Lateral hypothalamus drives early-onset sleep alterations in amyotrophic lateral sclerosis.

Lateral hypothalamic neurons producing melanin-concentrating hormone (MCH) and orexin/hypocretin are involved in sleep regulation. Both MCH and orexin neurons are altered in amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disease. However, sleep alterations are currently poorly characterized in ALS, and could represent either early symptoms or late consequences of disease progression. Here, we characterized sleep architecture using polysomnography in cohorts of both early ALS patients without respiratory impairment and presymptomatic carriers of mutations leading to familial ALS. We observed prominent sleep alterations, including increased wake and decreased deep sleep (non-rapid eye movement--NREM3) in both cohorts, which were replicated in two mouse models of familial ALS, Sod1G86R and Fus{Delta}NLS/+ mice. Importantly, altered sleep structure in mice was fully rescued by per os administration of a dual-orexin receptor antagonist, and partially rescued by intracerebroventricular MCH supplementation. Thus, our study shows the existence of a primary sleep alteration in ALS, driven by abnormal MCH and orexin signalling. One Sentence SummaryAmyotrophic lateral sclerosis is a tragic uncurable motor neuron disease, in this study we decribed for the first time sleep alterations in symptomatic patients and healthy gene carrier which can be reverted by per os administartion of a dual-orexin receptor antagonist in preclinical models.