Sleep and Rhythm Changes at the Time ofTrypanosoma bruceiInvasion of the Brain Parenchyma in the Rat

Abstract

Human African trypanosomiasis (HAT), or sleeping sickness, is a severe disease caused by Trypanosoma brucei (T.b.). The disease hallmark is sleep alterations. Brain involvement in HAT is a crucial pathogenetic step for disease diagnosis and therapy. In this study, a rat model of African trypanosomiasis was used to assess changes of sleep-wake, rest-activity, and body temperature rhythms in the time window previously shown as crucial for brain parenchyma invasion by T.b. to determine potential biomarkers of this event. Chronic radiotelemetric monitoring in Sprague-Dawley rats was used to continuously record electroencephalogram, electromyogram, rest-activity, and body temperature in the same animals before (baseline recording) and after infection. Rats were infected with T.b. brucei. Data were acquired from 1 to 20 d after infection (parasite neuroinvasion initiates at 11-13 d post-infection in this model), and were compared to baseline values. Sleep parameters were manually scored from electroencephalographic-electromyographic tracings. Circadian rhythms of sleep time, slow-wave activity, rest-activity, and body temperature were studied using cosinor rhythmometry. Results revealed alterations of most of the analyzed parameters. In particular, sleep pattern and sleep-wake organization plus rest-activity and body temperature rhythms exhibited early quantitative and qualitative alterations, which became marked around the time interval crucial for parasite neuroinvasion or shortly after. Data derived from actigrams showed close correspondence with those from hypnograms, suggesting that rest-activity could be useful to monitor sleep-wake alterations in African trypanosomiasis.

Trypanosoma brucei Invasion and T-Cell Infiltration of the Brain Parenchyma in Experimental Sleeping Sickness: Timing and Correlation with Functional Changes

“…b . brucei -infected rats, where SOREM episodes were noted but parasite neuroinvasion was not verified histologically [51]. The present study also demonstrates that the severity of these sleep alterations does not correlate with the parasite density in the neuropil at sacrifice.…”

The challenging problem of disease staging in human African trypanosomiasis (sleeping sickness): a new approach to a circular question

“…For example, late stage disease corresponding to the crossing of the BBB by the parasite has been shown to start to occur between days 11 and 13 after infection. 17 Furthermore, the mechanism of crossing the BBB in this model has been investigated in detail. 18 However, the timing of these events in the human disease, let alone the molecular mechanisms involved are far more challenging questions to address than they are in animal models where the conditions can be experimentally manipulated and controlled.…”

“…The description and use of polysomnography, in particular Sleep Onset Rapid Eye Movement periods (SOREMPs) by Buguet and colleagues, 14 raised the hope for this latter electrophysiological trait to become a biomarker of late stage HAT. However, SOREMPs have been demonstrated to be present both in early and late stages of the disease in the experimental and as well as the human disease, 17,43 and in the animal model, the occurrence of SOREMPs has been demonstrated to precede the crossing of the BBB by trypanosomes. 17 SOREMPs could, however, constitute a useful non-invasive tool for detecting disease relapses.…”

The Complex Interplay of Parasites, Their Hosts, and Circadian Clocks

“…An advance of the melatonin rhythm was also observed, but no change in core body temperature rhythm (Claustrat et al, 1998). In T. brucei-infected rats, however, both a phase shift of the temperature rhythm and changes in sleep profile were observed (Grassi-Zucconi et al, 1995;Seke Etet et al, 2012). Interestingly, some of the phenotypes were present even before parasites start accumulating in the brain, although they became more prominent after that stage (Seke Etet et al, 2012).…”

“…In T. brucei-infected rats, however, both a phase shift of the temperature rhythm and changes in sleep profile were observed (Grassi-Zucconi et al, 1995;Seke Etet et al, 2012). Interestingly, some of the phenotypes were present even before parasites start accumulating in the brain, although they became more prominent after that stage (Seke Etet et al, 2012). Disorganized sleep-wake cycles and a phase advance of rhythms controlled by the SCN central clock begs the question of whether the infection causes changes of circadian clocks themselves.…”