178 Chapter 6 cataplexy in hypocretin/ataxin-3 transgenic mice [261, 262]. Similar functional recordings in humans have not been performed yet but Shan et al. [250, 251] reported unchanged neuronal counts within the norepinephrinergic locus coeruleus and dopaminergic ventral tegmental area in the same human postmortem narcolepsy type 1 donors. This suggests that neuron count changes within these regions are unlikely. Loss of afferent hypocretinergic innervation of the reticular formation in narcolepsy type 1 might compromise functioning even though neurons in these nuclei remain structurally unchanged, akin to recent findings from narcolepsy rodent models [263]. The specific reduction in axonal density we observed in the midbrain, corpus callosum, and anterior cingulate gyrus, excluding the cerebellum, fits this hypothesis. However, the absence of a significant relationship between the remaining hypocretin cell counts and the degree of axonal loss did not indicate a direct dependency between the two measures in narcolepsy. The question as to whether the structural disintegrity in the reticular formation of narcolepsy type 1 is a direct cause of afferent hypocretinergic connection loss therefore remains inconclusive and warrants future studies. The observed axonal density loss in other regions aligns the previously reported whole-brain DTI differences [104-106, 238]. Hypocretin typically has widespread subcortical and cortical projections excluding the cerebellum. Previous human postmortem work in the same donors has uncovered profound effects of hypocretin deficiency on other neuronal systems, including 36% upregulation of histaminergic neuronal counts in the tuberomammilary nucleus and selective 88% lower corticotropin-releasing hormone-positive neurons in the paraventricular nucleus [250, 251]. Non-hypothalamic neuron counts so far seem unchanged except for a slight increase in dopaminergic substantia nigra neurons [251]. It is improbable that hypothalamic neuronal loss solely causes the widespread lower axonal density as there normally are only 50,000-80,000 hypocretin neurons per hemisphere [44, 264]. Chronic exposure to sleep-wake alterations and other narcolepsy symptoms likely contributes to the observed decrease in axonal density, especially as narcolepsy symptoms are diverse and known to involve many brain networks. This is emphasized by Jeon et al. who uncovered extensive faster cortical thinning in narcolepsy type 1 compared to healthy controls, especially in the frontal lobe and anterior cingulate [265]. Reduced white matter integrity and functional hyperactivity in the anterior cingulate gyrus in narcolepsy type 1 was previously attributed to impaired limbic functioning and the daytime vigilance complaints [84, 266]. The anterior corpus callosum was among the most heavily affected region in DTI studies and the reduced axonal density infers impaired interhemispheric communication
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