Thursday, June 26, 2008

It's All About Timing: Circadian Rhythms and Behavior

ResearchBlogging.org
Anyone who has ever tried to drastically alter his or her sleep schedule (e.g. going from working days to working nights) knows that it is one of the more difficult biological tasks we can take on. Even altering one’s sleep patterns by a couple of hours (such as the shift experienced by cross-country travelers) can be disruptive, and enough to make us feel tired, mentally unclear, and grumpy. But why are we so inflexible when it comes to our daily routine? Why are our otherwise diverse bodies so sensitive to an adjustment of our biological clocks by just a few hours? Perhaps it is because millions of years of evolution have led to a daily body clock so fine-tuned that this sensitivity is adaptive.

Circadian (from the Latin for “around” and “day”) rhythms are endogenous biological patterns that revolve around a daily cycle. They are found in all organisms that have a lifespan that lasts more than a day. They are adaptive in the sense that they allow an organism to anticipate changes in their environment based on the time of day, instead of just being a passive victim to them. Thus, to foster that readiness, they usually involve the coordination of a number of physiological activities, such as eating/drinking behavior, hormonal secretion, locomotor activity, and temperature regulation.

A major nucleus of the mammalian brain, located in the hypothalamus and called the suprachiasmatic nucleus (SCN), is responsible for acting as the master time-keeper in mammals. When the SCN is lesioned (i.e. in rodents), it results in a complete disruption of circadian rhythms. The animals will demonstrate no adherence to a daily schedule, sleeping and waking randomly (although still sleeping the same total amount of time each day).

The SCN receives information from ganglion cells in the retina, which keep it appraised of whether it is light or dark out, and maintain its synchrony with a diurnal schedule. It is not, however, completely dependent on visual input for keeping time. A number of other environmental cues, such as food availability, social interaction, and information about the physical environment (other than light) are thought to play an important role in the SCN’s ability to maintain regular daily rhythms.

Although the SCN is the center for circadian rhythms, it seems that many individual cells are not directly controlled by the SCN. Instead, they are thought to maintain their own time-keeping mechanisms. Known as peripheral oscillators, these cells are present in a number of organs throughout the body, and can be sensitive to environmental cues as well as the signals of the SCN.

So, how do the neurons of the SCN actually “keep time”? They appear to be controlled by a cycle of gene expression, which consists of a natural negative feedback mechanism. Throughout the day, a gene known as CLOCK (circadian locomotor output cycles kaput) is activated based on daytime environmental cues. This gene acts with another, BMAL1, as a transcription factor, driving the transcription of proteins period (PER) and cryptochrome (CRY). When large amounts of PER and CRY have been created, they form a complex, and act on the CLOCK and BMAL1 genes to inhibit their own expression. This occurs during the night, and the result is that PER and CRY proteins become diminished, allowing CLOCK and BMAL1 to begin transcribing them again. This happens around the morning of the next day. Thus, the feedback loop is synchronized with a 24-hour cycle, allowing the clock in the SCN to oscillate at a regular rate.

Disorders of the SCN can result in disruptive sleep problems, such as advanced sleep phase syndrome (early sleep and wake times) or delayed sleep phase syndrome (preference for evenings and delayed falling asleep). More attention is now being focused on the role a dysfunctional circadian system may play in already identified behavioral problems. A recent review in PloS Genetics examines the potential influence circadian rhythm disturbances may have in disorders like depression, schizophrenia, and even autism.

Circadian disruptions are present in all major affective disorders, including depression, bipolar disorder, and schizophrenia. Although the exact role circadian rhythms play in these disorders is not yet known, it may be substantial. This is supported by the influence changes in sleep patterns can have on the alleviation of primary symptoms of these disorders. For example, sleep deprivation has been demonstrated to have an antidepressant effect (albeit short-lived) in patients. And some affective disorders, such as seasonal affective disorder, seem to have a basis in the length of the day, and shape emotional states.

Autism spectrum disorders (ASD) are correlated with low melatonin levels, and a gene responsible for the synthesis of melatonin is considered a susceptibility gene for autism. Mice with a mutant form of this gene demonstrate deficits in social interaction, anxiety, and increased occurrence of seizures. It is postulated that behavioral problems in ASD may be influenced by the failure of an individual’s circadian clock to effectively take note of social and environmental cues.

Variants of a number of time-keeping genes, such as PER1, CLOCK, and CRY have been found to be associated with behavioral disorders. It has yet to be determined if these variations are causative, contributive, or unrelated to the disorders. Keeping in mind how influential a disturbance of circadian rhythms can be in our daily lives, however, it seems logical to investigate the possibility of their contribution to pathologies.

Reference:

Barnard, A.R., Nolan, P.M., Fisher, E.M. (2008). When Clocks Go Bad: Neurobehavioural Consequences of Disrupted Circadian Timing. PLoS Genetics, 4(5), e1000040. DOI: 10.1371/journal.pgen.1000040

3 comments :

PhysioProf said...

You've got the TIM thing wrong. In current models of the mammalian clock, it is CRY, not TIM, that is thought to participate with PER in negative transcriptional feedback.

concerned heart said...

One cause of the mutations that causes new-non-familial cases of developmental neurodevelopmental disorders is older paternal age. Sperm precursor cells collect mutations and pass them on to sperm. I don't know if this is of any interest. http://www.news.com.au/heraldsun/story/0,21985,23849196-5000117,00.html

PeteK said...

I love concise, information-dense essays like this, and the fact that we have only stratched the surface of scietific knowledge re this topic. Chronobiology needs to be better known to non-scientists, since the sleep-wake cycle dominates almost everything we do...any variations have profound ramifications...