Corticotropin-Releasing Hormone (CRH) in Murine Narcolepsy: What Do Genetic and Immune Models Tell Us?

Abstract

Narcolepsy type 1 is a chronic sleep disorder of putative autoimmune aetiology, primarily caused by the loss of orexin-producing neurons in the hypothalamus. An additional 88% reduction in corticotropin-releasing hormone-immunoreactive neurons of the paraventricular nucleus has been recently observed in post-mortem brains of individuals with narcolepsy type 1. It is, however, unknown whether this reduction is specific to the paraventricular nucleus or involves other brain regions expressing corticotropin-releasing hormone, such as the amygdala, which plays a central role in mood regulation, stress response and cataplexy. This study examined whether orexin neuron loss and/or hypothalamic neuroinflammation would affect the expression of corticotropin-releasing hormone and other neuropeptides, including melanin-concentrating hormone and histidine decarboxylase as a proof of concept. We used quantitative polymerase chain reaction to measure messenger RNA levels in three mice models of narcolepsy type 1: mice lacking orexin due to genetic disruption, mice with toxin-induced orexin neuron ablation and mice with autoimmune-mediated orexin neuron loss accompanied by hypothalamic neuroinflammation. We found no change in corticotropin-releasing hormone expression in both the hypothalamus and amygdala across all models, regardless of the timeline or mechanism of orexin loss. Similarly, the expression of melanin-concentrating hormone and histidine decarboxylase was unaffected. These findings suggest that the absence of orexin signalling alone is not sufficient to alter corticotropin-releasing hormone expression. Alternative mechanisms may account for the observation made in human narcolepsy type 1 post-mortem samples. Future human studies are warranted to identify the underlying processes and determine whether similar changes occur in other brain regions.