Canine brains offer clue to narcolepsy.

In a strain of dogs that sleep excessively and collapse when they are excited, investigators have discovered a withering away of axons, the communication cables that convey signals between nerve cells. That degeneration, if also evident in human brains, may finally offer an explanation for narcolepsy, a sleep disorder that afflicts an estimated 250,000 people in the United States.

"This is really the first evidence that something gets destroyed in the [narcoleptic] brain," says Jerry M. Siegel of the University of California, Los Angeles and Sepulveda Veterans Affairs Medical Center, who presented the research at last week's Society for Neuroscience annual meeting in San Diego.

Though the condition provokes many jokes, narcolepsy can be a debilitating disorder: Narcoleptics sometimes fall asleep in the middle of conversations or physical activities. Symptoms appear during the teenage years, with excessive daytime sleepiness usually marking the onset of the disorder. Many narcoleptics then begin to suffer from cataplexy, a sudden loss of voluntary motor control stimulated by intense emotions such as anger, fear, or joy. A simple joke can cause a narcoleptic's knees to buckle, head to drop, and jaw to go slack.

Narcoleptic dogs, mainly Doberman pinschers, have served as a model of the condition since the 1970s. In these dogs, symptoms normally appear at about 2 months of age. Simply playing fetch can trigger a cataplectic attack.

Examining the brains of young dogs, Siegel and his coworkers found three regions in which narcoleptic dogs showed much more axon degeneration than do normal dogs.

Investigators had previously linked the three affected brain areas-the medial septal nucleus, the diagonal band region, and the amygdala-to sleep inhibition, motor control, and the processing of emotions. "It's easy to explain the symptoms of narcolepsy with this damage," asserts Siegel.

The crucial issue, he acknowledges, is whether human narcolepsy results from similar degeneration. Since human narcoleptics live to normal ages, says Siegel, evidence of the axon degeneration could largely have disappeared by the time a patient dies, explaining why autopsies of narcoleptics have not revealed obvious brain abnormalities. With specific brain regions now implicated by the canine research, he says, investigators can more effectively examine human narcoleptics, either through brain imaging of live patients or detailed postmortem analysis.

Some narcolepsy investigators caution that the axon degeneration found in dogs may bear no relation to what causes human narcolepsy. "I don't think the dog has been a particularly excellent model," says Sharon L. Merritt of the Center for Narcolepsy Research at the University of Illinois at Chicago. "Maybe this will provide a lead, but considering the past, I'm skeptical."

Still, Merritt and other investigators agree on the need to fully explore the hypothesis of axon degeneration. Current therapies for narcolepsy-stimulants and antidepressants-alleviate some of the disorder's symptoms but do not provide a cure. "To develop better treatments, we need to know the mechanism of the disease," says Seiji Nishino of Stanford University's Sleep Disorders Research Center.