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 (T sc ) and core (T b ) 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, T sc 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 T sc was mitigated when mice had access to unlocked running wheels. In contrast to T sc , T b was largely maintained until day 42 in the DOX(-) condition even when the running wheel was locked. Acute changes in both T sc and T b 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 (T sc ) during the dark phase of the 24-h light/dark cycle. This reduction in dark phase T sc is mitigated by access to an exercise opportunity. In contrast to T sc , core body temperature (T b ) is largely maintained as the Hcrt/Ox neurons degenerate. Reduced T sc while T b 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 T sc and T b . Exercise may represent an effective intervention for mitigating heat loss resulting from Hcrt/Ox neuron loss in Narcolepsy.