Elsevier

Journal of Thermal Biology

Volume 37, Issue 8, December 2012, Pages 654-685
Journal of Thermal Biology

Review
Thermal physiology of laboratory mice: Defining thermoneutrality

https://doi.org/10.1016/j.jtherbio.2012.08.004Get rights and content

Abstract

In terms of total number of publications, the laboratory mouse (Mus musculus) has emerged as the most popular test subject in biomedical research. Mice are used as models to study obesity, diabetes, CNS diseases and variety of other pathologies. Mice are classified as homeotherms and regulate their core temperature over a relatively wide range of ambient temperatures. However, researchers find that the thermoregulatory system of mice is easily affected by drugs, chemicals, and a variety of pathological conditions, effects that can be exacerbated by changes in ambient temperature. To this end, a thorough review of the thermal physiology of mice, including their sensitivity and regulatory limits to changes in ambient temperature is the primary focus of this review. Specifically, the zone of thermoneutrality for metabolic rate and how it corresponds to that for growth, reproduction, development, thermal comfort, and many other variables is covered. A key point of the review is to show that behavioral thermoregulation of mice is geared to minimize energy expenditure. Their zone of thermal comfort is essentially wedged between the thresholds to increase heat production and heat loss; however, this zone is above the recommended guidelines for animal vivariums. Future work is needed to better understand the behavioral and autonomic thermoregulatory responses of this most popular test species.

Highlights

► Laboratory mice have become the predominant test species in most disciplines of biomedicine. ► Mice are housed at temperatures that subject them to moderate cold stress. ► Their temperature and metabolisms stability is susceptible to a variety of drugs and pathological conditions. ► This review focuses on the thermoneutral zone of laboratory mice. ► The impact of temperature on growth, reproduction, organ development, and behavior is explored in detail.

Introduction

There is little doubt that the popularity of the laboratory mouse as an experimental model in biomedical research is growing each year with no end in sight (Fig. 1A). In the early 1990s there were at least 10,000 more papers using rats than mice; however, beginning around 2003 the number of papers using mice first eclipsed the number of rat studies and, as of last year, there were approximately 10,000 more studies using mice. The heavy investment in mouse models in recent decades and the development of the hundreds of transgenic strains of mice is a primary reason for the explosion in the use of mice in experimental research. The genetic tractability of mice allowing for the regulated or inducible expression of any gene has turned the mouse, in this post-genome era, into a genetic toolbox ideal for both reductionist and systems biology approaches (Karp, 2012). This is partially responsible for the recent explosion in the use of mouse models in the past 10 years to study diabetes, obesity, stroke, and aging (Fig. 1B).

It is fair to say that most researchers who are not specialists in thermal physiology are nonetheless aware that body temperature and other thermal physiological characteristics of their mouse model may impact on their particular endpoint of interest. The thermal physiological characteristics of the mouse affect parameters or endpoints seemingly unrelated to temperature regulation, such as obesity, drug sensitivity, growth, reproduction, development, and many others. Issues can be as simple as knowing whether a particular treatment causes hypothermia or hyperthermia or complex such as how interactions in mouse strain, gender, ambient temperature, housing density, and choice of bedding affect the immunological response to an infectious agent. Moreover, the explosion in the number of transgenic models that can possess a myriad of autonomic or behavioral phenotypes should compel researchers to have a firm understanding of the thermal physiological characteristics of their murine model.

The recent advances in radiotelemetry over the past three decades have revolutionized our understanding of thermoregulation of mice and other rodents. A review on the thermal physiology of mice that incorporates the recent research developments is indeed a timely topic for not only thermal physiologists, but essentially all researchers using murine models. We have a much better understanding of the thermoregulatory characteristics of mice but there are certainly many gaps in the data that will be noted throughout this review.

To sum up, researchers in thermal physiology, as well as essentially all fields of biomedicine using mice, should endeavor to understand the zones or limits of thermoneutrality of their test subject. The term thermoneutrality is used broadly here, not only in the classic sense of thermoneutral zone for metabolic rate, but also to describe and explain how ambient and core temperature affect the thermoneutral zones of other parameters that are influenced by the mouse’s thermoregulatory response such as growth, organ development, food and water consumption, reproduction, etc. This is especially important to the development of guidelines for ideal thermal environments for laboratory mice and other species (NRC, 2011). Furthermore, there is a need to understand how the thermoregulatory motor responses of the mouse interact to influence the limits of thermoneutrality of these and other factors. In this review, readers may be surprised to see graphs of data that were published, in some cases, over 60 years ago. This author believes that many of these studies have been overlooked and new illustrative graphs have been created to demonstrate the limits of thermoneutrality for a variety of parameters and endpoints of the laboratory mouse.

As a preview of the topics to be presented in this review, the landmark threshold ambient and core temperatures associated with activation of thermophysiological, behavioral, and other responses is presented (Fig. 2A and B). Although references are provided for these responses in the figure legend, the reader should note that detailed discussion of these responses can be found throughout this review. Moreover, the threshold temperatures shown with each arrow should be considered close approximations that can vary according to the details of each study as reviewed below. One of the key facets of the ambient temperature snapshot is that the standard housing temperature of laboratory mice, including the newly recommended standards for housing mice (NRC, 2011), is below the metabolic thermoneutral zone and is associated with increased food consumption and affects growth and organ development. With regard to the core temperature snapshot, one take-home message is that mean core temperature of mice is 1 to 1.5 °C below that of rats. Core temperature of mice is subject to marked fluctuations over a 24 h period, even when housed under ideal conditions. Mice are capable of withstanding remarkable changes in core temperature, exhibiting lethal body temperatures as low as 10 °C and as high as 43 °C. Finally, regulated core temperature can fall precipitously when mice are faced with environmental challenges, drugs, or toxic chemicals that otherwise would do much less to rats and larger mammals (see Gordon, 2005). For example, exposure to hypoxia will lead to a voluntary (i.e., regulated) 6–7 °C fall in core temperature in as little as 90 min. These snapshots are meant to provide the reader with a general view of the thermoregulatory sensitivity and limits of mice. Detailed analysis of these data is provided below.

Section snippets

Thermoregulatory profile and the thermoneutral zone

It is best to begin with the definitions of the critical temperatures and zones of thermoregulation as agreed upon by the International Union of Physiological Sciences Thermal Commission (IUPS Thermal Commission, 2001). The thermoneutral zone is one of the most well recognized concepts of thermal physiology of homeothermic organisms (Fig. 3). The relationship between metabolic heat production and ambient temperature provides us with a plethora of information on the animal’s energetic

The lower critical temperature for heat production of mice

The lower critical temperature represents a threshold for activation of a regulatory response by the thermoregulatory system and is the point where additional heat must be generated to meet the demand for increased heat loss. As discussed above, the upper critical temperature in rodent studies can be elusive to identify. The threshold ambient temperature where evaporative water loss and metabolic rate increase at the upper end of the thermoneutral zone is unpredictable. On the other hand, the

Core temperature

The core temperature is the temperature of thermal core of the body and is typically defined operationally in small rodents as the rectal or colonic temperature measured with a hand held probe, intraabdominal temperature of the viscera measured by radiotelemetry, or brain measured with stereotaxically implanted probes (see IUPS Thermal Commission, 2001). A fundamental assumption of the concept of the thermoneutral zone is that the core temperature is stable over the range of ambient

Developmental changes the thermoneutral zone and limits of normothermy

From birth to weaning, mice behaviorally seek warmer temperatures than adults. They have underdeveloped insulation and their ability for shivering and non-shivering thermogenesis is limited, making behavioral thermoregulation a primary thermoeffector, especially in the first two weeks of life (see Section 6.4). Lagerspetz (1962) made literally thousands of measurements of skin temperature (clavicular and inguinal regions) of mice ranging in age from 1 to 28 day of age maintained at ambient

Thermoeffectors

The mouse is considered to posses and utilize the same thermoeffectors to control heat generation and heat loss as in other homeotherms. This is essentially true with exception that mice replace grooming saliva for sweating to increase evaporative heat loss and possess BAT as a source of heat production. Small quantities of BAT have been identified in humans; however, the role of BAT as a principal thermoeffector in humans and other large mammals is apparently minimal (see Cannon and

Thermoneutral limits of body weight, growth, and organ development

As discussed early in this review (Section 2), the thermoneutral zone is defined on the basis of the effect of ambient temperature on the metabolic heat production of a homeothermic animal (IUPS Thermal Commission, 2001). Up to this point of this review, the main focus has centered on the physical and biological factors that influence the metabolic rate and body temperature of laboratory mice. In view of the marked sensitivity to ambient temperature, one should not be surprised to find that

Fever and sickness

Considering the explosion in the popularity of mouse models in the study of immunity, infection, cancer, and other pathologies, it is incredible that we know so little about the effects of fever and other pathological conditions on the metabolic thermoneutral zone. Moreover, there is virtually no information on how the ambient limits of normothermy and other parameters of thermoneutrality as discussed in this review are affected by fever. As shown below, a successful fever in mice is expressed

Aging and senescence

Mice are becoming a popular model to study various aspects of aging (see Fig. 1B). As mentioned earlier in the discussion on torpor (Section 4.6), mice are often used in studies on caloric restriction and the impact on longevity. Caloric restriction lowers core temperature and this is thought to have a critical role in the extension of life span by reducing the production of free radicals and debilitating effects of oxidative stress.

There were a remarkable number of studies in the 1980s and

Behavioral and autonomic responses: Perspectives and consequences

A diagrammatic presentation of the interaction between the selected ambient temperature, the approximate thresholds for activation of thermoeffectors for heat loss and heat production, and the upper ambient temperature limits of normothermia illustrates many of the salient points of mouse thermoregulation presented in this review (Fig. 34). During the daytime the mouse prefers to occupy temperatures precariously close to the activation of thermoeffectors for heat production and heat loss. Its

A general view of the thermoneutral zone

The depictions of selected temperature and the thermoneutral zone in Fig. 34 is an oversimplification that does not take into account the many biological and physical factors that can affect the relationship. The overall sensitivity of a homeotherm to ambient temperature depends essentially on the slope and thresholds of the thermoeffectors for heat production and heat loss (Fig. 35). As discussed throughout this review, a variety of parameters are likely to affect either the slope and/or

Acknowledgements

I am most appreciative to the following for their thorough review of the manuscript: Drs. Karl Kaiyala, Lisa Leon, Steve Swoap, and Brianna Gaskill.

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