A combination of mapping and microarray analysis has just led to an exciting result — it has identified a gene that influences a specific pattern of brain activity that is associated with sleep.

For more than 70 years, electroencephalograms (EEGs) have been used to record brain activity as the voltage between electrodes placed on the scalp. Although controversial at times, there is no denying that distinct EEG patterns are associated with different behaviours.

A low-amplitude oscillation observed during sleep in humans and mice, called a theta rhythm, has also been seen in mice during exploratory behaviour. In this study, Tafti and colleagues crossed inbred mouse strains with either a high or low maximum theta-peak frequency (TPF) to map genes associated with differences in the TPF patterns. In one inbred line that had a reduced TPF during sleep they identified a mutation in the gene Acads . The enzyme encoded by this gene — acyl-coenzyme A dehydrogenase — catalyses the first step in β-oxidation of short-chain fatty acids: a pathway never previously associated with EEG patterns.

This curious finding led the group to perform whole-brain microarray analysis on mutant mice compared to wild type. They found that expression of one gene, Glo1 , was consistently upregulated in the mutants. Glo1 encodes an enzyme that is involved in metabolic detoxification in the glyoxalase pathway. Although none of the other inbred lines with slow theta rhythms carried mutations in Acads, Glo1 expression was significantly increased in all of them. The authors confirmed the link between Glo1 expression and low TPF in the inbred line by treating the animals with acetyl-L-carnitine, which removes excess short- and medium-chain fatty acids; this partially rescued the TPF and restored normal Glo1 expression.

The authors speculate that the link between Glo1 expression and TPF indicates that the glyoxalase pathway ultimately underlies the differences in theta frequency between the mouse strains tested. As the theta frequency in these mice is only affected during sleep, the results indicate not only that theta regulation is fundamentally different between waking and sleeping hours but also that β-oxidation might be required for normal sleep.