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

The typical core temperature (T(c)) profile displayed during heatstroke (HS) recovery consists of initial hypothermia followed by delayed hyperthermia. Anecdotal observations led to the conclusion that these T(c) responses represent thermoregulatory dysfunction as a result of brain damage. We hypothesized that these T(c) responses are mediated by a change in the temperature setpoint. T(c) (+/- 0.1 degrees C; radiotelemetry) of male C57BL/6J mice was monitored while they were housed in a temperature gradient with ambient temperature (T(a)) range of 20-39 degrees C to monitor behaviorally selected T(a) (T(s)) or an indirect calorimeter (T(a) = 25 degrees C) to monitor metabolism (V(O(2))) and calculate respiratory exchange ratio (RER). Responses to mild and severe HS (thermal area 249.6 +/- 18.9 vs. 299.4 +/- 19.3 degrees C.min, respectively) were examined through 48 h of recovery. An initial hypothermia following mild HS was associated with warm T(s) (approximately 32 degrees C), approximately 35% V(O(2)) decrease, and RER approximately 0.71 that indicated reliance on fatty acid oxidation. After 24 h, mild HS mice developed hyperthermia associated with warm T(s) (approximately 32 degrees C), approximately 20% V(O(2)) increase, and RER approximately 0.85. Severe HS mice appeared poikilothermic-like in the temperature gradient with T(c) similar to T(s) (approximately 20 degrees 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 T(c) were associated with behavioral and autonomic thermoeffectors that suggest HS elicits anapyrexia and fever, respectively. Taken together, T(c) responses of mild and severe HS mice suggest a need for reinterpretation of the mechanisms of thermoregulatory control during recovery.