Consideration of the importance of measuring thermal discomfort in biomedical research

Abstract

Core temperature stability is the result of a dynamically regulated balance of heat loss and gain, which is not reflected by a simple thermometer reading. One way in which these changes manifest is in perceived thermal comfort, 'feeling too cold' or 'feeling too hot', which can activate stress pathways. Unfortunately, there is surprisingly little preclinical research that tracks changes in perceived thermal comfort in response to either disease progression or various treatments. Without measuring this endpoint, there may be missed opportunities to evaluate disease and therapy outcomes in murine models of human disease. Here, we discuss the possibility that changes in thermal comfort in mice could be a useful and physiologically relevant measure of energy trade-offs required under various physiological or pathological conditions.

Keywords: energy trade-offs; feeling cold; immune suppression; mouse models; thermal preference; thermoregulation.

Figure 1.. Feeling cold induces many physiologic and behavioral changes designed to increase and conserve core body temperature.

Upon perception of chills, the autonomic nervous system triggers many physiological changes to preserve and generate heat. Multiple papers detail these responses, and we refer readers to a few here[1, 30]. In general, peripheral vasoconstriction and piloerection decrease heat loss. Shivering thermogenesis generates heat by ATP hydrolysis in skeletal muscles generating contractile movement. Non-shivering thermogenesis generates heat using UCP-1 and the proton gradient generated within the mitochondria of brown adipose tissue fat cells. Behavioral changes such as huddling, or environmental manipulation, as well as increased physical activity also assist in increasing heat production and reducing heat loss. Figure generated in Biorender.

Figure 2.. Summary of major changes induced by the sympathetic nervous system during the “fight or flight” response.

Upon detection of a “threat,” the hypothalamus signals through the autonomic nervous system to prepare to respond to the threat. Specifically, the sympathetic nervous system releases norepinephrine to increase cardiac and respiratory output and skeletal muscle blood flow. Simultaneously, immediately unnecessary systems are deprioritized, leading to decreased digestion, reproductive capacity, and immune activity. This system is well conserved across many species. Chronic activation of this pathway can lead to diseased states. Figure generated in Biorender.

Figure 3.. Etiology of Chills.

There are many causes of chills that can be acute (eg. fever) or chronic (cancer). Physiological causes outside of ambient temperature are not discussed here. The feeling of chills may cause the body to reallocate energy from other important processes to promote heat generation. This may impair general metabolism and immunity, potentially resulting in negative outcomes for patients and mouse studies. Figure generated in Biorender.

Figure 4.. Physiology of chronic cold stress.

Cold stress induces the release of norepinephrine to bind β3-ARs on brown adipose tissue fat cells and produce heat. Norepinephrine also binds β2-ARs on immune cells, altering their function to cause immune suppression. For in-depth review of adrenergic signaling regulation of immune cells, we refer readers to the following review papers[83, 84]. This immunosuppressive effect can be reversed by housing the mice at their thermoneutral temperature. Figure generated in Biorender.