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 javax.xml.bind.JAXBElement@77428ce5 ( javax.xml.bind.JAXBElement@6a38dce1 .) 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 javax.xml.bind.JAXBElement@14a55b18 subspecies. No information is available, however, on these peptidergic neurons after systemic infection with javax.xml.bind.JAXBElement@175fe124 , the etiological agent of 97% of HAT cases. The present study was aimed at the investigation of immunohistochemically characterized OX and MCH neurons after javax.xml.bind.JAXBElement@7419628e or javax.xml.bind.JAXBElement@586a6738 infection of a susceptible rodent, the multimammate mouse, javax.xml.bind.JAXBElement@66299ab6 javax.xml.bind.JAXBElement@e971196 . 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 javax.xml.bind.JAXBElement@31250fd8 infected javax.xml.bind.JAXBElement@3afded63 . A moderate decrease (21% and 24% reduction, respectively), which did not reach statistical significance, was found after javax.xml.bind.JAXBElement@10ab3ca0 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 javax.xml.bind.JAXBElement@26069482 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.