world of the small. Of course, he meets a bunch of really cool creatures, like various wasps and bees and moths and honey-ants, etc. But the one I remember the most was the ant-lion.

The antlion is actually quite pretty, yet short-lived, as an adult. But it is the larva that is really cool:

It digs a pit in the send and hides underneath the sand right under the bottom of the pit. When an ant, or some other insect comes by, it falls into the pit and has trouble climbing out of its steep walls again. The ant-lion lunges out of the sand (like a scence from "Tremors") and eats the poor bug:

Now the really cool part: the volume of the pit is bigger when the antlion is hungrier (or so they say at this marvelous website that I highly recommend you browse around). But, hungry or not, the ant-lion digs a bigger pit when the moon is full. Nobody has any idea why that would be so. Here is a photograph of a colony of ant-lions, each with its own little pit:

But here is the coolest part of all. If you take ant-lions out of the field and put them in little sandboxes in the laboratory and isolate them from any cues about the outside world they will still dig bigger pits roughly every four weeks - they have an internal lunar rhythm:

They have, somewhere in their brains, a lunar clock that tells them to dig larger pits whenever the moon is full even if they canot see the moon itself (e.g., on a dark cloudy night). If and when somebody figures out how this little brain works, I'll be sure to tell you all on my blog, but you may have to wait years for it - nobody is even thinking about studying it right now.

Time out of mind

This article, Time out of mind (hat-tip: Inkycircus), is quite good at explaining in lay terms Advanced Sleep Phase Syndrome, describing famous Siffre's experiment (more popular with lay people, I think, as most chronobiologists, me included, regularly forget to mention it when talking about the history of the field), and explaining recent research in subjective time perception.

What really floored me are the comments that reveal that people are mostly still ignorant about biological clocks. Without religious objections that evolution triggers, and with so much coverage in the media, I expected that people will know at least a little bit more. I'll just have to keep blogging, doing my part in educating people about this important aspect of biology.

Thursday, February 23, 2006

Circadian Clocks in Microorganisms

Many papers in chronobiology state that circadian clocks are ubiqutous. That has been a mantra since at least 1960. This suggests that most or all organisms on Earth possess biological clocks.

In the pioneering days of chronobiology, it was a common practice to go out in the woods and collect as many species as possible and document the existence of circadian rhythms. Technical limitations certainly influenced what kinds of organisms were usually tested.

Rhythms of locomotor activity are the easiest to measure. Rodents, as well as large walking insects like cockroaches, will turn running wheels, each revolution triggering a switch that sends a signal to the computer. Songbirds will jump from one perch to another, each perch flipping a switch connected to a computer. Lizards, while walking around the cage will tilt the cage from left to right around an axis - a metal bar on the bottom - which will turn a switch. Plants that exhibit leaf movements (closing at night, opening during the day) were the prime experimental models for a while (e.g., Kalanchoe, mimosa, tobacco).

Monitoring rhythms in other organisms is much harder: it is mighty difficult to make a fish run in a running wheel, or build hopping perches sensitive enough to be triggered by the landing of a butterfly. That was even harder back in the late 1940s and early 1950s when most of this work was done.

It is no suprise that nobody looked at microorganisms back then - it was just technically too hard. The fact is that most of the pioneers in the field came in from vertebrate physiology, ethology or ecology. It is easy for us, large mammals, to forget that we are not among the dominant life-forms on the planet - that title goes to bacteria, in terms of numbers of individuals, in terms of biodiversity, and in terms of total biomass. See if you can find mammals, or even all animals on the Tree of Life (click to enlarge):
Some old papers, mostly parts of Conference Proceedings of various kinds, mention as fact that Bacteria do not have clocks but do not provide any citations. It took me years to dig out three papers (Rogers and Greenbank, 1930, Halberg and Connor, 1961; and Sturtevant, 1973) with relevance to this question and all three are ambiguous about the final verdict. Why is nobody revisiting this with modern molecular techniques?

Being unicellular does not preclude one from having a clock, though, as single-cell Protista and Fungi all have circadian rhythms, which have been studied quite extensively since the 1970s or so (I intend to delve some more in that literature and write some posts on them in the future).

One group of bacteria does have a clock - the unicellular Cyanobacteria (if you are above a certain age, you may remember them under their old name: blue-green algae), in particular those species that do not form chains, e.g., Synechococcus and Nostoc. This was discovered very recently - only ten years ago (Mori et al. 1996). I was two years into my Masters when that paper appeared and I remember the excitement. I will certainly write a post or two on those soon:
There has not yet been a single study of any kind of rhythmicity in Archaea. Most of those microorganisms live in strange places - miles deep under the surface of the earth, in rocks, in ice, on the ocean floors and in the hydrothermal vents. They mostly do not inhabit rhythmic environments, so perhaps they do not need to have clocks - but it would be really nice to know if that is really the case:
Old Faithful, the famous geyser in Yellowstone park contains Archea. As the geyser erupts every 45 minutes or so, the microbes are suddenly exposed to very different environment: light, turbulence, lower temperature. Should we expect them to evolve a 45-minute clock that will help them predict the eruption so they can limit some sensitive biochemical reactions to the quiet periods and switch on the defenses agains light and cold every 45 minutes?

In The Geometry of Biological Time, Arthur T. Winfree suggested an experiment (on Page 580) that it
"... should be possible to demonstrate the effect by bacterial selection experiments in a chemostat. By alternating the nutrient influx from glucose without oxygen, to oxygen without glucose, to alanine and oxygen, cells would be forced into a three-point metabolic cycle." and "... reversing the order of the driving cycle, it should be possible also to select cells whose clocks run backward."
In a later edition (after we learned that cyanobacteria have clocks) he suggested, instead, to use
"one of the species of cyanobacteria that revealed no circadian rhythms in surveys before Mori et al. (1996), and use light as the alternative nutrient".
As of today, nobody has performed such an experiment, although Elowitz and Leibler (2000) came pretty close with a study in which they produced oscillations in Escherichia coli with periods of 3-4 hours, which are slower than the cell-division cycle:
So, if most of Life on Earth is Prokaryotic (Eubacteria and Archaea), and those groups do not have clocks, then clocks are not ubiqutous, are they? In my papers and in my Dissertation I try to hedge a bit by stating that they are found in "organisms that live on or close to the surface of the Earth", thus at least avoiding the deep-oceanic, deep-soil, and parasitic microorganisms (as well as burrowing and cave organisms that may have secondarily lost their clock).

Tuesday, February 21, 2006

Diurnal rhythm of alcohol metabolism

Why is breathalyzer a poor method of measuring blood alcohol levels for purposes of DUI tickets? Ed Brayton explains and links to DUI Blog with additional information.

Also, do not forget that every function in the body exhibits a circadian cycle. Likewise, alcohol metabolism:
This is from an old study, from the times when it was OK to recruit some college freshmen to drink alcoholic beverages in the name of science. This is a record of a diurnal rhythm in alcohol clearance, I believe (I cannot find the original paper I swiped this image from a long time ago).

It shows why we can drink more in the evening than at other times of day. You can save some serious money by downing a single shot at dawn, according to this graph.

So, at what time of day/night did the cops stop you to give you a breathalyzer test?

Sunday, February 19, 2006

Robustness of the Circadian Oscillator

Ricardo Azevedo of Newtons' Binomium wrote a great pair of posts on the robustness of biological systems, using circadian clock as the example.

Check them out: Blind Watchmaker or Swiss Designer? (Part I) and Blind Watchmaker or Swiss Designer? (Part II).

Lithium, Circadian Clocks and Bipolar Disorder

I have previously only touched on the immensely interesting topic of the possible connection between circadian clocks and the Bipolar Disorder. A recent paper prompted me to look into this in a little more detail.

Lithium Affects the Circadian Clock

First, let's go a little bit into the past, the early history of chronobiology. During the 1940s and 1950s, while the field was still in its pioneering spirit and little was known about the circadian clocks, many researchers were using survey (or shot-gun) approaches to the studies of biological rhythms: studying as many organisms as they could get their hands on in order to come up with generalities and evolutionary answers, surgically removing every possible organ or brain region in order to find locations of clocks in various organisms, exposing the organisms to every possible light regimen imaginable in order to study the oscillatory properties of biological clocks, etc.

One of the approaches was to administer to animals every chemical one could find on the lab-shelf to see how it affects the circadian rhythms. This line of work yielded a big surprise - biological clocks are amazingly resistant to pharmacological agents. The few substances that had an effect were hormone melatonin (naturally, as it is the main signaling molecule of the circadian system), heavy water (deuterium oxide) and lithium (a few others were found much later, including sex steroid hormones). Lithium had the same effect - slowing down the clock, i.e., increasing the period - in a number of philogenetically very distant organisms.

Lithium affects the Bipolar Disorder

At the same time, lithium was one of the most prescribed drugs for treating bipolar disorder (at that time usually called "manic-depressive disorder"). Soon enough, people started making the links between effects of lithium on bipolar dissorder and the effects of lithium on the circadian clock. Is the bipolar disorder essentialy a circadian clock disorder?

During periods of depression, the circadian rhythms are phase-advanced (click to enlarge):

Lithium is supposed to phase-delay the phase-advanced rhythms, i.e., bring them back to the normal phase. Here is an actograph of the sleep-wake cycle of a bipolar patient treated with various drugs, including lithium, as well as phase-shifts of the light-dark cycle, over a long period of time - click on the image to enlarge so you can read the text:

This does not appear to be a very efficient treatment by lithium in this particular patient, though.

Lithium Affects Circadian Pacemaker Cells in a dish

Much more recently, it was discovered that each individual pacemaker cell (in the suprachiasmatic nucleus of the hypothalamus) in the mammalian circadian system responds to lithium. In other words, the effects of lithium are not at the system level (e.g., interfering with cell-cell communication), but on the level of the cell. This suggests that lithium may act on a particular clock gene and the search for the gene in question commenced.

To make things easier, the candidate clock-gene target of lithium is likely not to be limited to mammals, or vertebrates, as lithium has the same effects on rhtyhms in other organisms, including the fruitfly Drosophila melanogaster. Thus, it is likely that the target clock gene is one that is shared by the circadian clocks in Invertebrates and Vertebrates, thus somewhat narrowing down the list of candidates.

Molecular Mechanism of Circadian Rhythm Generation in Mammals

Let me now try to explain how the mammalian circadian clock works on the molecular level in as simple way as possible, so the non-scientists reading this can - hopefully - understand. Biologists can follow the links for more detailed information if so inclined. In order to do this, I will first give a super-simple primer on molecular biology (I hope I don't make any stupid mistakes on this part as I type it very fast in order to get to the cool new stuff). This is an oversimplification, so I hope molecular biologists do not chastise me for omitting all the extraneous details, as much as they may be important. This is BIO 101.

We are all composed of billions of cells. All of the genetic material - DNA - is found in the nucleus of each cell. DNA is a very long linear molecule, built like a chain out of many, many links. The links in the chain are the nucleotides, each made of a sugar molecule, a phosphate and a nucleic acid. There are four types of nucleic acids in the DNA: adenine, thymine, cytosine and guanine (A, T, C and G). The order of links with different types of nucleic acids on the DNA chain is the "code".

A gene is a small string on the long DNA chain - a sequence of nucleotides that is transcribed as a unit. Transcription is the formation of an RNA molecule - also a chain - using the DNA as a template. Thus, transcription makes an RNA molecule that is a mirror image of the gene. Wherever in the DNA sequence there was C, in the RNA there will be G, and vice versa. Wherever there was T in the gene sequence, there will be A on the RNA transcript, and vice versa (with a little change here - RNA will have uracil - U - instead of T where appropriate).

Unlike DNA, RNA is capable of exiting the nucleus of the cell and entering the cytoplasm. It goes to a tiny little spherical organelle called the ribosome. There, aided by a bunch of enzymes (which are proteins) and some other types of short chains of RNA, the genetic trasncript gets tranlated into protein. The order of three consecutive nucleotides (a triplet) has a chemical meaning: it is a code for a particular amino-acid. The order of triplets, thus, determines the order of amino-acids placed in the chain.

Once the whole RNA sequence is translated, the chain of amino-acids is further modified by other enzymes - they change its shape, add little molecules to it, etc. These modifications are key to the proper function of the protein. For instance, adding an ion of iron to the hemoglobin makes it possible for this molecule to transport oxygen to every cell in the body. Adding a phosphate group gives the protein extra energy. Adding a short chain of sugars assigns the protein its "zip-code", i.e., tells other proteins in the cell where to take this protein to, so they can shuttle it across the cell along microtubules, to its destination where it will perform its fuction.

Some of the proteins (called "transcription factors") have a specific role to go back into the nucleus, find particular genes (they use particular gene sequences to find and recognize them), and bind to them. The binding has an effect in either stimulating or inhibiting the transcription of that gene into RNA. Thus, the protein of that gene will or will not be synthetized in that particular cell.

Genes involved in the generation of circadian rhythms can be loosely classified into core clock genes and associated clock genes. The core clock genes are almost all transcription factors. Their proteins act by inhibiting or stimulating transcription of other core clock genes (as well as regulating expression of other - downstream - genes that serve as functional outputs of the cell, i.e., telling the body when to relase a hormone and when not, when to sleep, when to wake up, etc.).

If core clock genes were all there is, the circadian cycle would last only a couple of hours, at best. That is how long it takes for all the players to switch on and off each other once. In order to prolong the cycle to be closer to 24 hours, oter genes are associated with the clock. Their protein products act as modifiers - they may add or remove phosphate groups on core clock genes, inhibit or stimulate expression of some of the core clock genes, degrade the core clock proteins either spontaneusly or upon receiving a signal that the retinae have perceived light, etc.

Here is a schematic of the mammalian circadian clock. Genes called Period, Cryptochrome, Clock and Bmal (or MOP) are the core clock genes in the mammals:

It is similar in other organisms, with some changes, and you can also watch a great animation movie here.

How lithium affects the molecular clock?

A couple of years ago, it was proposed that the protein involved in the clock mechanism that is sensitive to lithium is not one of the core clock genes, but one of the accessory genes - namely Glycogen Synthase Kinase 3ß (GSK3), which, in turn, acts on Rev-Erb, which in turn acts on Bmal.

Now, a new paper came out with more evidence that this is so:
Nuclear Receptor Rev-erb{alpha} Is a Critical Lithium-Sensitive Component of the Circadian Clock by Lei Yin, Jing Wang, Peter S. Klein and Mitchell A. Lazar. You can find the press-release and excellent media commentary here, here, here, here, and here.

According to this paper, lithium inhibits GSK3. GSK3 normally protects Rev-Erb from destruction. Rev-Erb normally inhibits expression of the core-clock gene Bmal (and perhaps also Period). Thus, when lithium is present, there is no GSK3 to protect Rev-Erb from being broken down. Without Rev-Erb, Bmal and Period get expressed again.

Perhaps this all means that in the Bipolar Disorder the clock gets "stuck" in some way. Perhaps Rev-Erb accumulates and stops the clock from running. Lithium indirectly aids the distruction of Rev-Erb, thus allowing the circadian cycle to proceed.

As they say:
"These results point to Rev-erb as a lithium-sensitive component of the human clock and therefore a possible target for developing new circadian-disorder drugs. Some patients taking lithium have developed kidney toxicity and other problems. Lazar surmises that new treatments that lead to the destruction of Rev-erb would have the potential of providing another point of entry into the circadian pathway."

Saturday, February 18, 2006


Sleepdoctor is salivating at the prospect of checking out this patient, one of many who claim they never sleep at all - except when monitored in a sleep lab.

He also reports on the new term - Z-pills - that encompasses drugs like Lunesta, Ambien and Sonata.

Thursday, February 16, 2006

Sleep Education

Sleep Education is a new website that answers a lot of questions about sleep, sleep disorders and treatments. Check it out. Hat-tip: Sleepdoctor.

Sex differences, puberty and insomnia

Periods bring on sleepless nights:

Adolescent girls appear to be at greater risk of insomnia after they begin menstruation, a study has found.

This suggests that hormonal changes play a role in developing the sleep disorder, the researchers say in the journal Pediatrics.

Researchers found that among more than 1000 13- to 16-year-olds in the study, nearly 11% had suffered insomnia at some point.

Insomnia, based on formal clinical criteria, was defined as problems falling asleep or staying asleep at least four times a week for a month or longer.

Typically, the study found, the teens started having sleep disturbances around the age of 11.

Before menstruation, girls were about as likely as boys to have insomnia.

But after they began their menstrual periods girls had more than twice the risk of insomnia as boys.

The findings suggest that the hormonal changes that come with menstruation contribute to girls' insomnia risk, according to the authors.

Such a physiological reason is one of two broad explanations for why menstruation would be related to insomnia, says lead author Dr Eric Johnson.

The other possibility is that the physical changes that come with puberty, like breast development, create "social pressures" that contribute to sleep problems, says Johnson, a researcher with RTI International.

But he says menstruation is related specifically to problems with staying asleep and getting enough deep sleep.

These forms of insomnia are more likely to have physiological causes, whereas problems with falling asleep in the first place can often be stress-related.

In addition, girls' higher risk of insomnia was not explained by higher rates of depression, which is often marked by sleep disturbances.

A long lasting problem

Another key finding, Johnson says, is that of all teens who ever suffered insomnia, 88% also had symptoms at the time of the study.

This, he says, signals that the problem is lasting for many teenagers.

"Insomnia seems to be common and chronic among adolescents," Johnson and his colleagues conclude.

Given the consequences of sleep deprivation among teenagers, including blunted mental acuity, poorer school performance, and even poorer physical and emotional health, prevention and treatment may need to become "important priorities", the researchers say.

Therapies for insomnia include lifestyle changes to promote sleep, like getting to bed and rising at regular times each day, cognitive behavioral therapy and sleep medications.

Alternatively, sex steroid hormones may alter the properties of the circadian clock - perhaps decreasing its amplitude along with well-documented delay in phase. As they always say "More research needs to be done"....

Monday, February 13, 2006

Mammalian Clock Genetics - new papers

Here are two new papers, for connoiseurs only:

Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions

Mammalian circadian rhythms are based on transcriptional and post-translational feedback loops. Essentially, the activity of the transcription factors BMAL1 (also known as MOP3) and CLOCK is rhythmically counterbalanced by Period (PER) and Cryptochrome (CRY) proteins to govern time of day–dependent gene expression1. Here we show that circadian regulation of the mouse albumin D element–binding protein (Dbp) gene involves rhythmic binding of BMAL1 and CLOCK and marked daily chromatin transitions. Thus, the Dbp transcription cycle is paralleled by binding of BMAL1 and CLOCK to multiple extra- and intragenic E boxes, acetylation of Lys9 of histone H3, trimethylation of Lys4 of histone H3 and a reduction of histone density. In contrast, the antiphasic daily repression cycle is accompanied by dimethylation of Lys9 of histone H3, the binding of heterochromatin protein 1alpha and an increase in histone density. The rhythmic conversion of transcriptionally permissive chromatin to facultative heterochromatin relies on the presence of functional BMAL1-CLOCK binding sites.

Feedback repression is required for mammalian circadian clock function

Direct evidence for the requirement of transcriptional feedback repression in circadian clock function has been elusive. Here, we developed a molecular genetic screen in mammalian cells to identify mutants of the circadian transcriptional activators CLOCK and BMAL1, which were uncoupled from CRYPTOCHROME (CRY)-mediated transcriptional repression. Notably, mutations in the PER-ARNT-SIM domain of CLOCK and the C terminus of BMAL1 resulted in synergistic insensitivity through reduced physical interactions with CRY. Coexpression of these mutant proteins in cultured fibroblasts caused arrhythmic phenotypes in population and single-cell assays. These data demonstrate that CRY-mediated repression of the CLOCK/BMAL1 complex activity is required for maintenance of circadian rhythmicity and provide formal proof that transcriptional feedback is required for mammalian clock function.

Friday, February 10, 2006

Melatonin Not Effective For Insomnias

Melatonin useless for sleeplessness - study

Paris - People who buy melatonin in the belief that it will cure jet lag or other forms of sleeplessness are wasting their money, a study published in Saturday's British Medical Journal (BMJ) says.

Melatonin is a hormone secreted in the pineal gland, a small organ about one centimetre long located at the base of the brain. It is indirectly stimulated by light received through the eyes.

The gland plays a key role in circadian rhythms - the body's state of alertness in response to daylight or darkness - and from this has been born the "alternative" therapy of taking melatonin rather than a sleeping pill to compensate for disrupted sleep.

Researchers at the University of Alberta in Canada reviewed 32 studies in which melatonin was tested on people with secondary sleep disorders (sleep problems associated with medical, neurological or substance misuse) and sleep disorders arising from jet lag or shift-work disorder.

Melatonin was ineffective in treating either kind of disorder, they say.

In the case of secondary sleep disorders, individuals who took melatonin boosted their duration of sleep by just 1.9 percent - less than 10 minutes in an eight-hour spell in bed - and this was so tiny as to be statistically insignificant.

As to whether melatonin is safe, the authors say it appears to be so, at least with short-term use.

Further work, though, is needed to see whether melatonin can be safely used for longer spells.

Related: The Sleep Racket: Who's making big bucks off your insomnia?

Sunday, February 05, 2006

Seasonal Affective Disorder - The Basics

So, why do I say that it is not surprising the exposure to bright light alleviates both seasonal depression and other kinds of depression, and that different mechanisms may be involved?

In mammals, apart from visual photoreception (that is, image formation), there is also non-visual photoreception. The receptors of the former are the rods and cones that you all learned about in middle school. The receptors for the latter are a couple of thousand Retinal Ganglion Cells (RGCs) located in the retina in each eye. Each of these cells expresses a photopigment melanopsin (the cryptochrome challenger apparently lost the contest about a year ago after several years of frantic research by proponents of both hypotheses).

The axons – nerve processes – from these cells go to and make connections in three parts of the brain. One is the brain center that controls pupillary reflex – when the light is bright the pupils constrict, while in the dark the pupils dilate.

The second is the brain center involved in the control of mood. There is still a lot to work out about this center, but that is probably the place where exposure to light helps alleviate regular, i.e., non-seasonal depression.

The third place where these RGCs project is the suprachiasmatic nucleus (SCN) – the main circadian pacemaker in the mammalian circadian system. The first light of dawn perceived by the eyes tells the SCN that it is day. Likewise, at dusk, the gradual decrease in light intensity perceived by these RGCs signals to the SCN that night is about to start.

Much of the work on seasonal depression (SAD) suggests that it appears in response to the changes in daylength – the photoperiod. While other aspects of the weather, e.g., brightness, temperature, etc., may modulate the response, the basic mechanism appears to be the same way other mammals time their seasonal activities, including breeding, migration, molting and hibernation. Recent studies indicate that other mammals also suffer from winter depresssion, which is triggered by long night and short days (that last link is to a really cool study - perhaps I should write a separate post just on that!).

What is important to keep in mind is that total amount of received light, its intensity and quality, do not matter in photoperiodic response in mammals. What matter is the duration of the night AS PERCEIVED BY THE SCN. One can fool the SCN by, for instance mimicking a long summer day with skeleton photoperiods (a light pulse in the morning and a pulse in the afternoon) – the clock perceives only two pulses of light (a total of a couple of hours of illumination), yet interprets is as a long day.

The output of the SCN, among else, is a projection to the superior cervical ganglia (SCG) in the upper neck region, which are part of the sympathetic (autonomic or vegetative) nervous system. The SCGs, in turn, project their axons onto the pineal gland where release of nor-epinephrine controls the synthesis and secretion of the pineal hormone melatonin. So, whenever the SCN ‘thinks’ it is night, the pineal secretes melatonin into the bloodstream.

During the day, the SCN inhibits the secretion of melatonin. The duration of melatonin secretion is the signal for the duration of the night. This signals is then “read and interpreted” by other parts of the brain that trigger changes in development, morphology, physiology, reproduction and behavior in a seasonally appropriate manner. So, it is the duration of exposure to melatonin, not any direct hormonal activity of melatonin, that is the key to seasonal phenomena.

Here is a schematic of the melatonin profile in the blood of normal people in summer and winter:

Such profiles are very important for fitness (survival and reproduction) in hamsters, sheep, deer and most other mammals. Humans are not so strikingly seasonal – we breed throughout the year – but our distant ancestors certainly were. Some traces of the seasonality of our ancestors can be seen. For instance we crave different foods in different seasons, put on or lose weight seasonally, etc. The best evidence for the human seasonality is the existence of SAD. Just like other mammals, we get slow, grouchy, and in severe cases, clinically depressed during the winter (yes, I know, there are some rare people who are opposite – depressed in summer, but they are seasonal, too, and their SAD is also due to photoperiodic time measurement).

How does exposure to bright light alleviate SAD? Most humans have an inherent freerunning period (tau) of their circadian clock somewhat longer than 24 hours – around 25, actually. Thus, the two figures I drew above are idealized – very few people have profiles exactly like that. We tend to wake up some hours after dawn. We sleep indoors in relatively dark rooms, perhaps under covers, with our eyes closed. The RGCs do not perceive the first light of dawn at the time of dawn but some time afterwards. Thus, the SCN entrains to the environmental light-dark cycle with a slight delay. Most humans are mild “owls” in this respect. And even when we get up, we expose ourselves only to the relatively weak artificial light, or the dim light of a dark and dreary winter morning.

In the evening, most people do not go to bed at dusk, but switch on the lights (curse you, Edison!) and go to bed much later – often around midnight. We phase-delay our clocks with our daily behaviors. Yet, the artificial light is not sufficiently intense to shut down the secretion of melatonin. What you get is something like this – an artificially lengthened night and even longer duration of the melatonin signal than what the actual duration of night warrants:

By exposure to very bright light (a ‘light-box’ that you can buy online) in the morning, we phase-advance our clocks every morning, just enough to place ourselves into a more normal phase. High intensity is needed as the speed and size of phase resetting is dependent on light intensity. This way, we reduce the perceived duration of the night to what it really is (instead of the artificially lengthened night), thus alleviating some of the mood-related effects of short photoperiods.
“Larks” are people whose clocks run with a period at or shorter than 24 hours and who are, thus, somewhat phase-advanced in relation to the environmetal light-dark cycles. The strategy for “larks” is to expose the RGCs to bright light in the evening, thus phase-delaying the clock and, again, reducing the perceived duration of night to the actual duration of night, hopefully eliminating mood-altering effects of long winter nights:

Melatonin supplements are often used in treatment of clock-related disorders. Melatonin has been suggested to treat jet-lag, effects of night-work and shift-work (“shift-lag”) and various clock-related insomnias. But beware – melatonin is also a signal of season.

I have not seen a study of this, but here is something that, in theory, can happen. If you are an extreme night owl, i.e., phase-delayed and try to reset your clock by taking melatonin earlier in the evening than your normal (i.e., very late) bed-time, what is going to happen?

Even if you do this in the middle of summer, the melatonin supplement will prolong the nightly melatonin signal (exogenous melatonin in early night + endogenous melatonin during late night). Your brain will interpret this as an abrupt onset of very long winter nights. If you are susceptible to winter depression (and if I remember some studies correctly, owls are more susceptible to SAD than larks), you will artificially trigger SAD in the middle of the summer. So, beware!

Now, you may understand why are people who live in very high latitudes chronically depressed. After all, they are exposed to a continuous night that lasts for several months! One wonders if the reindeer are depressed, too.

What I outlined here is just the very basic mechanism of SAD - the textbook version. There are, as one should expect, many more details, complications and strange data out there. Those are, frankly, outside my domain of expertise. I am a bird kind of guy, after all. So, if you want more details, or medical advice, you will be better off to ask somebody who does research on (and clinical work with) human subjects, or at least on mammals.

ClockQuotes (De Vries)

I write when I'm inspired, and I see to it that I'm inspired at nine o'clock every morning.
- Peter De Vries

No Link Between Lunar Phase and Births/Deliveries

The Claim: Baby Deliveries Are in Sync With the Moon:

Is there any link between childbirth and the lunar cycle? Many ancient cultures looked upon the moon as a sign of fertility, and since Roman times people have blamed full moons for all sorts of human behaviors, hence the word lunacy, from the Latin word for moon.

But as mysterious and alluring as the link between full moons and births may sound, scientific studies suggest that it is more romance than reality.

Over the years, more than a dozen different studies in several countries have looked for a connection, and almost all have found none.

One of the most recent, published last year in The American Journal of Obstetrics and Gynecology, examined about 564,000 births across 62 lunar cycles in North Carolina between 1997 and 2001.

The lunar cycle, the study found, had no predictable influence on deliveries or birth complications at all.

Another study, which appeared much earlier in The New England Journal of Medicine, looked at thousands of births across 51 lunar cycles. It also reached that conclusion.

But scientists have found several factors that do affect workloads in maternity wards.

Most births occur in the summer and in September and October, said Kathleen Capitulo, the director of the Kravis Children's Hospital and Women's Center at Mount Sinai Medical Center.

There are also weekly cycles. Most childbirths occur later in the week, she said, because many women prefer having labor induced before the weekend, full moon or not.

THE BOTTOM LINE: Studies show that workloads in maternity wards are not affected by the full moon.

Saturday, February 04, 2006

Light therapy shines on other conditions

Interesting, but not surprising, though the mechanism may be different in SAD and other disorders. From PsychCentral and APA:

Exposure to bright light–the treatment of choice for seasonal affective disorder, or SAD–may also help people with other mental health conditions including bulimia nervosa, antepartum depression and nonseasonal depression, preliminary research finds.

"The latest news is that light therapy is just as effective as antidepressants in treating nonseasonal depression–it's truly exciting," says Columbia University psychologist Michael Terman, PhD, a SAD researcher who uses both light and medications to treat patients. "The findings almost make me say that it's only by happenstance that light therapy was discovered and developed in the context of SAD."

That said, the literature in the area is still sparse, emphasizes Dan Oren, MD, a veteran SAD researcher at Yale University.

"No one has done any solid head-to-head comparisons that prove that one form of treatment is better than another in treating nonseasonal depression," he notes.

The excitement is the result of several studies that are emerging on the topic, including a meta-analysis in the April 2005 American Journal of Psychiatry (Vol. 162, No. 4, pages 656–662), by University of North Carolina at Chapel Hill psychiatrist Robert Golden, MD, and colleagues concurring that bright light treatment is effective both for SAD and for nonseasonal depression.

"Effect sizes [are] equivalent to those in most antidepressant pharmacotherapy trials," the authors write.

Meanwhile, a 2004 meta-analysis conducted for The Cochrane Collaboration, a not-for-profit organization that prepares systematic reviews of health-care therapies, found that light therapy offered help for nonseasonal depression, especially when administered during the first week of treatment, in the morning and as an adjunct to antidepressants. A revision of that meta-analysis is currently under way, Terman notes, indicating that light therapy plus medications is probably the best approach.

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