Cells in the mammalian suprachiasmatic nucleus (SCN) make two proteins, named Clock and Cycle, that bind together to form a dimer (a pair of proteins attached to each other). The Clock/Cycle dimer then binds to the cell’s DNA to promote the transcription of per and another gene, called cryptochrome (cry). The resulting Per and Cry proteins then bind to each other and to a third protein, Tau (it was a mutation of the tau gene that resulted in hamsters with a shortened period for the brain transplants that we discuss in the textbook).

Once formed, the Per/Cry/Tau protein complex enters the nucleus to inhibit the transcription of per and cry. This means that no new Per or Cry proteins are made for a while. But because the Per and Cry proteins degrade with time, eventually the inhibition will be lifted, starting the whole cycle over again (see Figure 1). The entire cycle takes about 24 hours to complete, and it is this 24-hour molecular cycle that drives the 24-hour activity cycle of SCN cells. Each SCN neuron uses this mechanism to keep time approximately, and then the neurons communicate with each other through electrical synapses (see Chapter 3), synchronizing their activity to produce a very consistent period of about 24 hours (Long et al., 2005). That period then drives circadian processes throughout the body.

Figure 1  A Molecular Clock in Flies and Mice
This is a simplified view. In reality, several per and cry genes are active in mammals, the protein called Tau here is also known as casein kinase l epsilon, and the mammalian version of Cycle is called Bmal1. (After Reppert and Weaver, 2002.)

How does light entrain the molecular clock to the light-dark cycle? In fruit flies, one of the molecules involved in the clock is degraded by exposure to light. So outside light passes through the fly’s body into brain cells to degrade the protein and synchronize the molecular clock. But things are different in thick-headed mammals like us. We use the retinohypothalamic pathway to get light information to the SCN. The retinal ganglion cells containing the photopigment melanopsin detect light and release the neurotransmitter glutamate in the SCN. Glutamate triggers a chain of events in SCN cells that promotes production of the Per protein. When the animal’s photoperiod is shifted, this light-mediated boosting of Per production shifts the phase of the molecular clock and therefore the animal’s behavior.

References

Long, M. A., Jutras, M. J., Connors, B. W., and Burwell, R. D. (2005). Electrical synapses coordinate activity in the suprachiasmatic nucleus. Nature Neuroscience 8: 61–66.

Reppert, S. M., and Weaver, D. R. (2002). Coordination of circadian timing in mammals. Nature 418: 935–941.