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

Abstract

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.

Increased cytokine and chemokine gene expression in the CNS of mice during heat stroke recovery

“…Both temporal and regional differences in gene expression changes were observed with the most robust responses occurring at ϳ2 h of HS recovery when mice displayed hypothermia. Despite several clinical reports suggesting that hypothermia is a consequence of heat-induced damage to the POAH, we showed previously that neither the POAH nor hippocampus was damaged in our mouse model at HD (21). While our data do not provide direct evidence for a cause-andeffect role of the inflammatory mediators measured in this study in regulation of the T c changes or sickness behaviors during HS recovery, there was a close temporal association between hypothermia and the most robust gene expression changes.…”

“…Black bar represents lights-off (active) period. increase in HSP72 and the microglia/macrophage activation marker CD14 in the hypothalamus and hippocampus of mice at HD despite an inability previously to detect histological damage to these CNS regions at this time point in our model (21). Reductions in the expression of Aif1 and CX 3 CR1 were also observed, which suggests glia and/or CNS infiltrating macrophages were affected by HS.…”

“…Based on the evidence provided in this study, we hypothesize that increased cytokine, chemokine, and/or PG gene expression in the hypothalamus may be the physiological mechanism that induces hypothermia and/or an increase in metabolic rate for the development of fever in our model. We showed previously that recovery from HD and development of fever during HS recovery was associated with ϳ20% increase in metabolic rate, but the mechanism(s) stimulating this response was not identified (21). Several cytokines (IL-1␤, IL-6) and chemokines (MIP-1␣, MIP-1␤) act as endogenous pyrogens in the hypothalamus during bacterial infection.…”

“…CNS damage has been implicated as a causal factor for the development of hypothermia and/or delayed fever during HS recovery in patients and animal models despite scant evidence to support this hypothesis (21,25). We observed a significant Fig.…”

“…However, not all pathophysiological responses associated with the SIRS show a direct correlate to brain regions that experience cellular damage with HS. For example, HS patients and animal models often display core temperature (T c ) disturbances (e.g., hypothermia, fever) during recovery that occur in the absence of damage to the preoptic anterior hypothalamus (POAH), which is considered the main thermoregulatory center in the brain (1,21,25). Since many of the thermoregulatory and sickness symptoms of HS are transient in nature, they are likely due to inflammatory changes rather than heat cytotoxicity and brain damage per se.…”