Thermal information from the skin: the signal processing and the role in behavioral thermoregulation.

Dear Editor-in Chief,

The Challenge Article “Temperature receptors in cutaneous nerve endings are thermostat molecules that induce thermoregulatory behaviors against thermal load” by Dr. Shigeo Kobayashi introduced a new model to explain the interaction between cold sensations and behavioral thermoregulation. According to the author, the proposed model differs from previous ones in the following respects: (1) the peripheral thermoTRP channels function as thermostat molecules in the thermoregulatory system, and (2) the thermostat signal activates thermal sensations and behavioral responses, and corrects signal errors (i.e., deviations from the set-point temperature). However, some aspects of the rationale for the model and data interpretation were unclear. In the present letter, I would like to ask the author to consider 3 fundamental questions that highlight my concerns regarding the manuscript.

Does behavioral thermoregulation directly maintain skin temperature?

The author explained that changes in skin temperature generate an error signal that triggers central effectors via TRPM8 receptors, located in the skin to protect against cooling for temperatures below a threshold value (28°C). The model assumes that skin temperature is a feedback signal. For example, when individuals become hyperthermic owing to an imbalance between heat production and dissipation (such as during exercise), the preferred environmental temperature is reduced. My understanding is that receptor inputs primarily protect the core body temperature. Skin temperature regulation could be an auxiliary effect, as Romanovsky has suggested.

Skin temperature varies among surface regions. Generally, the peripheral temperature is lower than that of the body trunk. In rats and mice, there is large difference in skin temperature between hairy and non-hairy areas. In cold weather, humans wear clothing that exposes only the face, neck, and hands, increasing regional differences in skin temperature. The author's proposed model suggests that behavioral responses to cold are initiated by thermostat molecules in the peripheral skin, because these regions reach the threshold temperature faster than other regions. Moreover, the peripheral skin has a role as an effector of autonomic thermoregulation. In cold conditions, skin blood flow decreases, resulting in a lower skin temperature and suppressing heat dissipation. This is largely attributed to reduced blood flow through arterio-venous anastomosis via sympathetic activation. The control system is unlikely to drive the skin temperature in opposite directions at the same time.

Do thermosensitive molecules act as thermostats?

I agree with the notion that the molecules in nerve endings (i.e., TRPM8 in cold conditions) function as thermostats. On–off signaling is common in cell membrane channels; in this case, the stimulus is temperature. However, physiological thermostat(s) must provide unified “on” or “off” information to the controller system. If the neural activity at a threshold temperature denotes the output signal from the thermostats, the threshold temperature for all cold-sensitive neurons in the skin must be the same or similar (a). In addition, if cold-sensitive neurons directly interact with neurons involved in cold sensation and/or behavioral thermoregulation, the abundance of neural signals transmitted to central regulators must determine the intensities of sensations and behaviors, and not the frequency of the action potential (b). However, the thermostat model is not consistent with hypotheses (a) and (b) because the skin temperature is expected to activate all cold-sensitive neurons simultaneously. The thermostat model does not explain the common phenomena of feeling cold and/or activating cold-escape behaviors (e.g., wearing thicker clothes) as the environmental temperature decreases; changes in skin temperature, e.g., <1°C, can be detected at the hands. Neural activation increases as the temperature decreases (i.e., the frequency of the action potential) and it is likely that this frequency determines cold sensation.

Does sensing cold activate behavioral thermoregulation?

In humans, thermal perception comprises thermal sensation and comfort. In addition, thermal comfort/discomfort is thought to activate behavioral thermoregulation. Behavioral thermoregulation in rats and mice may not be directly comparable; however, I do not believe cold sensation directly activates behavioral responses. Matsuda et al. showed that, in a cold environment, hot stimuli applied to a local skin area in naked humans (e.g., the face, chest, abdomen, and thigh, controlling for skin area and temperature) induce similar heat sensations. However, thermal comfort (or, feeling warm) was not evoked in the face. These results indicate that protection against changes in skin temperature is not always the aim of behavioral thermoregulation. In addition, behavioral thermoregulation does not reflect cold sensation. Our group also found that local heating of the brain (∼39°C) delays cold-escape behavior in rats (for rats exposed to a floor temperature of 20°C, unpublished data). Thus, there must be mechanisms by which organisms evaluate thermal inputs at the skin and initiate behavioral responses.