The technique involves genetically engineering mice to produce a "tracer" protein only in a certain population of neurons. The tracer, a nontoxic fragment of the tetanus toxin, transfers itself from one neuron in retrograde fashion to neurons "upstream" -- those from which the tracer-producing neuron receives signals. Researchers then track the tracer to map the upstream neurons.

Dr. Yanagisawa and his colleagues are the first to apply the technique in order to study a specific neural pathway. They introduced the tracer into mice so that it was expressed only in orexin neurons, which are found in a part of the brain called the lateral hypothalamus. The researchers found that some of the upstream neurons in the anterior hypothalamus, known to be active only during sleep, send inhibitory signals to orexin neurons preventing them from releasing orexin.

"Neurons producing orexin keep you awake, and they also stabilize wakefulness," Dr. Yanagisawa said. "In order to fall sleep, you somehow must inhibit these orexin neurons. It appears that sleep-active neurons in a specific region of the brain are doing just that, keeping the animals asleep."

The researchers also found that during wakefulness, orexin neurons activate cells in other parts of the brain that negatively feed back to the sleep-active neurons in the anterior hypothalamus, keeping them from becoming active.

"This makes perfect sense," said Dr. Yanagisawa, a Howard Hughes Medical Institute investigator at UT Southwestern. "When one group of neurons is active, the other group must be inactive, and vice versa. It's a seesaw, or flip-flop, mechanism. That's important because you don't want to be half-asleep. You want to be either completely awake or completely asleep."

Another finding from the Neuron study may help explain why once you're awake and moving around, you tend to stay awake,
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Contact: Amanda Siegfried
amanda.siegfried@utsouthwestern.edu
214-648-3404
UT Southwestern Medical Center
21-Apr-2005