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Thermoregulation: some concepts have changed.
Functional architecture of the thermoregulatory
system
Andrej A. Romanovsky
292:37-46, 2007. First published Sep 28, 2006; Am J Physiol Regulatory Integrative Comp Physiol doi:10.1152/ajpregu.00668.2006 You might find this additional information useful.
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Am J Physiol Regul Integr Comp Physiol 292: R37–R46, 2007.
First published September 28, 2006; doi:10.1152/ajpregu.00668.2006.
CALL FOR PAPERS Physiology and Pharmacology of Temperature Regulation
Thermoregulation: some concepts have changed.
Functional architecture of the thermoregulatory system Andrej A. Romanovsky
Systemic Inflammation Laboratory, Trauma Research, St. Joseph's Hospital and Medical Center, Phoenix, Arizona Submitted 21 September 2006; accepted in final form 23 September 2006 99 –101, 104, 106, 107, 110, 111, 115, 118, 120, 123–127), changed. Functional architecture of the thermoregulatory system. Am four reviews (20, 31, 32, 108), ten editorials (33, 68a, 70, 89, J Physiol Regul Integr Comp Physiol 292: R37–R46, 2007. First 90, 95, 109, 112, 113, 121) and one point (57)-counterpoint published September 28, 2006; doi:10.1152/ajpregu.00668.2006.— (11) exchange within the Special Call for Papers on Physiology While summarizing the current understanding of how body tempera- and Pharmacology of Temperature Regulation published in ture (Tb) is regulated, this review discusses the recent progress in the several issues of the American Journal of Physiology—Regu- following areas: central and peripheral thermosensitivity and temper- latory, Integrative and Comparative Physiology over the past ature-activated transient receptor potential (TRP) channels; afferentneuronal pathways from peripheral thermosensors; and efferent ther- two years. While closing this Call, the present review summa- moeffector pathways. It is proposed that activation of temperature- rizes the recent progress in our understanding of how body sensitive TRP channels is a mechanism of peripheral thermosensitiv- temperature is regulated. To give readers an idea of how ity. Special attention is paid to the functional architecture of the remarkable this progress is, the new understanding (based on thermoregulatory system. The notion that deep Tb is regulated by a the latest developments) is compared with the information unified system with a single controller is rejected. It is proposed that provided by a typical textbook chapter on thermoregulation. It Tb is regulated by independent thermoeffector loops, each having its seems that this chapter may need some updates, especially in own afferent and efferent branches. The activity of each thermoeffec- its coverage of thermosensors, thermoeffectors, and the func- tor is triggered by a unique combination of shell and core Tbs.
tional architecture of the thermoregulatory system.
Temperature-dependent phase transitions in thermosensory neuronscause sequential activation of all neurons of the corresponding ther- moeffector loop and eventually a thermoeffector response. No com-putation of an integrated Tb or its comparison with an obvious or hidden set point of a unified system is necessary. Coordination between thermoeffectors is achieved through their common controlled A typical textbook chapter would say that brain temperature is detected by central thermosensory neurons (central "thermo- b. The described model incorporates Kobayashi's views, but Kobayashi's proposal to eliminate the term sensor is rejected. A receptors"). Most of them are warm-sensitive, that is, they case against the term set point is also made. Because this term is increase their activity with an increase in brain temperature.
historically associated with a unified control system, it is more The abundance of warm-sensitive central sensors is consistent misleading than informative. The term balance point is proposed to with the following two facts. First, our thermal physiology is designate the regulated level of Tb and to attract attention to the "asymmetrical:" Tb is positioned very closely, within just a few multiple feedback, feedforward, and open-loop components that con- degrees Celsius, to the upper survival limit (which is possibly tribute to thermal balance.
determined by the denaturation of regulatory proteins) butrelatively far, a few tens of degrees, from the lower limit(which is likely determined by the freezing of water). There- BY USING POWERFUL AUTONOMIC and even more powerful behav- fore, core overheating is much more dangerous than overcool- ioral means, our species survives while being exposed to a ing. Second, humans are endothermic animals (meaning that wide range of ambient temperatures: from ⫺110°C (the sur- their principal source of heat is their own body), as opposed to face of the Moon) to 2,000°C (the air around a space shuttle as ectothermic animals (that receive heat primarily from the it reenters the atmosphere). Even in these diversified thermal environment). Hence, sensors for limiting heat gain have to be environments, we usually manage to maintain our deep (core) located inside the body. Although much less common, cold- body temperature (Tb) within a few tenths of a degree Celsius.
sensitive neurons (i.e., those that increase their activity with a In fact, an exodus of Tb from its usual range is so suggestive of decrease in brain temperature) also exist. However, the cold a pathological condition, that Tb is monitored regularly in all sensitivity of most of them seems to be due to inhibitory hospitalized patients and reported in every medical history.
synaptic input from nearby warm-sensitive neurons.
Various aspects of Tb regulation have been discussed in fifty- Thermoregulatory responses in a variety of animal species one original articles (4, 7, 13, 22, 23, 29, 35–38, 40 – 42, 45, 46, can be elicited by local thermal stimulation of various areas in 48 –51, 54, 55, 59, 61, 62, 64 – 66, 71, 73, 76, 77, 79, 80, 85, 88, the central nervous system, including several brain stem neu- Address for reprint requests and other correspondence: A. A. Romanovsky, The costs of publication of this article were defrayed in part by the payment Trauma Research, St. Joseph's Hospital, 350 W. Thomas Rd., Phoenix, AZ of page charges. The article must therefore be hereby marked "advertisement" 85013 (E-mail: [email protected]).
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
0363-6119/07 $8.00 Copyright 2007 the American Physiological Society IN FOCUS: THERMOREGULATION 2007 ronal groups [that used to be referred to as the reticular shows a powerful dynamic (phasic) component: these cells are formation(s) of the medulla oblongata, pons, and midbrain; see very active when the temperature is changing, but quickly Ref. 9] and the spinal cord, but thermosensitive neurons of the adapt to a stable temperature. Such a response enables the preoptic anterior hypothalamus (POA) are considered to be the organism to rapidly react to environmental changes. In addition most important for triggering autonomic thermoeffector re- to superficial cold- and warm-sensitive neurons, there are sponses. It bears mentioning that the locations of thermosen- peripheral deep-body sensors, which respond to the core body sitive neurons triggering various thermoregulatory behaviors temperature. They are located in the esophagus, stomach, large are largely unknown (see Behavioral effectors).
intra-abdominal veins, and other organs.
For a long time, it was assumed that the roles of cold- and This basic information about peripheral thermosensors has warm-sensitive POA neurons are reciprocal and "symmetri- been recently updated with three developments: 1) the discov- cal," that is, that all thermoregulatory responses could be ery of a subclass of transient receptor potential (TRP) ion triggered by either activation of one class of the temperature- channels known as thermoTRP channels; 2) the progress in sensitive neurons or inhibition of the other (10); your textbook identifying thermoafferent pathways and their differential in- is likely to share this assumption. During the past decade, volvement in thermosensation and Tb regulation; and 3) the however, the idea of equally important roles of warm- and challenge to the old idea that a separate neuronal network cold-sensitive neurons was put to rest. Elegant studies by computes some integrated Tb (from codes of local Tbs) and Kanosue and colleagues (21, 128), involving thermal and compares it to a set point Tb to form a thermal sensation and to chemical stimulation of POA cells, showed that both cold- send "orders" to thermoeffectors.
defense and heat-defense autonomic responses are initiated bythe corresponding changes in the activity of warm-sensitive neurons; increased activity of warm-sensitive POA neuronstriggers heat-defense responses, while decreased activity trig- The mammalian TRP superfamily consists of ⬃30 channels gers cold-defense responses.
divided in six subfamilies known as the TRPC (canonical), Morphological identification of thermosensitive neurons has TRPV (vanilloid), TRPM (melastatin), TRPML (mucolipin), been another major achievement. Griffin et al. (43) showed that TRPP (polycystin), and TRPA (ankyrin). Of these, the heat- these cells are characterized by the horizontal orientation of activated TRPV1-V4, M2, M4, and M5 and the cold-activated their dendrites: toward the third ventricle medially and the TRPM8 and A1 are often referred to as the thermoTRP medial forebrain bundle laterally. Because neurons conveying channels. Involvement of these recently cloned and character- temperature signals from the body surface and viscera enter the ized channels in thermoregulation has been studied intensively.
hypothalamus via the periventricular stratum and medial fore- In the present Call for Papers, these studies are represented by brain bundle (24), such an orientation seems ideal for receiving the original articles by Ni et al. (80) and Wechselberger et al.
input through both projections. The present Call for Papers has (123), the invited review by Caterina (20), and, to a certain contributed to our understanding of the functional properties of extent, the point-counterpoint exchange between Kobayashi et thermosensitive neurons (11, 57, 123). Because warm-sensitive al. (57) and Boulant (11). While referring the reader to the POA neurons display spontaneous membrane depolarization, review by Caterina (20) and several other recent reviews (30, as shown by Boulant and colleagues (123, 129), these cells are 87, 102) for more detailed information, I would like to empha- considered pacemakers; their thermosensitivity is due to cur- size a few points.
rents that determine the rate of spontaneous depolarization First, activation of all thermoTRP channels results in an between successive action potentials. It is true, however, that inward nonselective cationic current and, consequently, in an mechanisms of hypothalamic thermosensitivity continue to be increase in the resting membrane potential. This mechanism disputed (57). The changes in ion currents that underlie both agrees more readily with a role for these channels in peripheral central (vide supra) and peripheral (vide infra) thermosensitiv- thermosensitivity (83) rather than hypothalamic thermosensi- ity are likely to involve temperature-dependent phase transi- tivity (11, 129). Furthermore, the TRPV4 channel (which is likely to play a physiological role in thermoregulation; videinfra) does not seem to be expressed in the bodies of POAneurons (39), but it is expressed by the neuronal bodies of dorsal root ganglia (44).
There are also peripheral thermosensory neurons (peripheral Second, although each thermoTRP channel is activated "thermoreceptors") that detect shell temperatures in the skin within a relatively narrow temperature range, the range that and in the oral and urogenital mucosa. A typical textbook they cover cumulatively is very wide: from noxious cold to chapter would state that most superficial sensors are cold- noxious heat (Fig. 1). Furthermore, they cover this temperature sensitive. Because central thermosensors are concerned mainly range in an overlapping fashion, and their activities have with warmth, specialization of peripheral sensors in cold sen- different sensitivities to temperature. These features make the sitivity is not that surprising. Skin cold sensors are located in or thermoTRP channels well suited to the job of peripheral immediately beneath the epidermis. Their signals are conveyed thermosensors. It is important to note, however, that the tem- by thin myelinated A␦ fibers. The less common warm sensors perature ranges shown in Fig. 1 were obtained in vitro. In vivo, are located slightly deeper in the dermis; their signals travel via a specific cell type on which a thermoTRP channel is expressed unmyelinated C fibers. Peripheral thermosensors are not pace- and concomitant activation with chemical ligands affect the makers, and mechanisms of peripheral thermosensitivity are temperature range in which the channel is activated and, in thought to involve changes in the resting membrane potential.
some cases, bring it closer to physiological values of deep Tb.
Importantly, the response of most peripheral thermosensors Indeed, although the TRPV1 channel is widely thought to be AJP-Regul Integr Comp Physiol • VOL 292 • JANUARY 2007 • www.ajpregu.org

IN FOCUS: THERMOREGULATION 2007 ies of these bipolar cells are located in the dorsal root ganglia,and the central axons project to the dorsal horn of the spinalcord (mostly lamina I), where they synapse with secondarymonopolar neurons. Axons of these secondary neurons crossthe midline and ascend in the lateral funiculus of the spinalcord. It was believed for a long time that the secondary neuronsproject directly to the ipsilateral ventrobasal complex of thethalamus, from where their signals are conveyed to the ipsilat-eral somatosensory cortex (postcentral gyrus) by tertiary neu-rons, and your textbook may hold this to be true. According toCraig (27, 28), however, this pathway, which is involved intactile sensation, is uninvolved in temperature sensation. In-stead, the lamina-I neurons carry temperature signals to theinsular cortex (the island of Reil) with a relay in the postero-lateral thalamus (specifically, the posterior part of the ventro-medial nucleus) or with two relays (in the parabrachial nucleus Fig. 1. Schematic representation of the dependence of the activity of cold-activated (blue) and heat-activated (red) thermoTRP channels on temperature.
and the basal part of the ventromedial nucleus of the thalamus) The thresholds of activation and temperatures of maximal activation are based (Fig. 2). These two branches of the spino-thalamo-cortical on the activity of the channels in heterologous systems; some of the thresholds pathway are involved in discriminative temperature sensation.
are means of values obtained in several studies. The figure is adapted from A functional magnetic resonance imaging study in humans by Patapoutian et al. (87). Information on the TRPM2 is added based on Togashi Hua et al. (48) published in this Call for Papers shows that this et al. (119); information on the TRPM4 and M5 is added based on Talavera etal. (114); the added lines are dashed. Please note that quantitative aspects of the pathway is organized topically, as evident from the topical relationships shown should be looked upon with great skepticism, as the figure representation of skin temperature in the insula. This pathway does not account for several important factors (81). Nevertheless, this figure allows for sensing temperature at a high spatial resolution (e.g., illustrates how well thermoTRP channels are suited for detecting physiologi- temperature of the surface under the tip of an individual finger cally relevant temperatures both in the shell and core.
can be assessed). Therefore, this pathway is important formaking decisions about a wide range of issues related to activated at pain-inducing temperatures of ⬎42°C (20, 30), Ni interactions with the environment, but it appears to have little et al. (80) showed that increasing temperature within the to do with Tb regulation, that is, with triggering thermoeffector normal physiological range (perhaps as low as ⬃34.5°C) can responses to defend deep Tb. It should also be noted that the exert a direct stimulatory effect on pulmonary sensory neurons, spino-thalamo-cortical pathway (as described here for humans) and this effect is likely mediated through the activation of the is not the same in other vertebrates, as several interspecies TRPV1 channel and other subtypes of TRPV channels. For differences have been noticed (27).
some TRPV channels (namely, the V3 and V4), likely physi- Homeostatic control. Thermoeffector responses are trig- ological roles have been established (63, 74). Other thermo- gered by thermal exposures massive enough to affect heat TRP channels are currently under investigation.
exchange between the body and the environment. Tempera- Afferent Pathways ture-generated signals from large areas of the shell are sent tothe brain through the spino-reticulo-hypothalamic pathway Discriminative sensation. There is little doubt that afferent (Fig. 2), in which the secondary lamina-I neurons project to the pathways start with primary thermosensory neurons. The bod- reticular formation (medullar, pontine, and midbrain neuronal Fig. 2. Afferent neuronal pathways for discriminative sensa-tion/localization of a thermal stimulus and for homeostaticcontrol of body temperature. DRG, dorsal root ganglion; PBN,parabrachial nucleus; POA, preoptic anterior hypothalamus;VMb, basal part of the ventromedial nucleus of the thalamus(formerly known as the parvicellular part of the ventroposteriormedial nucleus); VMpo, posterior part of the ventromedialnucleus of the thalamus; ?, unknown location(s) within themedulla, pons, and midbrain.
AJP-Regul Integr Comp Physiol • VOL 292 • JANUARY 2007 • www.ajpregu.org IN FOCUS: THERMOREGULATION 2007 groups). In this pathway, thermosensory "lines" converge at fector determines which combinations of core and shell Tbs the level of lamina-I neurons (i.e., a single lamina-I cell receive activate this effector (see Thermoeffector Loops).
inputs from multiple thermosensory neurons; see Ref. 82) and Despite its conceptual strength, Kobayashi's model has not possibly at other levels, so that downstream neurons (e.g., brain become widely accepted yet, perhaps because the author favors stem neurons in thermoeffector pathways) can collect signals rather drastic terminological changes: he proposes to call from large thermoreceptive fields (5, 6). The tertiary neurons of sensors thermostats (or comparators). Kobayashi is certainly the afferent spino-reticulo-hypothalamic pathway project to right that, from the engineering point of view, the role of hypothalamic structures (including the POA) either via the thermoreceptors in his model is that of thermostats, and not of periventricular stratum passing along the wall of the third sensors. However, in the minds of the majority of medical and ventricle or via the medial forebrain bundle, which passes more biological scientists and students, the current terms (sensor, laterally. As described above, warm-sensitive POA neurons thermosensor, sensory, somatosensory, etc.) are associated have a dendrite orientation ideal for collecting information with no particular engineering analog. Hence, biologists feel no from both the periventricular stratum and the medial forebrain urge whatsoever to get rid of the entire family of widely used bundle. More precise delineation of this homeostatic, spino- biological terms or to start translating them to the engineering reticulo-hypothalamic pathway, especially of the "reticulo" language. (Later in this review, I will discuss a different term, part of it, requires further study.
set point, which is associated with a false idea in the minds ofmost biologists and physicians and, therefore, must be re- Thermosensors or Thermostats? placed.) In the case of thermosensors, a more productive approach might be to save the term, but to provide it with a Our views on how temperature is sensed have been chal- different meaning.
lenged recently by Kobayashi and colleagues (56, 58, 83). Thepre-Kobayashi models of Tb regulation assumed that thermo- receptors code temperatures of different parts of the body (intoneuronal activity codes) and that these codes of local temper- atures are then integrated by a separate network (that consists Your textbook is likely to name various autonomic ther- of several neurons with different roles) into some mean tem- moeffectors and possibly some behavioral ones, to discuss perature. The location of the integrating network was unclear their anatomy, mechanisms of physiological control, and ef- (8a). Nevertheless, it was often assumed that this integrating fects on heat balance. Various aspects of thermoregulatory skin network also compares the integrated temperature with an vasoconstriction (29, 118) and vasodilation (4, 55, 71, 127), external or internal reference signal and, based on such a thermogenesis in brown adipose tissue (BAT) (79), shivering comparison, somehow generates individual orders to thermoef- (62), and thermoregulatory behavior (41) have been addressed in the present Call for Papers. Some interactions between Kobayashi and colleagues proposed a different scenario (56, thermogenesis, energy metabolism, and body temperature reg- 58, 83). According to them, a sensory neuron is wired through ulation have been analyzed in several original articles (37, 45, a number of neurons to an effector cell. When the temperature 49, 124), two editorials (112, 113), and the invited review by to which the temperature-sensitive part of a sensory neuron is Diepvens et al. (31). I would also like to refer the reader to the exposed reaches the activation threshold of this neuron, the fundamental review on BAT by Cannon and Nedergaard (17) neuron fires and, through its connections, sends a signal to the published in Physiological Reviews. What your textbook is effector cell. If a large number of sensory neurons sends unlikely to cover is the efferent neuronal pathways to ther- signals to their effector cells, a thermoeffector response occurs.
In this model, a decision to trigger an effector is made "auto-matically" (principally, by sensory neurons) and involves nei- Efferent Pathways ther a separate decision-making network nor operations withtemperature codes (computation of a mean Tb). According to Autonomic effectors. Efferent pathways to thermoeffectors this model, a sensation is a "side product" of the activation of have not been well characterized in humans, although this topic those neurons that are wired to cause certain effector responses has recently started receiving attention (34). Even in the rat, the (i.e., feeling cold means having activated those neurons that most studied laboratory species, not all thermoeffector path- trigger cold-defense responses). The same principle is used by ways have been mapped. Some of the neuronal circuitries Kobayashi and colleagues (58) to explain how we sense other connecting the warm-sensitive hypothalamic neurons to auto- modalities as well.
nomic thermoeffectors in the rat, particularly the BAT and Kobayashi's model also explains how deep Tbs and periph- skeletal muscles (heat-production effectors) and the vascula- eral (e.g., skin) Tbs contribute to thermoregulation. Deep Tbs ture of the tail (a specialized heat-exchange organ), have been are regulated variables, and they are very stable. From the point characterized during the past decade (Fig. 3). Studies of these of view of the control theory, they serve as feedback signals.
pathways have been propelled by the development of transsyn- Peripheral Tbs, on the other hand, are not regulated; they are aptic retrograde tracing techniques using pseudorabies virus, highly variable (97). They are feedforward signals that, accord- along with the refinement of techniques for discrete lesioning ing to the control theory, allow the body to respond to a and pharmacological stimulation and inhibition of neural struc- thermal load "in advance," that is, before deep Tbs start tures. The revealed pathways appeared complex, and their changing. In Kobayashi's model, both deep and peripheral Tbs detailed description is beyond the scope of the present paper; drive effector responses in a similar way. Which central and see the invited review by DiMicco and Zaretsky (32) in the peripheral sensory neurons are wired to a particular thermoef- present issue, as well as the reviews by Nagashima et al. (78) AJP-Regul Integr Comp Physiol • VOL 292 • JANUARY 2007 • www.ajpregu.org

IN FOCUS: THERMOREGULATION 2007 Fig. 3. Efferent neuronal pathways for con-trol of skin vasomotor tone, nonshiveringthermogenesis in brown adipose tissue, andshivering in the rat. The concept was takenfrom Nagashima et al. (78); the figure wassubstantially modified and published in Ro-manovsky (93) by permission from Elsevier.
The Romanovsky (93) version is reproducedhere with a minor modification and by per-mission from both Elsevier and BlackwellPublishing. DMH, dorsomedial hypothala-mus; IML, intermediolateral column; PAG,periaqueductal gray matter; cPAG, caudalPAG; rPAG, rostral PAG; PH, posterior hy-pothalamus; PVN, paraventricular nucleus;RF, reticular formation; RPA, raphe´/peripy-ramidal area; RRF, retrorubral field; SG,sympathetic ganglia; VH, ventral horn;VMH, ventromedial hypothalamus; VTA, ventral tegmental area.
and Morrison (75) published elsewhere. However, a few points and editorial foci by DiMicco and Zaretsky (33) and McAllen As shown in Fig. 3, both the BAT and skin vasculature are Behavioral effectors. Evidence (mostly from stimulation controlled by sympathetic ganglia, with the bodies of pregan- experiments) suggests that different thermoregulatory behav- glionic neurons located in the intermediolateral column of the iors in the rat (e.g., relaxed postural extension, thermoregula- spinal cord. These spinal neurons receive direct input from tory grooming, and locomotion) use distinct neural circuitries cells located primarily in the raphe´/peripyramidal area of the (92). However, the neuroanatomic substrate of no thermoreg- medulla. These medullary cells are under the control of hypo- ulatory behavior has been studied extensively, and little is thalamic (dorsomedial and paraventricular nuclei), midbrain known about the neuroanatomy of behavioral thermoregulation (periaqueductal gray matter, retrorubral field, and ventral teg- (78). This situation is likely to change, as behavioral thermo- mental area), and possibly pontine (locus coeruleus) neurons regulation is becoming a subject of keen attention (1, 2, 59, 60, that receive input from warm-sensitive POA cells (8, 18, 84).
68). In the present issue, Konishi et al. (59) report that neurons Although the efferent pathways for skin vasomotor tone and in the median preoptic nucleus are involved in the intensifica- nonshivering thermogenesis have some similarities, they are tion of an operant thermoregulatory behavior (moving to a not identical, and both differ substantially from the pathway reward zone during heat exposure to trigger a breeze of cold controlling shivering. Within the shivering pathway, ␥ and ␣ air) caused by hypertonic saline. For a different behavioral motoneurons of the ventral horn receive direct and indirect response (moving to a cold environment during bacterial li- inputs from the midbrain and brain stem, including the raphe´/peripyramidal area of the medulla (116). Axons of the mid- popolysaccharide-induced shock), two other substrates have brain neurons descend the spinal cord with the reticulospinal been recently identified by Almeida et al. (2): neurons of the and rubrospinal tracts. These midbrain neurons are under dorsomedial hypothalamic nucleus and fibers passing through control of posterior hypothalamic neurons, which, in turn, the paraventricular hypothalamic nucleus. By studying receive inhibitory input from warm-sensitive POA cells.
warmth- and cold-seeking behaviors of rats in six different The efferent pathways described are to a large extent inhib- tests, Almeida et al. (2) also showed that these behaviors do not itory. Consequently, thermoeffector activation involves disin- require an intact POA, whereas autonomic thermoregulatory hibition of tonically inhibited neurons. Importantly, thermoef- responses do.
fectors are controlled relatively independently of each other(69, 78), and certain portions of the pathways may be recruited FUNCTIONAL ARCHITECTURE OF THE
in a thermoregulatory response in a stimulus-specific fashion.
The latter speculation is supported by findings that the para-ventricular nucleus (16, 47, 67) and locus coeruleus (3) seem to "Think simple" as my old master used to say—meaning mediate a thermogenic response to bacterial lipopolysaccharide reduce the whole of its parts into the simplest terms, getting or prostaglandin E back to first principles. 2 but not cold-induced thermogenesis or a —Frank Lloyd Wright (1868 –1959) b rise in rodents. In the present Call for Papers, neural circuitries of autonomic thermoeffector responses have "The ability to simplify means to eliminate the unnecessary been subjects of original articles by Nakamura and Morrison so that the necessary may speak." (79), Ootsuka and McAllen (85), Tanaka and McAllen (115) —Hans Hofmann (1880 –1966) AJP-Regul Integr Comp Physiol • VOL 292 • JANUARY 2007 • www.ajpregu.org IN FOCUS: THERMOREGULATION 2007 controlled by a distinct group of neurons (see ThermoeffectorLoops).
Thermoregulatory pathways form distinct thermoeffec- It is also accepted now that the anatomically distinct ther- tor loops. The efferent parts of the loops clearly differ, because moeffectors function largely independently (105), and a body each effector has its own efferent pathway (Fig. 3); the article of experimental data has been accumulated showing that dif- by Ootsuka and McAllen (85) in this Call for Papers provides ferent effectors sometimes defend drastically different levels of further support for this thesis. The afferent parts are also not Tb (for a review, see Ref. 94). An example of differential identical, as each effector receives a unique combination of responses of thermoeffectors is endotoxin shock: it is accom- signals from peripheral and central thermosensors. The ques- panied by a large (2°C) decrease in the threshold hypothalamic tion as to which temperatures (thermosensors in which parts of temperature for activation of cold-induced thermogenesis, but the body) trigger which effectors has been recently revisited in a small (a few tenths of a degree) or no decrease in the several studies (14, 116), including the one by Nakamura and threshold hypothalamic temperature for triggering tail skin Morrison (79) in the present issue.
vasodilation (98). Data showing independent effector re- In general (although fully realizing that generalization may sponses are often questioned (e.g., Refs. 15 and 19) based on not be the best approach in this particular case), behavioral the fact that a thermoeffector can be recruited by another responses depend more on signals from peripheral thermosen- homeostatic system to meet a competing demand and, hence, sors (shell temperatures) than central thermosensors (core tem- can become unavailable for thermoregulation. In the example perature) (92), whereas deep Tb is relatively more important with endotoxin shock (98), skin vasoconstriction is needed to for triggering autonomic responses (52, 103). Such an organi- maintain blood pressure, thus preventing thermoregulatory zation reflects the fact that behavioral responses are often skin vasodilation. The real question, however, is not whether aimed at escaping the forthcoming thermal insult. In contrast, an "unusual" thermoeffector response has a compelling teleo- autonomic cold-defense responses (energetically expensive) logical explanation, but whether the thresholds of different and heat-defense responses (water-consuming) are often re- thermoeffectors can change independently of each other. The cruited only when deep Tb starts changing because behavioral data accumulated (reviewed in Ref. 94) clearly show that mechanisms were ineffective or could not be used (e.g., due to thermoeffector thresholds often change independently, and this competing behavioral demands). Even within the autonomic is a rather strong argument against a unified model of the responses, different thermoeffector responses are triggered by thermoregulatory system with a single controller. Models of different combinations of peripheral and central Tbs. Because the thermoregulation system with multiple controllers (rela- peripheral thermosensors are mostly cold sensors, information tively independent thermoeffector loops) to replace the unified from peripheral sensors is relatively more important for trig- system have been proposed (e.g., Ref. 53).
gering cold-defense effectors (14, 79, 103, 116) than heat- Furthermore, it has been realized that any regulatory system defense ones (103). Because central thermosensors are mostly can exist, using the words of Partridge (86), as a group of warm sensors, information from central sensors is relatively relatively autonomous controllers, acting in a common envi- more important for triggering heat-defense responses (103).
ronment with generally compatible rules, but at any particular Combinations of shell and core Tbs that trigger the same time, operating with only limited active coordinating linkages, thermoeffector response in different species are also likely to and at no time acting as a unified system with a single differ. The great thermal inertia of large animals makes tran- controller. In fact, almost any regulated variable in the body, sient thermal exposures less threatening, which decreases the for example, arterial blood pressure (39), is likely to be an importance of feedforward regulation. Indeed, peripheral ther- emergent product of a decentralized control system.
mosensitivity is relatively more important in smaller animals, Coming back to the thermoregulatory system, basic coordi- whereas central thermosensitivity is relatively more important nation between thermoeffectors is likely to be achieved in larger animals (72). Therefore, caution should be exercised through their dependence on a common variable: Tb. Such while extrapolating results obtained in rats (this section of the coordination can be explained, in a simplified way, as follows.
present review is based primarily on such results) to human When one thermoeffector is activated, its activity changes Tb, which changes the position of Tb relative to the thresholds ofother thermoeffectors, which, in turn, triggers activation or cessation of other thermoeffector mechanisms (for a moredetailed description, see Ref. 93).
Usually, the recruitment of thermoeffectors into a thermo- regulatory response looks like a highly coordinated event.
What To Do with the Term Set Point? Those effectors that affect heat balance in the opposite direc-tions are typically not activated simultaneously. Energetically On a related issue, there has been a recent upsurge of interest expensive and water-consuming responses are typically trig- in the term set point (12, 15, 19, 93, 94, 96). The original gered after those that do not consume a lot of energy or water.
meaning of the term—a physical (thermal, electric, etc.), ex- For a long time, such coordination between thermoeffectors ternally originated reference signal in a unified control sys- was explained with the help of a complex neuronal network tem—is now considered invalid almost unanimously. How- (coordinator) within a single integrated system, the same (or a ever, the term is still used widely, mostly in the following three similar) network that was thought to be responsible for the meanings. First, it is used to designate some internal property formation of thermal sensations (see Thermosensors or Ther- of the unified thermoregulatory system that substitutes for an mostats?). However, the coordinator has never been found external reference signal. Needless to say, such a usage is experimentally. Furthermore, each effector was found to be obviously wrong as it refers to the same unified system.
AJP-Regul Integr Comp Physiol • VOL 292 • JANUARY 2007 • www.ajpregu.org IN FOCUS: THERMOREGULATION 2007 Second, it is used to designate some internal characteristics unified control system. To understand how thermoeffector (usually thresholds) of individual thermoeffector loops or their loops work, we need to study, among other things, thermosen- subcomponents (e.g., Kobayashi's "thermostats" or individual sors (including the thermoTRP channels; Fig. 1), as well as the thermoTRP channels). There is nothing wrong with such a afferent (Fig. 2) and efferent (Fig. 3) portions of thermoeffector usage of the term, except that it creates confusion: this usage loops. Figures 1–3 represent an attempt to summarize the refers to a set point as a property of an individual component, recent progress achieved in these three areas. I invite the whereas all definitions of thermoregulatory responses (see next readers to use these figures in the classroom to complement the paragraph) use the term set point while referring to the entire thermoregulation chapter they are currently using. I encourage viewing these figures as drafts and asking your students to Third, many colleagues use this term to designate a regu- correct and update them. A major shortcoming of these figures lated level of Tb (e.g., Refs. 12, 15, 19). Such a usage is in is that they follow the organization of the same unified ther- accordance with the most recent thermophysiological glossary moregulatory system that is extensively criticized in this re- (25), and many definitions of thermoregulatory responses (fe- view. Although the central controller is eliminated, different ver, anapyrexia, hypothermia, hyperthermia) are built upon this thermoeffectors loops are cut across to represent the same level definition of the set point. However, in the minds of biologists, of all loops in each cross section: sensors, afferent pathways, physicians, and students, the term set point is strongly, perhaps and efferent pathways. To correct this shortcoming would inseparably, associated with the reference signal of a unified require constructing a figure for each thermoeffector that thermoregulatory system. Even today, it is not unusual for would represent the entire loop. Inspirational examples of such scientists outside the thermoregulation field to talk about the constructs can be found in the article of Nakamura and Mor- set point temperature (117) or about neurons that detect the rison (79) in the present issue. Investigations of the roles of error signal (26). Even for scientists within the thermoregula- individual thermoTRP channels in the control of different tion field, it is rather typical to seemingly accept the relative thermoeffectors have just been started, for example, by mutual independence of individual thermoeffector loops, but to Almeida et al. (1, 2), who used TRPV1 and TRPM8 agonists to use (whether intentionally or not) the unified model with a cause thermoregulatory locomotion.
single controller while describing how Tb is regulated (12, 15), to still conclude that all thermoeffectors operate according to a common plan (15), and to propose a neuronal model of a set I thank all of the past and present members of my laboratory, especially Drs.
point of a unified thermoregulation system (12).
Alexandre A. Steiner, Victoria F. Turek, and M. Camila Almeida, for helping In other words, the intrinsic association of the term set point me with the work on which the current review was partially built, for educating with nonexistent physical signals (a computed mean T me on various aspects of thermoregulation, and for discussing with me early drafts of this manuscript and the figures. My views on how T b is regulated have b) within the nonexistent unified thermoregulatory been influenced by enlightening discussions with Drs. Kazuyuki Kanosue and system complicates the usage of this term. It provides reference the late Lloyd D. Partridge. A draft of Fig. 3 was discussed with Drs. Shaun F.
to the engineering analogies that are more misleading than Morrison and Christopher J. Madden. Dr. Thomas M. Hamm and F. E. Farmer informative. To eliminate this often unintended reference, I read an early version of this review and provided important feedback.
have proposed to use the term balance point when talking about This review closes the Special Call for Papers on Physiology and Pharma- cology of Temperature Regulation of the American Journal of Physiology— the regulated level of Tb (93, 94, 96). The balance point-based Regulatory, Integrative and Comparative Physiology (volumes 288 –292, definitions work for all cases where the set point-based defi- 2005–2007). As Guest Editor for this Call, I thank Dr. Pontus B. Persson, nitions of thermoregulatory responses work (25). More impor- Editor-in-Chief, for accepting the proposal for this project. I also thank the tantly, they also work for all cases where the set point-based authors of the more than 100 manuscripts submitted in response to this Call, aswell as the many colleagues in the field who expertly reviewed these submis- definitions may not work (94). As an added benefit of such a sions. Special thanks go to Olivia Kaferly, Assistant to the Editor-in-Chief.
substitution, the term balance point redirects the scientific Like a good mother takes care of her children, Olivia took an excellent care of search from looking for the location of the set point (or the editors, authors, and referees involved. She successfully led us through the building a new model of it) to studying the multiple feedback, project and made sure we would not fall in various organizational, technical, feedforward, and open-loop components that contribute to ethical, and other potholes.
thermal balance in the thermoregulatory system operating as afederation of independent thermoeffector loops. Interestingly, many scientists in the field are already avoiding using the term The author's research reviewed in this paper has been supported by grants set point altogether or replacing it with different terms (e.g., from the National Institute of Neurological Disorders and Stroke (NS41233),Arizona Biomedical Research Commission (8016), and St. Joseph's Founda- Ref. 10). In his editorial about the regulation of body fat content, Wade (122) suggests to put the notions of lipostats andset points behind us and to move on. Applying Wade's sug- gestion to Tb regulation, it is time to free the thermophysi-ological terminology of remnants of the unified control system 1. Almeida MC, Steiner AA, Branco LGS, and Romanovsky AA.
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