Peptide missing in narcolepsy patients plays unique role in brain

24 April 2014

A neuron (green) surrounded by nerve fibres.

Image: A neuron (green) surrounded by nerve fibres from orexin/hypocretin neurons (red). ©  Dr Cornelia Schöne, Burdakov lab.

Narcolepsy, a brain disorder that affects a patient's sleep-wake cycle, is caused by the loss of a peptide - a short chain of amino acids - called orexin/hypocretin in the brain.

Now, research has shown that natural release of orexin/hypocretin generates a unique signature of brain activity.

The work was led by Dr Denis Burdakov at the Medical Research Council's National Institute for Medical Research (NIMR; now part of the Francis Crick Institute). He explained: "Like a swan smoothly gliding on water with frantic paddling underneath, the orexin system is thought to make numerous computations and corrections to make consciousness flow smoothly from one state to the next.

"However, beyond this normally smooth surface, control signals generated by orexin remain hidden from sight, and so it is not clear why loss of orexin produces unstable consciousness."

Dr Burdakov's team stimulated the orexin circuit and measured outputs of brain histamine cells (which stimulate wakefulness, explaining drowsiness caused by anithistamine drugs) . This enabled them to obtain experimental estimates of the input-output computations performed by orexin in the brain.

The results suggest that orexin is required for generating a unique kind of brain activity - sustained and integrative impulses in brain cells that promote wakefulness. These kinds of signals could not be generated by glutamate, one of the most common signalling molecules (neurotransmitters) in the brain. The findings help to explain why the brain uses energy making peptide neurotransmitters such as orexin/hypocretin in addition to glutamate.

Dr Burdakov said: "The results are interesting because they suggest a specific task for which orexins are required in brain circuits.

"Our study offers new insights into the brain signals that are lacking in people with narcolepsy and point to processes that need to be mimicked by treatments for the condition."

The paper, Coreleased orexin and glutamate evoke nonredundant spike outputs and computations in histamine neurons, is published in Cell Reports.

  • A study led by the Medical Research Council's National Institute for Medical Research shows that a peptide lacking in the brains of patients with narcolepsy is needed for a unique type of brain activity. 
  • Narcolepsy is a relatively rare sleep disorder that affects the brain's ability to regulate a person's sleep-wake cycle. It can cause excessive daytime drowsiness, disturbed night sleep, 'sleep attacks', where sufferers fall asleep suddenly and involuntarily at inappropriate times, and cataplexy - temporary episodes of muscle weakness triggered by strong emotions such as laughter, anger and surprise. The debilitating disorder affects around one in 2,000 people and has no cure.