A research team at the UCLA Center for Sleep Research has discovered that an excess of brain cells containing histamine may be the cause of the loss of hypocretin cells in human narcoleptics. The death of hypocretin cells, the researchers said, helps explain the sleepiness of narcolepsy.

The surplus of histamine causes loss of hypocretin, an arousing chemical that keeps people awake and elevates both mood and alertness. In a report published in the current online edition of Annals of Neurology, UCLA professor of psychiatry Jerome Siegel and colleagues show people with narcolepsy have an increased number of brain cells containing the chemical histamine.

The findings come on the heels of a previous study by the same team, showing that people suffering from narcolepsy had 90% fewer neurons containing the neuropeptide hypocretin in their brains than healthy people. Subsequent work by this group and others demonstrated that the death of hypocretin cells helps explain the sleepiness of narcolepsy. Until now, it has remained unclear what kills these cells.
For the study, researchers examined five narcoleptic brains and seven control brains from human cadavers. Prior to death, all the narcoleptics had been diagnosed by a sleep disorder center as having narcolepsy with cataplexy. These brains were also compared with the brains of three narcoleptic mouse models and with the brains of narcoleptic dogs.
The researchers found that the humans with narcolepsy had an average of 64% more histamine neurons. Interestingly, the team did not see an increased number of these cells in any of the animal models of narcolepsy.
“We know that narcolepsy in the animal models is caused by engineered genetic changes that block hypocretin function; however, in humans, we did not know why the hypocretin cells die,” said Siegel, who directs the Center for Sleep Research at the UCLA Semel Institute for Neuroscience and Human Behavior and is the senior author of the research. “Our current findings indicate that the increase of histamine cells that we see in human narcolepsy may cause the loss of hypocretin cells.”
The study results may also further scientific understanding of brain plasticity. Scientists have known of the existence of neurogenesis—the process by which the brain is populated with new neurons—but it was thought to function mainly to replace existing cells that had died.
“This paper shows for the first time that neuronal numbers can increase greatly and not just serve as replacement cells,” Siegel said. “In the current example, this appears to be pathological with the destruction of hypocretin, but in other circumstances, it may underlie recovery and learning and open new routes to treatment of a number of neurological disorders.”