Probing brain that never sleeps

Sleep is the single most important behaviour we experience. On average 36 per cent of our lives are spent asleep, which means that if you live to be 90, approximately 32 years will have been spent asleep. Despite this overwhelming and powerful fact, sleep has not attracted the attention it so clearly deserves, and our understanding of how the brain generates this remarkable behaviour is only just beginning to emerge.

We now know that sleep does not arise from a single part of the brain. Rather sleep is a profoundly complex physiological state that comes from an interaction of multiple brain regions and neurotransmitter systems. Within the brain a diverse network of nerve cells either drives the brain into consciousness and the body into activity or inhibits the wake state and promotes sleep. It seems counter intuitive that some regions of the brain are even more active during sleep than during wakefulness.

Such increased activity relates to cellular restoration events, including the synthesis of new proteins involved in metabolic pathways and the replenishment of neurotransmitters. Sleep is also the time when we turn our short-term memories into a more permanent record of our experiences. Electrical recordings from the brain during sleep suggest that experiences and events are replayed in those neuronal circuits that captured them during wakefulness, before being consolidated and retained in deeper parts of the brain during sleep. The old view that the brain simply shuts down during sleep is completely wrong. The brain never truly sleeps – only parts of it.

Understanding how the brain and eyes generate our 24-hour cycle of sleep and wake is now an active and exciting area of neuroscience research across the world. The results emerging are truly remarkable, allowing us to describe for the first time how these vital states arise, and providing us with our first glimpses of how the brain generates consciousness and works around the clock even when we are asleep.

By their contribution to our genes, our parents are still telling us what time to go to bed

At the heart of our 24-hour cycle of sleep and wake is the body clock. Deep within the hypothalamus, at the base of the brain, a small cluster of around 50,000 nerve cells form the suprachiasmatic nuclei (SCN). If the SCN is damaged, then all our circadian rhythms, including the 24-hour sleep cycle, are lost and sleep becomes completely fragmented, occurring in short bouts between periods of wake. The SCN acts as the “master clock” telling us when to sleep and when to wake.

Each neurone of the SCN contains its own clock and, by working together, these produce the collective 24-hour rhythmic output of the SCN. The mechanisms that allow a single cell to act as a clock arise from a complex set of molecular feedback loops based upon 12 to 14 key clock genes. Remarkably, subtle changes in these genes have been linked to an individual’s tendency to be either a “lark” (going to sleep early and rising early) or “owl”, and these preferences are inherited. So by their contribution to our genes, our parents are still telling us what time to go to bed.

A clock is no use unless it is set to local time. The classic example of a miss-match between the internal day generated by the SCN and the environmental day is jet lag. We eventually recover from jet lag because the eyes detect the light/dark cycle in the new time zone and this shifts the SCN to the new location. Recent discoveries have shown that the light sensitive cells in the eye that bring about this adjustment are quite different from the photoreceptors that give us our sense of vision.

The visual cells in the eye, the rods and cones, detect light reflected from objects and this provides us with our image of the world. But another group of cells, called photosensitive retinal ganglion cells (pRGCs), detect the amount of light at dawn and dusk. This brightness information is then used to set the clock.

The process is a bit like adjusting a grandfather clock to the time signal on the radio. Body clocks, like old mechanical clocks, are not exactly 24 hour, but run a little bit fast or slow. They have to be adjusted on a daily basis so that internal time and the external world coincide. Individuals who have lost their eyes can never make this adjustment and their rhythms drift with bed times occurring at a slightly different time on each subsequent day. There are diseases of the eye that destroy the rods and cones, but leave the pRGCs fully able to detect light. Such individuals are visually blind, with absolutely no ability to see, but they are not clock blind. Such findings are redefining the diagnosis and understanding of “blindness” in hospitals all over the world.

Perhaps the most intuitive mechanism driving sleep has been termed “sleep pressure”. This refers to the phenomenon that, while we are awake, the need for sleep builds. The longer we are awake, the greater the sleep pressure and more tired we feel. This pressure then dissipates during the next period of sleep. Although intuitive, our understanding of the sleep pressure signals remains poor. Adenosine, a by-product of energy metabolism, is clearly important and concentrations have been shown to build-up in the brain with increased metabolism, neural activity and wakefulness. If adenosine is injected directly into the brain it causes sleepiness. This all explains the action of caffeine and theophylline in coffee and tea. They block adenosine receptors in the brain and so act as stimulants to increase alertness and reduce sleepiness.

Professor Russell Foster, FRS, is head of the Nuffield Laboratory of Ophthalmology, and director of the Sleep and Circadian Neuroscience Institute at the University of Oxford.