Regulation of Body Temperature by the Nervous System
2018; Cell Press; Volume: 98; Issue: 1 Linguagem: Inglês
10.1016/j.neuron.2018.02.022
ISSN1097-4199
AutoresChan Lek Tan, Zachary A. Knight,
Tópico(s)Neuroendocrine regulation and behavior
ResumoThe regulation of body temperature is one of the most critical functions of the nervous system. Here we review our current understanding of thermoregulation in mammals. We outline the molecules and cells that measure body temperature in the periphery, the neural pathways that communicate this information to the brain, and the central circuits that coordinate the homeostatic response. We also discuss some of the key unresolved issues in this field, including the following: the role of temperature sensing in the brain, the molecular identity of the warm sensor, the central representation of the labeled line for cold, and the neural substrates of thermoregulatory behavior. We suggest that approaches for molecularly defined circuit analysis will provide new insight into these topics in the near future. The regulation of body temperature is one of the most critical functions of the nervous system. Here we review our current understanding of thermoregulation in mammals. We outline the molecules and cells that measure body temperature in the periphery, the neural pathways that communicate this information to the brain, and the central circuits that coordinate the homeostatic response. We also discuss some of the key unresolved issues in this field, including the following: the role of temperature sensing in the brain, the molecular identity of the warm sensor, the central representation of the labeled line for cold, and the neural substrates of thermoregulatory behavior. We suggest that approaches for molecularly defined circuit analysis will provide new insight into these topics in the near future. Birds and mammals have the remarkable ability to regulate their internal temperature within a narrow range that is higher than the surroundings. The reason for this is unknown. One hypothesis is that elevated body temperature evolved as a secondary consequence of the higher metabolic rates needed for sustained activity (e.g., flight) or occupation of new ecological niches (e.g., nocturnal foraging and cold climates) (Bennett and Ruben, 1979Bennett A.F. Ruben J.A. Endothermy and activity in vertebrates.Science. 1979; 206: 649-654Crossref PubMed Google Scholar, Crompton et al., 1978Crompton A.W. Taylor C.R. Jagger J.A. Evolution of homeothermy in mammals.Nature. 1978; 272: 333-336Crossref PubMed Google Scholar, Heinrich, 1977Heinrich B. Why have some animals evolved to regulate a high body temperature?.Am. Nat. 1977; 111: 623-640Crossref Google Scholar). Over time, this elevated body temperature may have become defended as a means to enable the optimization of cellular processes for a specific temperature range (Heinrich, 1977Heinrich B. Why have some animals evolved to regulate a high body temperature?.Am. Nat. 1977; 111: 623-640Crossref Google Scholar). Whatever the reason, the emergence of elevated but stable body temperature was a key event that accompanied the proliferation of birds and mammals across the globe, and an understanding of the thermoregulatory system is central to understanding our own physiology. In this review, we describe the neural mechanisms that regulate body temperature in mammals. First, we outline some of the basic principles of the thermoregulatory system as a whole. Next, we summarize what is known about the molecules, cells, and tissues that measure temperature at different sites in the body and the pathways by which they communicate this information to the brain. We then describe our current understanding of the circuits in the brain that integrate temperature information and coordinate the behavioral and autonomic response. Finally, we highlight some of the key questions that remain to be answered. Body temperature is not a single value but varies depending on where it is measured. In studies of thermoregulation, it is common to divide the body into two compartments: (1) the external shell, which includes the skin and largely fluctuates in temperature along with the environment; and (2) the internal core, which includes the CNS and viscera and has a relatively stable temperature (Jessen, 1985Jessen C. Thermal afferents in the control of body temperature.Pharmacol. Ther. 1985; 28: 107-134Crossref PubMed Scopus (19) Google Scholar, Romanovsky et al., 2009Romanovsky A.A. Almeida M.C. Garami A. Steiner A.A. Norman M.H. Morrison S.F. Nakamura K. Burmeister J.J. Nucci T.B. The transient receptor potential vanilloid-1 channel in thermoregulation: a thermosensor it is not.Pharmacol. Rev. 2009; 61: 228-261Crossref PubMed Scopus (178) Google Scholar). The core temperature is the regulated variable in the thermoregulatory system (Hensel, 1973Hensel H. Neural processes in thermoregulation.Physiol. Rev. 1973; 53: 948-1017Crossref PubMed Google Scholar) and is maintained by a combination of feedback and feedforward mechanisms (Kanosue et al., 2010Kanosue K. Crawshaw L.I. Nagashima K. Yoda T. Concepts to utilize in describing thermoregulation and neurophysiological evidence for how the system works.Eur. J. Appl. Physiol. 2010; 109: 5-11Crossref PubMed Scopus (44) Google Scholar). Feedback responses are those that are triggered when the core temperature deviates from the defended range: for example, exercise generates heat that can increase internal temperature by several degrees Celsius (Fuller et al., 1998Fuller A. Carter R.N. Mitchell D. Brain and abdominal temperatures at fatigue in rats exercising in the heat.J. Appl. Physiol. (1985). 1998; 84: 877-883Crossref PubMed Scopus (144) Google Scholar, Walters et al., 2000Walters T.J. Ryan K.L. Tate L.M. Mason P.A. Exercise in the heat is limited by a critical internal temperature.J. Appl. Physiol. (1985). 2000; 89: 799-806Crossref PubMed Google Scholar) (Figure 1). Such changes in internal temperature are detected by specialized thermoreceptors located throughout the body core, including the viscera, brain, and spinal cord (Jessen, 1985Jessen C. Thermal afferents in the control of body temperature.Pharmacol. Ther. 1985; 28: 107-134Crossref PubMed Scopus (19) Google Scholar). Localized heating or cooling of any of these internal structures induces global feedback responses that oppose the applied temperature change. Feedforward mechanisms are triggered in the absence of any change in core temperature and instead enable preemptive responses to anticipated thermal challenges. The most common example of feedforward control is the detection of a change in air temperature by thermoreceptors in the skin, which triggers thermoregulatory responses that precede and prevent any change in core temperature (Nakamura and Morrison, 2008Nakamura K. Morrison S.F. A thermosensory pathway that controls body temperature.Nat. Neurosci. 2008; 11: 62-71Crossref PubMed Scopus (271) Google Scholar, Nakamura and Morrison, 2010Nakamura K. Morrison S.F. A thermosensory pathway mediating heat-defense responses.Proc. Natl. Acad. Sci. USA. 2010; 107: 8848-8853Crossref PubMed Scopus (128) Google Scholar, Romanovsky, 2014Romanovsky A.A. Skin temperature: its role in thermoregulation.Acta Physiol. (Oxf.). 2014; 210: 498-507Crossref PubMed Scopus (155) Google Scholar). Although feedforward and feedback signals convey different kinds of information about body temperature, they are thought to converge on a common set of neural substrates in the preoptic area (POA) of the hypothalamus. Body temperature is regulated by two types of mechanisms: physiologic and behavioral (Figure 2). Physiologic effectors are involuntary, mostly autonomic responses that generate or dissipate heat. The primary physiologic responses to cold exposure are brown adipose tissue (BAT) thermogenesis and skeletal muscle shivering, which generate heat, and the constriction of blood vessels (vasoconstriction), which prevents heat loss. Exposure to warmth triggers a complementary set of autonomic responses, including suppression of thermogenesis and facilitation of heat loss through water evaporation (e.g., sweating) and dilation of blood vessels (vasodilation). Different species sometimes use different strategies to achieve the same physiologic effect. For example, humans achieve evaporative heat loss primarily by sweating, whereas dogs rely on panting and rodents spread saliva on their fur (Jessen, 1985Jessen C. Thermal afferents in the control of body temperature.Pharmacol. Ther. 1985; 28: 107-134Crossref PubMed Scopus (19) Google Scholar). Likewise the effects of vasodilation are enhanced in species that have specialized thermoregulatory organs, such as the rat tail or rabbit ears, which can rapidly dissipate heat due to their large surface area. Despite these superficial differences, the major classes of physiologic responses are thought to be governed by a common set of neural substrates that are conserved across mammals. Behavior is also an important mechanism for body temperature control. Whereas physiologic responses are involuntary, thermoregulatory behaviors are motivated, meaning that they are flexible, goal-oriented actions that are learned by reinforcement and driven by the expectation of reward (Carlton and Marks, 1958Carlton P.L. Marks R.A. Cold exposure and heat reinforced operant behavior.Science. 1958; 128: 1344Crossref PubMed Google Scholar, Epstein and Milestone, 1968Epstein A.N. Milestone R. Showering as a coolant for rats exposed to heat.Science. 1968; 160: 895-896Crossref PubMed Google Scholar, Weiss and Laties, 1961Weiss B. Laties V.G. Behavioral thermoregulation.Science. 1961; 133: 1338-1344Crossref PubMed Google Scholar). The most basic thermoregulatory behaviors are cold and warmth seeking, in which animals move between microenvironments in their habitat in order to alter the rate of heat loss or absorption. More complex thermoregulatory behaviors include nest or burrow making, in which animals create their own thermal microenvironment (Terrien et al., 2011Terrien J. Perret M. Aujard F. Behavioral thermoregulation in mammals: a review.Front. Biosci. 2011; 16: 1428-1444Crossref PubMed Scopus (0) Google Scholar); social behaviors such as huddling between conspecifics (Batchelder et al., 1983Batchelder P. Kinney R.O. Demlow L. Lynch C.B. Effects of temperature and social interactions on huddling behavior in Mus musculus.Physiol. Behav. 1983; 31: 97-102Crossref PubMed Scopus (33) Google Scholar); and human behaviors such as wearing clothing or using air-conditioning. The engagement of specific thermoregulatory mechanisms is hierarchical, meaning that different effectors become activated at different temperature thresholds. In general, behavioral responses are utilized in preference to autonomic effectors, and autonomic effectors are activated in a stereotyped sequence. This sequence is thought to reflect the cost of activating different responses, either in terms of their energy use or the trade-offs they require with competing physiologic systems. For example, heat challenge triggers vasodilation at lower temperatures than sweating, possibly because sweating results in water loss that upsets fluid balance (Costill and Fink, 1974Costill D.L. Fink W.J. Plasma volume changes following exercise and thermal dehydration.J. Appl. Physiol. 1974; 37: 521-525Crossref PubMed Google Scholar). Similarly cold challenge activates vasoconstriction before shivering or BAT thermogenesis, in accordance with the relative energy cost of these different mechanisms. The existence of these distinct temperature thresholds has been interpreted as evidence that the thermoregulatory circuit contains multiple effector loops, each of which operates to some extent independently (McAllen et al., 2010McAllen R.M. Tanaka M. Ootsuka Y. McKinley M.J. Multiple thermoregulatory effectors with independent central controls.Eur. J. Appl. Physiol. 2010; 109: 27-33Crossref PubMed Scopus (71) Google Scholar, Satinoff, 1978Satinoff E. Neural organization and evolution of thermal regulation in mammals.Science. 1978; 201: 16-22Crossref PubMed Google Scholar). The core temperature defended by the thermoregulatory system (the balance point or set point) is not a fixed value but fluctuates in response to internal and external factors. Many of these factors are unrelated to temperature per se and instead reflect interactions with other physiologic systems. One example is fever, which is the controlled increase of body temperature that occurs most commonly in response to an infection (Figure 3). Fever is triggered by bacterial lipids and other molecules (pyrogens) that directly or indirectly induce the production of prostaglandin E2 (PGE2) by endothelial cells lining the POA (Evans et al., 2015Evans S.S. Repasky E.A. Fisher D.T. Fever and the thermal regulation of immunity: the immune system feels the heat.Nat. Rev. Immunol. 2015; 15: 335-349Crossref PubMed Scopus (298) Google Scholar). PGE2 is thought to inhibit the activity of POA neurons that function to reduce body temperature, thereby producing a regulated hyperthermia that increases the likelihood of surviving an infection. Sleep is a second example of a physiologic process that modulates, and is modulated by, the thermoregulatory system (Krueger and Takahashi, 1997Krueger J.M. Takahashi S. Thermoregulation and sleep. Closely linked but separable.Ann. N Y Acad. Sci. 1997; 813: 281-286Crossref PubMed Google Scholar). The onset of sleep tracks closely the rate of decline in body temperature, and, during sleep, entry into epochs of rapid eye movement (REM) is accompanied by near complete inhibition of thermoregulatory responses in many species (Krueger and Takahashi, 1997Krueger J.M. Takahashi S. Thermoregulation and sleep. Closely linked but separable.Ann. N Y Acad. Sci. 1997; 813: 281-286Crossref PubMed Google Scholar). Overlaid on these effects of sleep are slower timescale, diurnal fluctuations in body temperature that arise from circadian rhythms (Heller et al., 2011Heller H.C. Edgar D.M. Grahn D.A. Glotzbach S.F. Sleep, Thermoregulation, and Circadian Rhythms.Compr. Physiol. 2011; 1: 1361-1374Google Scholar). Sleep, circadian rhythms, and body temperature are all controlled by dedicated neural circuits in the anterior hypothalamus, but the interconnections between these circuits have not been defined. Thermoregulation is also tightly interconnected with the energy and fluid homeostasis systems, due to the substantial demands that thermoregulatory effectors place on bodily resources. For example, cold-induced thermogenesis consumes approximately 60% of total energy expenditure when mice are maintained at an ambient temperature of 4°C (Abreu-Vieira et al., 2015Abreu-Vieira G. Xiao C. Gavrilova O. Reitman M.L. Integration of body temperature into the analysis of energy expenditure in the mouse.Mol. Metab. 2015; 4: 461-470Crossref PubMed Google Scholar). To satisfy this energy need, mice exposed to cold will double their daily food intake (Bauwens et al., 2011Bauwens J.D. Schmuck E.G. Lindholm C.R. Ertel R.L. Mulligan J.D. Hovis I. Viollet B. 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The primary input into the thermoregulatory system comes from sensory neurons that measure the temperature of the body. Most of these sensory neurons have cell bodies located in peripheral ganglia and axons that extend out to measure the temperature of key thermoregulatory tissues (e.g., the skin, spinal cord, and abdominal viscera; discussed below). A separate set of sensory neurons are located within the brain itself and measure the temperature of the hypothalamus. Peripheral temperature sensing is mediated primarily by two classes of sensory neurons that are activated by innocuous warmth (∼34–42°C) or cold (∼14–30°C). These neurons have cell bodies located in trigeminal ganglion (for innervation of the head and face) and dorsal root ganglia (DRG; for innervation of the rest of the body). They are pseudounipolar, meaning that their axons split into two branches, one of which innervates the skin or viscera and the other projects to the dorsal horn of the spinal cord or to the spinal trigeminal nucleus in the brainstem (Figure 4). Peripheral thermosensation has been comprehensively reviewed elsewhere (Ma, 2010Ma Q. Labeled lines meet and talk: population coding of somatic sensations.J. Clin. Invest. 2010; 120: 3773-3778Crossref PubMed Scopus (98) Google Scholar, Vriens et al., 2014Vriens J. Nilius B. Voets T. Peripheral thermosensation in mammals.Nat. Rev. Neurosci. 2014; 15: 573-589Crossref PubMed Scopus (163) Google Scholar). Here we briefly outline the key facts relevant to thermoregulation. TRPM8 is the primary peripheral cold sensor in the thermoregulatory system. This channel is activated in vitro by mild cooling ( 42°C). However, this may reflect the presence of co-agonists or post-translational modifications that can lower the TRPV1 temperature threshold in vivo (Tominaga et al., 1998Tominaga M. Caterina M.J. Malmberg A.B. Rosen T.A. Gilbert H. Skinner K. Raumann B.E. Basbaum A.I. Julius D. The cloned capsaicin receptor integrates multiple pain-producing stimuli.Neuron. 1998; 21: 531-543Abstract Full Text Full Text PDF PubMed Scopus (2364) Google Scholar, Vellani et al., 2001Vellani V. Mapplebeck S. Moriondo A. Davis J.B. McNaughton P.A. Protein kinase C activation potentiates gating of the vanilloid receptor VR1 by capsaicin, protons, heat and anandamide.J. Physiol. 2001; 534: 813-825Crossref PubMed Scopus (420) Google Scholar). Peripheral TRPV1 antagonists induce hyperthermia, whereas TRPV1 agonists induce hypothermia, consistent with a role in thermoregulation (Gavva, 2008Gavva N.R. Body-temperature maintenance as the predominant function of the vanilloid receptor TRPV1.Trends Pharmacol. 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Warm-Sensitive Neurons that Control Body Temperature.Cell. 2016; 167: 47-59.e15Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholarsome effects of peripheral TRPV1 agonists may be centrally mediatedHori, 1984Hori T. Capsaicin and central control of thermoregulation.Pharmacol. Ther. 1984; 26: 389-416Crossref PubMed Scopus (0) Google Scholar, Romanovsky et al., 2009Romanovsky A.A. Almeida M.C. Garami A. Steiner A.A. Norman M.H. Morrison S.F. Nakamura K. Burmeister J.J. Nucci T.B. The transient receptor potential vanilloid-1 channel in thermoregulation: a thermosensor it is not.Pharmacol. Rev. 2009; 61: 228-261Crossref PubMed Scopus (178) Google Scholarperipheral TRPV1 antagonists induce hyperthermiaGavva, 2008Gavva N.R. Body-temperature maintenance as the predominant function of the vanilloid receptor TRPV1.Trends Pharmacol. Sci. 2008; 29: 550-557Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Gavva et al., 2007Gavva N.R. Bannon A.W. Surapaneni S. Hovland Jr., D.N. Lehto S.G. Gore A. Juan T. Deng H. Han B. Klionsky L. et al.The vanilloid receptor TRPV1 is tonically activated in vivo and involved in body temperature regulation.J. Neurosci. 2007; 27: 3366-3374Crossref PubMed Scopus (0) Google ScholarTRPV1 antagonist-induced hyperthermia is independent of temperatureRomanovsky et al., 2009Romanovsky A.A. Almeida M.C. Garami A. Steiner A.A. Norman M.H. Morrison S.F. Nakamura K. Burmeister J.J. Nucci T.B. The transient receptor potential vanilloid-1 channel in thermoregulation: a thermosensor it is not.Pharmacol. Rev. 2009; 61: 228-261Crossref PubMed Scopus (178) Google Scholar, Steiner et al., 2007Steiner A.A. Turek V.F. Almeida M.C. Burmeister J.J. Oliveira D.L. Roberts J.L. Bannon A.W. Norman M.H. Louis J.C. Treanor J.J. et al.Nonthermal activation of transient receptor potential vanilloid-1 channels in abdominal viscera tonically inhibits autonomic cold-defense effectors.J. Neurosci. 2007; 27: 7459-7468Crossref PubMed Scopus (0) Google ScholarTRPV1 can be activated by warm temperatures following sensitization by endogeneous co-agonistsCao et al., 2013Cao E. Cordero-Morales J.F. Liu B. Qin F. Julius D. TRPV1 channels are intrinsically heat sensitive and negatively regulated by phosphoinositide lipids.Neuron. 2013; 77: 667-679Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, Tominaga et al., 1998Tominaga M. Caterina M.J. Malmberg A.B. Rosen T.A. Gilbert H. Skinner K. Raumann B.E. Basbaum A.I. Julius D. The cloned capsaicin rec
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