Effects of Rodent Thermoregulation on Animal Models in the Research Environment

Abstract

The thermal biology of laboratory mice encompasses a robust, dynamic, and multifaceted mixture of behavior and physiology. Physical and physiologic adaptations provide the remarkable capacity for mice to survive in temperatures as low as 4 °C and as high as 43 °C. 54,89 Comprehension of these complex systems necessitates a clear definition and solid understanding of the murine thermoneutral zone (TNZ), which is the range of temperatures across which the resting metabolic rate of heat production is at equilibrium with the animal's evaporative heat loss to the surrounding environment. 14,54 Within the TNZ, animals can maintain stable core body temperatures by responsive behaviors, peripheral vessel diameter, and body postures. 54 The overall mouse TNZ is bound by the lower and upper critical temperature limits, beyond which mice must engage in heating or cooling adjustments, respectively; further definition of these critical temperatures is provided in a glossary of terms for thermal physiology. 22 TNZ is determined by body size and weight, morphology, condition, and resting metabolic rate and is particularly narrow in mice, spanning just 1 to 3 °C, because of a large surface-to-volume ratio and meager body insulation (for example, body hair). 54,74,120 These responses to the ambient environment lead to dramatic increases in metabolic rate and alterations in thermal profiles (Figure 1). 14,54 Long-term (chronic) cold-induced exposures for mice often alter experimental results, described across multiple disciplines. 8,10,27,92,118,129 As a result, the biomedical scientific community has asserted the need to account for and better support the thermal biology of mice, 35,40,65,75,92 although dissenting opinions on this matter have been expressed. 127 Unlike many large endotherms, mice do not have stable core temperatures. Their body temperature oscillates over short bursts of approximately 1 °C even within the TNZ. Mice also show circadian fluctuations in their core temperatures and sleep patterns at standard housing temperatures: mice in barren caging conditions at 23.5 °C maintain a core body temperature of 36.2 °C during the light cycle and 37.5 °C during the dark cycle. 48,72 When provided with deep bedding for nesting, light cycle core temperatures increase to an average 37.2 °C, while the dark cycle temperatures remain at 37.5 °C. 48 The mouse's core temperature and related physiologic state should not be attributed to a static number but instead should be viewed as a dynamic value dependent on environmental context. Over many generations of exposure to particular conditions, mice acclimate through the development of anatomic differences based on their rearing temperatures. Mice raised in colder environments grow significantly shorter tails 55 and ears, 4 have longer fur for increased insulation, 4,60 develop larger livers and kidneys 55 and bones, 3 and have larger deposits of brown adipose tissue (BAT) with increased thermogenic capacity. 63,89 The evolutionary strategy of energy conservation through environme...

Adrenergic stress constrains the development of anti-tumor immunity and abscopal responses following local radiation

“…Relative to this problem, during pre-clinical research using murine models of cancer and graft versus host disease, our lab has clearly demonstrated that Institutional Animal Care and Use Committee (IACUC)-mandated mild cool housing temperature for laboratory mice (typically~22-23°C) is sufficient to cause chronic adrenergic stress 22 with activation of sympathetic nerves resulting in norepinephrine release needed for adaptive thermogenesis [23][24][25] . That this has a direct impact on the outcomes of studies involving a variety of disease models, including studies involving immune responses has been shown by comparing outcomes in mice housed under standard vs. thermoneutral temperatures [24][25][26][27] . Furthermore, our lab discovered that this chronic stress suppresses baseline anti-tumor immunity and accelerates tumor growth and metastasis 28,29 , while it also suppresses graft versus host disease following allogeneic hematopoietic stem cell transplantation 30,31 .…”

Thermoneutral Housing Temperature Improves Survival in a Murine Model of Polymicrobial Peritonitis

“…The studies presented here demonstrate that thermoneutral housing at 30°C resulted in improved survival as compared with standard housing at 22°C. Several recent reviews have described similar impact of thermoneutral housing on survival in other mouse models of human disease ( 12 , 15 , 22 , 23 ), including those used in metabolism, cancer, and infectious disease research. For instance, housing at thermoneutrality resulted in slower tumor growth and reduced metastasis in mouse cancer models compared with housing at standard temperatures, due to enhanced antitumor immune responses ( 23 , 28 ).…”

“…Several studies have shown the housing temperature of mice influences experimental phenotypes ( 13 ), model development ( 12 ), and translation of study results ( 12 – 15 ). In particular, temperature-related alteration of immune responses has direct effects on mouse models of cancer ( 16 ), graft-versus-host-disease ( 17 ), LPS-induced inflammation ( 18 , 19 ), and infectious disease ( 20 , 21 ).…”

“…Overall, reviews of the controversies surrounding housing temperature emphasize the importance of conducting preliminary experiments at warmer temperatures to see how the difference affects experimental outcomes ( 15 , 23 ). While it has been shown that short-term, perioperative warming decreases sepsis mortality after CLP ( 24 ), the effect of chronic housing at thermoneutral temperatures remains to be ascertained.…”

Impact of Ambient Temperature on Inflammation-induced Encephalopathy in Endotoxemic Mice—Role of Phosphoinositide 3-Kinase Gamma

“…at 26°C [15]. Importantly, recent guidelines for preclinical studies in sepsis research [32,33] and cerebrovascular research [34][35][36], with the emphasis to improve reproducibility and translational impact, neglected the impact of ambient temperature on pathogenesis of inflammatory diseases or did not consider that their recommended lower baseline limit for housing temperatures of small rodents causes chronic 'cold' stress [37,38]. Furthermore, ignoring the role of ambient temperature on basal physiological responsiveness in small animals frequently used in preclinical sepsis models leads to far-reaching repercussions of profound misinterpretation: Time course of body temperature lowering and development of hypothermia is used for prognosis prediction while mice are under chronic cold stress for mice [39][40][41][42][43].…”