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Scientists nail down the network topology of the human circadian clock

Life has a certain kind of layered rhythm to it. Our own circadian clock controls things as diverse and important as sleep, hunger, body temperature, hormone levels, and even cell cycles. For a while we’ve been reasonably sure it’s controlled by the suprachiasmatic nucleus of the hypothalamus — the SCN for short. But recent experiments on cryptochrome photopigments have led scientists to question the nature and involvement of light in pseudovisual senses like the magnetic sense in some animals, and the circadian sense of time, which seems to function even in the absence of light.

Circadian rhythms are found in all kingdoms of life, and they depend on things called zeitgebers to keep the individual’s circadian rhythm beating in time with the world around it. Scientists from several American colleges now report that they’ve used a neurotoxin to confuse the SCN so that they could watch it recover, and in so doing, create a wiring diagram for the human circadian clock.

The anatomical correlate of the circadian clock is in the SCN. It’s a tiny structure with dual hemispheres and distinct substructures, a core and a shell. But until now, we hadn’t mapped out its network connectivity to understand what the substructures do. “The SCN has been so challenging to understand because the cells within it are incredibly noisy,” said John Abel, first author of the report and graduate student at Harvard’s School of Engineering and Applied Sciences. “There are more than 20,000 neurons in the SCN, each of which not only generates their own autonomous circadian oscillations but also communicates with other neurons to maintain stable phase lengths and relationships. We were able to cut through that noise and figure out which cells share information with each other.”

Both sides of the SCN beat in close sync, transferring information between the retina, the SCN, other places in the hypothalamus, and even to the pineal gland where it mediates the production of cortisol and melatonin. That harmony can be disrupted, though, by external influences. In this experiment, the scientists used pufferfish neurotoxin to chemically scramble the timewise behavior of the SCN, so its two halves would beat out of phase with each other. The SCN receives input from the retina, and blue light can disrupt the firing synchrony of its two halves. But the researchers watched SCN neurons with single-cell resolution as they applied and then washed away the neurotoxin. They confirmed that the SCN didn’t depend on retinal input to recover synchrony.

Information moves freely within the core region, but less so in the shell. “We were surprised to find that the shell lacked a functionally connected cluster of neurons,” said Abel. “We’ve known that exposure to an artificially long day can split the SCN into core and shell phase clusters, which oscillate out of sync with each other. We’ve assumed that the neurons in the shell communicated to synchronize that rhythm, but our research suggests that phase clustering in the shell is actually mediated by the core neurons.”

The upshot of all this is that we now have a network topology of the circadian clock. It means that we can trace input and output, with an eye to treating conditions like shift work sleep disorder — otherwise known as the reason third shift employees often have a robust caffeine habit. And it also means that we have more evidence to flesh out the connection between artificial light and disorders of circadian rhythm. But we’re still waiting for someone to wire up a circadian alarm clock.

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