Altered wiring of sleep-wake regulatory hypothalamic neurons in a murine model of chronic neuroinflammation

Peptidergic neurons of the lateral hypothalamus containing orexin (OX) or melanin-concentrating hormone (MCH) are implicated in several physiological functions, including energy homeostasis and sleep regulation. In particular, OX neurons play a role in wakefulness consolidation and MCH neurons are sleep-active. Sleeping sickness (African trypanosomiasis), caused by the extracellular parasites African trypanosomes, is a severe chronic inflammatory condition, fatal if untreated, which causes in humans neuropsychiatric disturbances including characteristic sleep-wake alterations documented also in rodent models of the infection. The pathogenetic mechanisms of these alterations remain to be fully clarified. Using an established approach to the quantitative evaluation of synaptic input to hypothalamic peptidergic neurons (Cristino et al., PNAS 2013), we here analyzed glutamatergic and GABAergic synapses apposed to OX-A and MCH somata in African trypanosome-infected mice, maintained under a 12h/12h light/dark cycle. By triple immunofluorescence (synaptophysin, OX-A or MCH, V-glut or V-GAT), inhibitory and excitatory terminals were analyzed during the encephalitic stage of the infection versus controls, in mice sacrificed during daytime. The total number of synapses apposed to OX-A and MCH neurons was not altered in the infected mice. However, interestingly, inhibitory inputs were significantly increased and excitatory inputs significantly decreased, leading to an overall pattern of synaptic input to OX-A and MCH neurons of infected mice opposite to that found in control mice. The striking alteration of the balance between excitatory and inhibitory inputs to OX-A and MCH neurons opens questions on the susceptibility of the synaptic wiring of these cells to neuroinflammatory signaling and their functional correlates