Brain cells for alertness fire without cues. (No Rest for the Waking).

The brain cells that keep people awake fire spontaneously and continuously on their own, neuroscientists have found. This result suggests that sleep depends on signals from other brain regions that quiet these neurons.

Scientists previously discovered these brain cells while studying people and animals with narcolepsy, a condition marked by sudden bouts of deep sleep. Human narcolepsy generally stems from a shortage of the neurons, which produce the excitatory neurotransmitter known both as hypocretin and orexin (SN: 29/2/00, p. 148). In contrast, narcoleptic dogs' brains are short on molecules that bind the neurotransmitter (SN: 8/14/99, p. 100).

The alertness cells are in a forebrain region known as the hypothalamus. They aren't the only brain cells that control sleep and waking, but these so-called hypocretin-orexin (Hcrt/Orx) neurons seem to be at the top of the brain's wake-promoting chain of command, says neuroscientist Michel Muhlethaler of Centre Medical Universitaire in Geneva, Switzerland. To investigate further, he and his colleagues prepared thin hypothalamus slices from young rats and then used electrodes to record the activity of individual Hcrt/Orx neurons.

The nerve cells fired continuously, Muhlethaler's team reports in the March 1 Journal of Neuroscience. That activity persisted even when the researchers prevented the Hcrt/Orx neurons from receiving signals from surrounding neurons and neighboring brain cells in the slices remained inactive. The wake-promoting cells' activity is "completely intrinsic," says Muhlethaler.

Most nerve cells at rest are electrically polarized, with positive ions on the outside of the membrane and negative ions on the inside. Neurons usually fire only when their membranes depolarize in response to signals from other neurons. In contrast, Hcrt/Orx neurons are always depolarized to their trigger point for firing, Muhlethaler explains. As a result, the cells fire repeatedly, even without any input.

Treatment with gamma-aminobutyric acid (GABA), a neurotransmitter that inhibits neuron firing, dampened Hcrt/Orx neurons' activity. Nerve cells that produce GABA are known to connect with the brain region containing Hcrt/Orx neurons, Muhlethaler says. Presumably, activity of GABA-producing cells suppresses the wake-promoting system and lets people get some sleep, he adds.

"It's rather surprising," says neuroscientist Emmanuel Mignot of the Stanford University Center for Narcolepsy. "It suggests that the hypocretin system is indeed very special--having physiological properties that make it always active." Perhaps syndromes characterized by overactivity, such as mania, result from a malfunction in the brain centers that normally suppress Hcrt/Orx neurons, Mignot speculates. The cells may also underlie sleep disturbances associated with head trauma and other ailments, he says.

"It's a nice demonstration" of how wake-promoting neurons work at the cellular level, adds neurobiologist Jerome M. Siegel of the University of California, Los Angeles Center for Sleep Research. However, nerve activity measured in brain slices might not accurately reflect the workings in a living animal, he cautions.