Nature Neuroscience

A circadian clock within the brain ensures that we sleep at night and are awake during the day. But as anyone who has stayed up all night and fallen into a deep sleep the next morning knows, the timing of sleep also depends on the need for sleep. Now a paper in the October issue of Nature Neuroscience reports that sleep homeostatic processes, which cause the urge to sleep to depend on prior amounts of sleep or wakefulness, influence the circadian clock.

Johanna Meijer and colleagues monitored the vigilance state of rats by recording their brain (EEG) and muscle (EMG) signals. At the same time, the experimenters recorded neuronal activity within a brain region called the suprachiasmatic nucleus (SCN) to monitor the output of the circadian clock. Driven by cycles of gene transcription and translation, activity in the SCN normally oscillates with day and night cycles. They found a clear correlation between vigilance states and activity in the SCN. Furthermore, by using sleep deprivation experiments, they tested for a casual relationship. Indeed, during sleep deprivation, neuronal activity in the SCN failed to show expected changes in electrical activity for the time of day, demonstrating that activity in the SCN is determined not only by the molecular machinery of the circadian clock, but also by sleep need. A next step will be to determine how changes in need for sleep are communicated to the SCN at the molecular level.

Nature Neuroscience

People infected with the human immunodeficiency virus type 1 (HIV-1) may develop dementia due to the death of neurons in the brain. However, HIV-1 does not infect neurons, suggesting that an indirect process is at work. A potent neurotoxin produced by a complex interaction of signals from non-neuronal brain cells may be the answer, reports a study in the October issue of Nature Neuroscience. This work suggests that drugs already in clinical trials for another disease may be effective for treating HIV-associated dementia.

The authors found that when certain immune cells (called macrophages) were infected with HIV-1, they released a substance toxic to neurons. Further examination revealed that the substance, an inactive form of a protein called matrix metalloprotease 2 (MMP2), was itself not the killer, but rather was converted by neurons into an enzyme that cleaves another protein, called stromal-derived factor (SDF) 1. SDF-1 has a number of normal functions in the brain, but the shortened form of SDF-1 was highly toxic to neurons. Rats given the inactive MMP2 showed loss of neurons and exhibited behavioral problems. By using drugs that block the activation of MMP2 (and thus the cleavage of SDF-1), the researchers could diminish the toxic effects. Such MMP2 inhibitors are already in clinical trials for cancer.