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April 18th, 2025
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University of California, Los Angeles
neuroscience
biorxiv

Brainstem pathology in human narcolepsy: Neurodegeneration in the locus coeruleus in narcoleptic humans, but not in genetically narcoleptic mice or dogs

Thannickal, T. C.Open in Google Scholar•Wu, M.-F.Open in Google Scholar•Cornford, M. E.Open in Google Scholar•Siegel, J.Open in Google Scholar

Our earlier study led to the conclusion that human narcolepsy with cataplexy was caused by the loss of forebrain hypocretin (orexin) neurons in the hypothalamus. We now report that humans having narcolepsy with cataplexy also have a 46% decrease in the number and an 18% increase in the size of brainstem neuromelanin-pigmented locus coeruleus (LC) neurons and increased microglial activity in LC. However, no such changes are observed in the LC of hypocretin peptide depleted narcoleptic mice, hypocretin neuron depleted orexin-tTA/TetO-DTA (orexin-DTA) narcoleptic mice or in narcoleptic dogs. Sodium oxybate, an effective treatment for narcolepsy, decreased the size of LC norepinephrine neurons and increased the number and size of LC microglial cells in mice. Our results indicate that the autoimmune process believed to cause human narcolepsy affects both forebrain Hcrt neurons and brainstem LC norepinephrine cells. Addressing both forebrain and brainstem pathologies may improve understanding of, and treatments for, human narcolepsy.

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