Effects of Ambient Temperature on Sleep and Cardiovascular Regulation in Mice: The Role of Hypocretin/Orexin Neurons

Abstract

The central neural pathways underlying the physiological coordination between thermoregulation and the controls of the wake-sleep behavior and cardiovascular function remain insufficiently understood. Growing evidence supports the involvement of hypocretin (orexin) peptides in behavioral, cardiovascular, and thermoregulatory functions. We investigated whether the effects of ambient temperature on wake-sleep behavior and cardiovascular control depend on the hypothalamic neurons that release hypocretin peptides. Orexin-ataxin3 transgenic mice with genetic ablation of hypocretin neurons (n = 11) and wild-type controls (n = 12) were instrumented with electrodes for sleep scoring and a telemetric blood pressure transducer. Simultaneous sleep and blood pressure recordings were performed on freely-behaving mice at ambient temperatures ranging between mild cold (20°C) and the thermoneutral zone (30°C). In both mouse groups, the time spent awake and blood pressure were higher at 20°C than at 30°C. The cold-related increase in blood pressure was significantly smaller in rapid-eye-movement sleep (REMS) than either in non-rapid-eye-movement sleep (NREMS) or wakefulness. Blood pressure was higher in wakefulness than either in NREMS or REMS at both ambient temperatures. This effect was significantly blunted in orexin-ataxin3 mice irrespective of ambient temperature and particularly during REMS. These data demonstrate that hypocretin neurons are not a necessary part of the central pathways that coordinate thermoregulation with wake-sleep behavior and cardiovascular control. Data also support the hypothesis that hypocretin neurons modulate changes in blood pressure between wakefulness and the sleep states. These concepts may have clinical implications in patients with narcolepsy with cataplexy, who lack hypocretin neurons.

Sleep Apnea Research in Animals. Past, Present, and Future

“…First, IH laboratories should attempt to standardize protocols using clinically realistic conditions, and detailed parameters of oxyhemoglobin profile should be provided in all experiments. Second, unrecognized cold stress at usual laboratory temperatures affects all aspects of rodent research (69), and is especially problematic for sleep (70) and hypoxia (54) research. Figure 5.…”

Orexins and the cardiovascular events of awakening

“…Conversely, a later study on young adult ORX-ATX3 mice on a mixed (75% C57Bl/6J and 25% DBA/2J) genetic background indicated that, on passing from wakefulness to NREM sleep, these mice showed a significantly blunted decrease in ABP but not in heart period (the reciprocal of HR) compared with wildtype mice. 42 This was because ABP was significantly lower in these hybrid ORX-ATX3 mice than in hybrid wild-type mice during wakefulness, but not during NREM sleep. 42 Other experiments, performed without taking sleep into account on ORX-KO 43 and ORX-ATX3 44 mice with mixed genetic background, reported lower values of ABP during behaviorallydetermined wakefulness in these mice compared with wild-type mice.…”

“…42 This was because ABP was significantly lower in these hybrid ORX-ATX3 mice than in hybrid wild-type mice during wakefulness, but not during NREM sleep. 42 Other experiments, performed without taking sleep into account on ORX-KO 43 and ORX-ATX3 44 mice with mixed genetic background, reported lower values of ABP during behaviorallydetermined wakefulness in these mice compared with wild-type mice. Experiments on ORX-ATX3 rats found lower values of ABP compared with wild-type rats, with similar increases in ABP and HR upon awakening from NREM sleep.…”

“…53 Conversely, work on mice indicated that the difference in ABP between NREM sleep and wakefulness was greater at 30 C than at 20 C ambient temperature. 42 Notably, the cardiovascular effects of changes in ambient temperature are even greater in mice than in rats, likely because mice have a higher ratio between body surface area and volume. 57 Thus, it remains unclear whether increases in skin SNA may contribute to increase systemic vascular resistance and ABP upon awakening from NREM sleep.…”

“…41 However, a report on mice showed that the cardiovascular effects of mild cold stress did not differ in any wake-sleep state between ORX-ATX3 mice, who lack the whole orexin neurons, and wild-type mice. 42 To summarize, orexin neuron deficiency in NT1 patients may alter the skin temperature upon awakening from NREM sleep in the sense of higher distal skin temperature during wakefulness, but this effect has not received direct support by experiments on animal models. Again, this effect seems to depend on one or more undefined biological modifiers, and its autonomic, hemodynamic, and central neural mechanisms remain unclear.…”