title: Alterations of orexinergic and melanin-concentrating hormone neurons in experimental sleeping sickness.
abstract: Human African trypanosomiasis or sleeping sickness is a severe, neglected tropical disease caused by the extracellular parasite Trypanosoma brucei. The disease, which leads to chronic neuroinflammation, is characterized by sleep and wake disturbances, documented also in rodent models. In rats and mice infected with Trypanosoma brucei brucei, we here tested the hypothesis that the disease could target neurons of the lateral hypothalamus (LH) containing orexin (OX)-A or melanin-concentrating hormone (MCH), implicated in sleep/wake regulation. In the cerebrospinal fluid of infected rats, the OX-A level was significantly decreased early after parasite neuroinvasion, and returned to the control level at an advanced disease stage. The number of immunohistochemically characterized OX-A and MCH neurons decreased significantly in infected rats during disease progression and in infected mice at an advanced disease stage. A marked reduction of the complexity of dendritic arborizations of OX-A neurons was documented in infected mice. The evaluation of NeuN-immunoreactive neurons did not reveal significant neuronal loss in the LH of infected mice, thus suggesting a potential selective vulnerability of OX-A and MCH neurons. Immunophenotyping and quantitative analysis showed in infected mice marked activation of microglial cells surrounding OX-A neurons. Day/night oscillation of c-Fos baseline expression was used as marker of OX-A neuron activity in mice. In control animals Fos was expressed in a higher proportion of OX-A neurons in the night (activity) phase than in the day (rest) phase. Interestingly, in infected mice the diurnal spontaneous Fos oscillation was reversed, with a proportion of OX-A/Fos neurons significantly higher at daytime than at nighttime. Altogether the findings reveal a progressive decrease of OX-A and MCH neurons and dysregulation of OX-A neuron diurnal activity in rodent models of sleeping sickness. The data point to the involvement of these peptidergic neurons in the pathogenesis of sleep/wake alterations in the disease and to their vulnerability to inflammatory signaling.
authors.affiliation: Department of Neurological and Movement Sciences, University of Verona, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Palomba
authors.affiliation: Department of Neurological and Movement Sciences, University of Verona, Italy.
authors.forename: P F
authors.initials: PF
authors.lastname: Seke-Etet
authors.affiliation: Department of Neurological and Movement Sciences, University of Verona, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Laperchia
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Tiberio
authors.affiliation: Department of Neurological and Movement Sciences, University of Verona, Italy.
authors.forename: Y-Z
authors.initials: YZ
authors.lastname: Xu
authors.affiliation: Department of Neurological and Movement Sciences, University of Verona, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Colavito
authors.affiliation: Department of Neurological and Movement Sciences, University of Verona, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Grassi-Zucconi
authors.affiliation: Department of Neurological and Movement Sciences, University of Verona, Italy. Electronic address: marina.bentivoglio@univr.it.
authors.forename: M
authors.initials: M
authors.lastname: Bentivoglio
mesh_terms: D000818:Animals; D002452:Cell Count; D002940:Circadian Rhythm / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D007028:Hypothalamic Hormones / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008543:Melanins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000469:parasitology / Q000473:pathology / Q000502:physiology; D009474:Neurons / Q000469:parasitology / Q000473:pathology / Q000502:physiology*; D000068797:Orexins / Q000378:metabolism*; D010907:Pituitary Hormones / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D014346:Trypanosoma brucei brucei; D014353:Trypanosomiasis, African / Q000473:pathology / Q000503:physiopathology*
chemical_list: D007028:Hypothalamic Hormones; D008543:Melanins; D000068797:Orexins; D010907:Pituitary Hormones; D016760:Proto-Oncogene Proteins c-fos; C019463:melanin-concentrating hormone
keywords: African trypanosomiasis; Fos; Trypanosoma brucei; orexin/hypocretin; sleep; wakefulness