Thermoregulatory, behavioral, and metabolic responses to heatstroke in a conscious mouse model

Abstract

The typical core temperature (Tc) profile displayed during heatstroke (HS) recovery consists of initial hypothermia followed by delayed hyperthermia. Anecdotal observations led to the conclusion that these Tc responses represent thermoregulatory dysfunction as a result of brain damage. We hypothesized that these Tc responses are mediated by a change in the temperature setpoint. Tc (± 0.1°C; radiotelemetry) of male C57BL/6J mice was monitored while they were housed in a temperature gradient with ambient temperature (Ta) range of 20–39°C to monitor behaviorally selected Ta (Ts) or an indirect calorimeter (Ta = 25°C) to monitor metabolism (V̇o2) and calculate respiratory exchange ratio (RER). Responses to mild and severe HS (thermal area 249.6 ± 18.9 vs. 299.4 ± 19.3°C·min, respectively) were examined through 48 h of recovery. An initial hypothermia following mild HS was associated with warm Ts (∼32°C), ∼35% V̇o2 decrease, and RER ∼0.71 that indicated reliance on fatty acid oxidation. After 24 h, mild HS mice developed hyperthermia associated with warm Ts (∼32°C), ∼20% V̇o2 increase, and RER ∼0.85. Severe HS mice appeared poikilothermic-like in the temperature gradient with Tc similar to Ts (∼20°C), and these mice failed to recover from hypothermia and develop delayed hyperthermia. Cellular damage (hematoxylin and eosin staining) was undetectable in the hypothalamus or other brain regions in severe HS mice. Overall, decreases and increases in Tc were associated with behavioral and autonomic thermoeffectors that suggest HS elicits anapyrexia and fever, respectively. Taken together, Tc responses of mild and severe HS mice suggest a need for reinterpretation of the mechanisms of thermoregulatory control during recovery.