Abstract
Neuron populations of the lateral hypothalamus which synthesize the orexin (OX)/hypocretin or melanin-concentrating hormone (MCH) peptides play crucial, reciprocal roles in regulating wake stability and sleep. The disease human African trypanosomiasis (HAT), also called sleeping sickness, caused by extracellular Trypanosoma brucei (T. b.) parasites, leads to characteristic sleep-wake cycle disruption and narcoleptic-like alterations of the sleep structure. Previous studies have revealed damage of OX and MCH neurons during systemic infection of laboratory rodents with the non-human pathogenic T. b. brucei subspecies. No information is available, however, on these peptidergic neurons after systemic infection with T. b. gambiense, the etiological agent of 97% of HAT cases. The present study was aimed at the investigation of immunohistochemically characterized OX and MCH neurons after T. b. gambiense or T. b. brucei infection of a susceptible rodent, the multimammate mouse, Mastomys natalensis. Cell counts and evaluation of OX fiber density were performed at 4 and 8 weeks post-infection, when parasites had entered the brain parenchyma from the periphery. A significant decrease of OX neurons (about 44% reduction) and MCH neurons (about 54% reduction) was found in the lateral hypothalamus and perifornical area at 8 weeks in T. b. gambiense-infected M. natalensis. A moderate decrease (21% and 24% reduction, respectively), which did not reach statistical significance, was found after T. b. brucei infection. In two key targets of diencephalic orexinergic innervation, the peri-suprachiasmatic nucleus (SCN) region and the thalamic paraventricular nucleus (PVT), densitometric analyses showed a significant progressive decrease in the density of orexinergic fibers in both infection paradigms, and especially during T. b. gambiense infection. Altogether the findings provide novel information showing that OX and MCH neurons are highly vulnerable to chronic neuroinflammatory signaling caused by the infection of human-pathogenic African trypanosomes.
Highlights
Many infections disturb sleep, and somnolence is part of the so-called sickness behavior in response to infections (Poon et al, 2015)
OX and melanin-concentrating hormone (MCH) Cell Bodies In M. natalensis, OX-immunolabeled neurons showed a distribution similar to that described in laboratory rodents (Peyron et al, 1998; Mintz et al, 2001) and in a variety of African higher power, the intensity of the soma immunostaining appeared relatively preserved in the infected animals, but with less extensive dendritic filling than in matched controls, and some cell bodies appeared shrunken (Figures 3C–F)
The present findings show that T. b. gambiense infection leads to progressive quantitative decrease of OX and MCH neurons, and that this is more marked than that caused by T. b. brucei infection in the same host species, susceptible to both parasite subspecies
Summary
Somnolence is part of the so-called sickness behavior in response to infections (Poon et al, 2015). The alterations of sleep in human African trypanosomiasis (HAT) are, so characteristic and severe that they gave to the disease the alternative name of sleeping sickness (Buguet et al, 2014; Büscher et al, 2017). Brucei-infected rats (Darsaud et al, 2003; Seke Etet et al, 2012; Laperchia et al, 2016, 2017) recall the chronic sleep disorder narcolepsy (Sateia, 2014; Scammell, 2015), whose pathogenesis is due to impaired orexinergic signaling (Liblau et al, 2015) Such alterations point, to dysfunction of neurons which contain the orexin (OX)/hypocretin peptides, located in the posterior lateral hypothalamus. To fill this gap of knowledge, the present study was aimed at the histopathological investigation of OX and MCH cell bodies and OX fibers in the animal model of T. b. The density of OX innervation was here evaluated in these two diencephalic targets of orexinergic projections, the peri-SCN region and PVT, given their high functional relevance for interactions between circadian and vigilance state regulation (Colavito et al, 2015)
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