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EDITORIAL FOCUS
ESSAYS ON APS CLASSIC PAPERS
John B. Pierce Laboratory and Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut 06519
ABSTRACT
This essay looks at the historical significance of three APS classic papers that are freely available online:
Hammel HT, Hardy JD, and Fusco MM. Thermoregulatory responses to hypothalamic cooling in unanesthetized dogs. Am J Physiol 198: 481—486, 1960 (http://ajplegacy.physiology.org/cgi/reprint/198/3/481).
Hammel HT, Jackson DC, Stolwijk JAJ, Hardy JD, and Strømme SB. Temperature regulation by hypothalamic proportional control with an adjustable set point. J Appl Physiol 18: 1146—1154, 1963 (http://jap.physiology.org/cgi/reprint/18/6/1146).
Hellstrøm B and Hammel HT. Some characteristics of temperature regulation in the unanesthetized dog. Am J Physiol 213: 547—556, 1967 (http://ajplegacy.physiology.org/cgi/reprint/213/2/547).
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Based on research with humans in the Russel Sage calorimeter at Cornell, Dr. Hardy proposed that the thermal drive for these thermal regulatory responses was 1/4 core and 3/4 average skin temperature where each skin thermocouple output was weighted in proportion to the area of the body surface represented by that thermocouple. However, this hypothesis puzzled Ted because he was unable to repeatedly predict the thermal regulatory responses caused by skin and core temperatures in conscious dogs. There had to be a better way to explain how core and surface temperatures are utilized by the central nervous system to elicit the appropriate responses to cold and hot environments.
At the time, it was known that the hypothalamus was strongly implicated in the regulation of body temperature. So, around 1957 Ted decided to implant thin-walled stainless steel tubes, sealed at their lower ends, next to the POAH nuclei. He called these tubes "thermodes" as opposed to "electrodes." He constructed a small double-chamber system that allowed him to heat or cool the POAH nuclei at will and to any degree of temperature he chose, while the dog was enclosed in a calorimeter. By this means, he was able to open the feedback loop involved in the regulation of body temperature. In 1960 Ted presented these findings (3) at the International Union of the Physiological Sciences meeting held in Buenos Aires. His roommate at the meeting was Theodor Benzinger. Ted recalls that when he told Dr. Benzinger that he was able to cool the POAH nuclei of conscious dogs in a hot environment and cause them to shiver "he did not believe me." At the time, Benzinger's vision of the "human thermostat" did not allow the temperature of the hypothalamus to elicit shivering. He believed that a high hypothalamic temperature could only lessen shivering already elicited by cold receptors in the skin activated by cold exposure. But a low hypothalamic temperature alone could not elicit shivering.
In 1961 Ted followed Dr. Hardy to the John B. Pierce Laboratory and Yale University and continued to heat and cool the POAH nuclei of dogs. It was clear to Ted that shivering could be elicited by cooling the POAH nuclei and panting could be elicited by heating the POAH nuclei. Furthermore, the threshold hypothalamic temperatures for shivering and panting increased in the cold environment, and these threshold temperatures decreased in the hot environment. With this information and more, he published the article titled "Temperature regulation by hypothalamic proportional control with an adjustable set point" in the Journal of Applied Physiology (4). The title of the manuscript told the story. The original manuscript had a figure that depicted how Ted imagined neurons in the POAH might be related so as to yield the results he reported. Loren Carlson was Editor for the Environmental Physiology Section of the Journal of Applied Physiology at the time and thought it would not be appropriate to speculate to this extent, so the figure was left out. It took Ted two years to get the figure published in a chapter titled "Neurons and Temperature Regulation" in Physiological Controls and Regulations, edited by W. S. Yamamoto and J. R. Brobeck (2).
Ted published a series of papers using this awake dog model. Bjørn Hellstrøm spent a year in his laboratory and measured the temperature of the POAH when resting dogs were exposed to ambient temperatures from 10°C to 40°C. The POAH temperature fluctuated a few tenths of a degree centigrade at each ambient temperature, but the fluctuations at 10°C could not be distinguished from the fluctuations at 40°C (5). Because of these observations Ted wondered if "the POAH nuclei were needlessly sensitive to temperature?" However, Ted and Bjørn had missed something. When they later plotted evaporative heat loss via panting in the dog as a function of POAH temperature, the relationship was good enough to demonstrate some characteristics of the POAH regulator. Their new analysis indicated that the threshold hypothalamic temperature for panting increased with decreasing skin and core temperatures. Second, the slope of the response curve (the gain of the regulator) also increased with decreasing skin and core temperatures. Ted used this information to modify his neuronal model. The model depicted the firing rates of the temperature-insensitive neurons being facilitated by cold receptors from the skin and core. The neurons for activating panting were depicted as activated when facilitation from the temperature-sensitive neurons exceeded inhibition from the temperature-insensitive neurons. Thus, this could explain why placing the dog in a cold environment facilitated the temperature-insensitive neurons and these, in turn, increased inhibition of the "panting" neurons.
Ted continues to be active today and can usually be found wandering around the annual American Physiological Society meeting. His thoughts on this topic are as fresh and exciting today as they were in 1963. Ted's contributions and insights into to the field of temperature regulation should remind latter-day scientists of the remarkable work of their forebears and its relevance to the research today.
FOOTNOTES
Address for correspondence: G. W. Mack, 290 Congress Ave., New Haven, CT 06519 (E-mail: mack{at}jbpierce.org).
REFERENCES
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