Peripheral vs. Core Body Temperature as Hypocretin/Orexin Neurons Degenerate: Exercise Mitigates Increased Heat Loss

Hypocretins/Orexins (Hcrt/Ox) are hypothalamic neuropeptides implicated in diverse functions, including body temperature regulation through modulation of sympathetic vasoconstrictor tone. In the current study, we measured subcutaneous (Tsc) and core (Tb) body temperature as well as activity in a conditional transgenic mouse strain that allows the inducible ablation of Hcrt/Ox-containing neurons by removal of doxycycline (DOX) from their diet (orexin-DTA mice). Measurements were made during a baseline, when mice were being maintained on food containing DOX, and over 42 days while the mice were fed normal chow which resulted in Hcrt/Ox neuron degeneration. The home cages of the orexin-DTA mice were equipped with running wheels that were either locked or unlocked. In the presence of a locked running wheel, Tsc progressively decreased on days 28 and 42 in the DOX(-) condition, primarily during the dark phase (the major active period for rodents). This nocturnal reduction in Tsc was mitigated when mice had access to unlocked running wheels. In contrast to Tsc, Tb was largely maintained until day 42 in the DOX(-) condition even when the running wheel was locked. Acute changes in both Tsc and Tb were observed preceding, during, and following cataplexy. Our results suggest that ablation of Hcrt/Ox-containing neurons results in elevated heat loss, likely through reduced sympathetic vasoconstrictor tone, and that exercise may have some therapeutic benefit to patients with narcolepsy, a disorder caused by Hcrt/Ox deficiency. Acute changes in body temperature may facilitate prediction of cataplexy onset and lead to interventions to mitigate its occurrence. Highlights Hypocretin/Orexin (Hcrt/Ox) neuron degeneration results in the sleep disorder Narcolepsy and reduced subcutaneous body temperature (Tsc) during the dark phase of the 24-h light/dark cycle. This reduction in dark phase Tsc is mitigated by access to an exercise opportunity. In contrast to Tsc, core body temperature (Tb) is largely maintained as the Hcrt/Ox neurons degenerate. Reduced Tsc while Tb is maintained suggests increased heat loss, possibly through modulation of sympathetic vasoconstrictor tone. Hcrt/Ox neuron loss in Narcolepsy results in cataplexy, whose occurrence is associated with acute changes in both Tsc and Tb. Exercise may represent an effective intervention for mitigating heat loss resulting from Hcrt/Ox neuron loss in Narcolepsy.