177 Axonal Loss in Narcolepsy Type 1 to controls (Appendix A, Supplementary Table 2). No qualitative observations of demyelination or myelin swelling were made in the sections. Discussion Significantly lower axonal density was seen in the white matter of the midbrain, corpus callosum and anterior cingulate gyrus in narcolepsy type 1. No significant axonal density changes were observed in the cerebellum. In combination with the lower axonal density in the other regions, this is in line with the known typical projection pattern of hypocretin neurons [208]. Axonal orientation, axonal injury and myelin integrity measures were comparable between groups, except for decreased myelin integrity in the secondary visual gyrus in narcolepsy type 1. Our results support the hypothesis that axonal density is lower in narcolepsy type 1 and serves as an essential driver for the recently observed DTI alterations, but they do not support the widespread myelin integrity alterations that we had also anticipated. Axonal density We observed significant decreases in axonal density within the mesencephalic reticular formation, a vital network of integral nuclei of the ascending reticular activating system, including the norepinephrinergic locus coeruleus, dopaminergic ventral tegmental area and serotonergic dorsal raphe nucleus [253]. These nuclei are normally strongly modulated by hypocretinergic projections from the hypothalamus, and crucial for promoting wakefulness and suppress muscle atonia and REM sleep [254]. Their involvement in typical narcolepsy symptomatology has been suggested, including sleeponset REM periods, increased REM sleep without atonia, muscle weakness during cataplexy, sleep paralysis and hypnagogic hallucinations [255-257]. Recent in-vivo quantitative MRI of the reticular formation has shown reduced neuromelanin in the absence of myelin and proton density differences in humans with narcolepsy type 1, indicating neuronal abnormalities similar to our findings [258]. These findings were attributed to the locus coeruleus. The locus coeruleus normally not only stimulates arousal but also modulates muscle atonia during REM sleep and increases sleep state stability by suppressing transitions from NREM to REM sleep [259, 260]. DTI-measured white matter abnormalities have also been found in proximity to the ventral tegmental area and dorsal raphe nucleus in narcolepsy [84]. Besides an essential role in reward processing, the ventral tegmental area has more recently been identified as a gatekeeper for REM sleep onset in wild-type rodents, and a modulator of 6
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