In Focus
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
Romanovsky AA. Thermoregulation: some concepts have
changed. Functional architecture of the thermoregulatory system. Am
J Physiol Regul Integr Comp Physiol 292: R37–R46, 2007. First
published September 28, 2006; doi:10.1152/ajpregu.00668.2006.—
While summarizing the current understanding of how body temperature
(Tb) is regulated, this review discusses the recent progress in the
following areas: central and peripheral thermosensitivity and temperature-activated
transient receptor potential (TRP) channels; afferent
neuronal pathways from peripheral thermosensors; and efferent thermoeffector
pathways. It is proposed that activation of temperaturesensitive
TRP channels is a mechanism of peripheral thermosensitivity.
Special attention is paid to the functional architecture of the
thermoregulatory system. The notion that deep Tb is regulated by a
unified system with a single controller is rejected. It is proposed that
Tb is regulated by independent thermoeffector loops, each having its
own afferent and efferent branches. The activity of each thermoeffector
is triggered by a unique combination of shell and core Tbs.
Temperature-dependent phase transitions in thermosensory neurons
cause sequential activation of all neurons of the corresponding thermoeffector
loop and eventually a thermoeffector response. No computation
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
variable, Tb. The described model incorporates Kobayashi’s views,
but Kobayashi’s proposal to eliminate the term sensor is rejected. A
case against the term set point is also made. Because this term is
historically associated with a unified control system, it is more
misleading than informative. The term balance point is proposed to
designate the regulated level of Tb and to attract attention to the
multiple feedback, feedforward, and open-loop components that contribute
to thermal balance.
BY USING POWERFUL AUTONOMIC and even more powerful behavioral
means, our species survives while being exposed to a
wide range of ambient temperatures: from Ϫ110°C (the surface
of the Moon) to 2,000°C (the air around a space shuttle as
it reenters the atmosphere). Even in these diversified thermal
environments, we usually manage to maintain our deep (core)
body temperature (Tb) within a few tenths of a degree Celsius.
In fact, an exodus of Tb from its usual range is so suggestive of
a pathological condition, that Tb is monitored regularly in all
hospitalized patients and reported in every medical history.
Various aspects of Tb regulation have been discussed in fiftyone
original articles (4, 7, 13, 22, 23, 29, 35–38, 40–42, 45, 46,
48–51, 54, 55, 59, 61, 62, 64–66, 71, 73, 76, 77, 79, 80, 85, 88,
99–101, 104, 106, 107, 110, 111, 115, 118, 120, 123–127),
four reviews (20, 31, 32, 108), ten editorials (33, 68a, 70, 89,
90, 95, 109, 112, 113, 121) and one point (57)-counterpoint
(11) exchange within the Special Call for Papers on Physiology
and Pharmacology of Temperature Regulation published in
several issues of the American Journal of Physiology—Regulatory,
Integrative and Comparative Physiology over the past
two years. While closing this Call, the present review summarizes
the recent progress in our understanding of how body
temperature is regulated. To give readers an idea of how
remarkable this progress is, the new understanding (based on
the latest developments) is compared with the information
provided by a typical textbook chapter on thermoregulation. It
seems that this chapter may need some updates, especially in
its coverage of thermosensors, thermoeffectors, and the functional
architecture of the thermoregulatory system.
THERMOSENSORS
Central Thermosensors
A typical textbook chapter would say that brain temperature
is detected by central thermosensory neurons (central “thermoreceptors”).
Most of them are warm-sensitive, that is, they
increase their activity with an increase in brain temperature.
The abundance of warm-sensitive central sensors is consistent
with the following two facts. First, our thermal physiology is
“asymmetrical:” Tb is positioned very closely, within just a few
degrees Celsius, to the upper survival limit (which is possibly
determined by the denaturation of regulatory proteins) but
relatively far, a few tens of degrees, from the lower limit
(which is likely determined by the freezing of water). Therefore,
core overheating is much more dangerous than overcooling.
Second, humans are endothermic animals (meaning that
their principal source of heat is their own body), as opposed to
ectothermic animals (that receive heat primarily from the
environment). Hence, sensors for limiting heat gain have to be
located inside the body. Although much less common, coldsensitive
neurons (i.e., those that increase their activity with a
decrease in brain temperature) also exist. However, the cold
sensitivity of most of them seems to be due to inhibitory
synaptic input from nearby warm-sensitive neurons.
Thermoregulatory responses in a variety of animal species
can be elicited by local thermal stimulation of various areas in
the central nervous system, including several brain stem neuAddress
for reprint requests and other correspondence: A. A. Romanovsky,
Trauma Research, St. Joseph’s Hospital, 350 W. Thomas Rd., Phoenix, AZ
85013 (E-mail: aromano@chw.edu).
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked “advertisement”
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Am J Physiol Regul Integr Comp Physiol 292: R37–R46, 2007.
First published September 28, 2006; doi:10.1152/ajpregu.00668.2006.
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ronal groups [that used to be referred to as the reticular
formation(s) of the medulla oblongata, pons, and midbrain; see
Ref. 9] and the spinal cord, but thermosensitive neurons of the
preoptic anterior hypothalamus (POA) are considered to be the
most important for triggering autonomic thermoeffector responses.
It bears mentioning that the locations of thermosensitive
neurons triggering various thermoregulatory behaviors
are largely unknown (see Behavioral effectors).
For a long time, it was assumed that the roles of cold- and
warm-sensitive POA neurons are reciprocal and “symmetrical,”
that is, that all thermoregulatory responses could be
triggered by either activation of one class of the temperaturesensitive
neurons or inhibition of the other (10); your textbook
is likely to share this assumption. During the past decade,
however, the idea of equally important roles of warm- and
cold-sensitive neurons was put to rest. Elegant studies by
Kanosue and colleagues (21, 128), involving thermal and
chemical stimulation of POA cells, showed that both colddefense
and heat-defense autonomic responses are initiated by
the corresponding changes in the activity of warm-sensitive
neurons; increased activity of warm-sensitive POA neurons
triggers heat-defense responses, while decreased activity triggers
cold-defense responses.
Morphological identification of thermosensitive neurons has
been another major achievement. Griffin et al. (43) showed that
these cells are characterized by the horizontal orientation of
their dendrites: toward the third ventricle medially and the
medial forebrain bundle laterally. Because neurons conveying
temperature signals from the body surface and viscera enter the
hypothalamus via the periventricular stratum and medial forebrain
bundle (24), such an orientation seems ideal for receiving
input through both projections. The present Call for Papers has
contributed to our understanding of the functional properties of
thermosensitive neurons (11, 57, 123). Because warm-sensitive
POA neurons display spontaneous membrane depolarization,
as shown by Boulant and colleagues (123, 129), these cells are
considered pacemakers; their thermosensitivity is due to currents
that determine the rate of spontaneous depolarization
between successive action potentials. It is true, however, that
mechanisms of hypothalamic thermosensitivity continue to be
disputed (57). The changes in ion currents that underlie both
central (vide supra) and peripheral (vide infra) thermosensitivity
are likely to involve temperature-dependent phase transitions
(91).
Peripheral Thermosensors
There are also peripheral thermosensory neurons (peripheral
“thermoreceptors”) that detect shell temperatures in the skin
and in the oral and urogenital mucosa. A typical textbook
chapter would state that most superficial sensors are coldsensitive.
Because central thermosensors are concerned mainly
with warmth, specialization of peripheral sensors in cold sensitivity
is not that surprising. Skin cold sensors are located in or
immediately beneath the epidermis. Their signals are conveyed
by thin myelinated A␦ fibers. The less common warm sensors
are located slightly deeper in the dermis; their signals travel via
unmyelinated C fibers. Peripheral thermosensors are not pacemakers,
and mechanisms of peripheral thermosensitivity are
thought to involve changes in the resting membrane potential.
Importantly, the response of most peripheral thermosensors
shows a powerful dynamic (phasic) component: these cells are
very active when the temperature is changing, but quickly
adapt to a stable temperature. Such a response enables the
organism to rapidly react to environmental changes. In addition
to superficial cold- and warm-sensitive neurons, there are
peripheral deep-body sensors, which respond to the core body
temperature. They are located in the esophagus, stomach, large
intra-abdominal veins, and other organs.
This basic information about peripheral thermosensors has
been recently updated with three developments: 1) the discovery
of a subclass of transient receptor potential (TRP) ion
channels known as thermoTRP channels; 2) the progress in
identifying thermoafferent pathways and their differential involvement
in thermosensation and Tb regulation; and 3) the
challenge to the old idea that a separate neuronal network
computes some integrated Tb (from codes of local Tbs) and
compares it to a set point Tb to form a thermal sensation and to
send “orders” to thermoeffectors.
ThermoTRP Channels
The mammalian TRP superfamily consists of ϳ30 channels
divided in six subfamilies known as the TRPC (canonical),
TRPV (vanilloid), TRPM (melastatin), TRPML (mucolipin),
TRPP (polycystin), and TRPA (ankyrin). Of these, the heatactivated
TRPV1-V4, M2, M4, and M5 and the cold-activated
TRPM8 and A1 are often referred to as the thermoTRP
channels. Involvement of these recently cloned and characterized
channels in thermoregulation has been studied intensively.
In the present Call for Papers, these studies are represented by
the original articles by Ni et al. (80) and Wechselberger et al.
(123), the invited review by Caterina (20), and, to a certain
extent, the point-counterpoint exchange between Kobayashi et
al. (57) and Boulant (11). While referring the reader to the
review by Caterina (20) and several other recent reviews (30,
87, 102) for more detailed information, I would like to emphasize
a few points.
First, activation of all thermoTRP channels results in an
inward nonselective cationic current and, consequently, in an
increase in the resting membrane potential. This mechanism
agrees more readily with a role for these channels in peripheral
thermosensitivity (83) rather than hypothalamic thermosensitivity
(11, 129). Furthermore, the TRPV4 channel (which is
likely to play a physiological role in thermoregulation; vide
infra) does not seem to be expressed in the bodies of POA
neurons (39), but it is expressed by the neuronal bodies of
dorsal root ganglia (44).
Second, although each thermoTRP channel is activated
within a relatively narrow temperature range, the range that
they cover cumulatively is very wide: from noxious cold to
noxious heat (Fig. 1). Furthermore, they cover this temperature
range in an overlapping fashion, and their activities have
different sensitivities to temperature. These features make the
thermoTRP channels well suited to the job of peripheral
thermosensors. It is important to note, however, that the temperature
ranges shown in Fig. 1 were obtained in vitro. In vivo,
a specific cell type on which a thermoTRP channel is expressed
and concomitant activation with chemical ligands affect the
temperature range in which the channel is activated and, in
some cases, bring it closer to physiological values of deep Tb.
Indeed, although the TRPV1 channel is widely thought to be
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activated at pain-inducing temperatures of Ͼ42°C (20, 30), Ni
et al. (80) showed that increasing temperature within the
normal physiological range (perhaps as low as ϳ34.5°C) can
exert a direct stimulatory effect on pulmonary sensory neurons,
and this effect is likely mediated through the activation of the
TRPV1 channel and other subtypes of TRPV channels. For
some TRPV channels (namely, the V3 and V4), likely physiological
roles have been established (63, 74). Other thermoTRP
channels are currently under investigation.
Afferent Pathways
Discriminative sensation. There is little doubt that afferent
pathways start with primary thermosensory neurons. The bodies
of these bipolar cells are located in the dorsal root ganglia,
and the central axons project to the dorsal horn of the spinal
cord (mostly lamina I), where they synapse with secondary
monopolar neurons. Axons of these secondary neurons cross
the midline and ascend in the lateral funiculus of the spinal
cord. It was believed for a long time that the secondary neurons
project directly to the ipsilateral ventrobasal complex of the
thalamus, from where their signals are conveyed to the ipsilateral
somatosensory cortex (postcentral gyrus) by tertiary neurons,
and your textbook may hold this to be true. According to
Craig (27, 28), however, this pathway, which is involved in
tactile sensation, is uninvolved in temperature sensation. Instead,
the lamina-I neurons carry temperature signals to the
insular cortex (the island of Reil) with a relay in the posterolateral
thalamus (specifically, the posterior part of the ventromedial
nucleus) or with two relays (in the parabrachial nucleus
and the basal part of the ventromedial nucleus of the thalamus)
(Fig. 2). These two branches of the spino-thalamo-cortical
pathway are involved in discriminative temperature sensation.
A functional magnetic resonance imaging study in humans by
Hua et al. (48) published in this Call for Papers shows that this
pathway is organized topically, as evident from the topical
representation of skin temperature in the insula. This pathway
allows for sensing temperature at a high spatial resolution (e.g.,
temperature of the surface under the tip of an individual finger
can be assessed). Therefore, this pathway is important for
making decisions about a wide range of issues related to
interactions with the environment, but it appears to have little
to do with Tb regulation, that is, with triggering thermoeffector
responses to defend deep Tb. It should also be noted that the
spino-thalamo-cortical pathway (as described here for humans)
is not the same in other vertebrates, as several interspecies
differences have been noticed (27).
Homeostatic control. Thermoeffector responses are triggered
by thermal exposures massive enough to affect heat
exchange between the body and the environment. Temperature-generated
signals from large areas of the shell are sent to
the brain through the spino-reticulo-hypothalamic pathway
(Fig. 2), in which the secondary lamina-I neurons project to the
reticular formation (medullar, pontine, and midbrain neuronal
Fig. 1. Schematic representation of the dependence of the activity of coldactivated
(blue) and heat-activated (red) thermoTRP channels on temperature.
The thresholds of activation and temperatures of maximal activation are based
on the activity of the channels in heterologous systems; some of the thresholds
are means of values obtained in several studies. The figure is adapted from
Patapoutian et al. (87). Information on the TRPM2 is added based on Togashi
et al. (119); information on the TRPM4 and M5 is added based on Talavera et
al. (114); the added lines are dashed. Please note that quantitative aspects of the
relationships shown should be looked upon with great skepticism, as the figure
does not account for several important factors (81). Nevertheless, this figure
illustrates how well thermoTRP channels are suited for detecting physiologically
relevant temperatures both in the shell and core.
Fig. 2. Afferent neuronal pathways for discriminative sensation/localization
of a thermal stimulus and for homeostatic
control 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 ventroposterior
medial nucleus); VMpo, posterior part of the ventromedial
nucleus of the thalamus; ?, unknown location(s) within the
medulla, pons, and midbrain.
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groups). In this pathway, thermosensory “lines” converge at
the level of lamina-I neurons (i.e., a single lamina-I cell receive
inputs from multiple thermosensory neurons; see Ref. 82) and
possibly at other levels, so that downstream neurons (e.g., brain
stem neurons in thermoeffector pathways) can collect signals
from large thermoreceptive fields (5, 6). The tertiary neurons of
the afferent spino-reticulo-hypothalamic pathway project to
hypothalamic structures (including the POA) either via the
periventricular stratum passing along the wall of the third
ventricle or via the medial forebrain bundle, which passes more
laterally. As described above, warm-sensitive POA neurons
have a dendrite orientation ideal for collecting information
from both the periventricular stratum and the medial forebrain
bundle. More precise delineation of this homeostatic, spinoreticulo-hypothalamic
pathway, especially of the “reticulo”
part of it, requires further study.
Thermosensors or Thermostats?
Our views on how temperature is sensed have been challenged
recently by Kobayashi and colleagues (56, 58, 83). The
pre-Kobayashi models of Tb regulation assumed that thermoreceptors
code temperatures of different parts of the body (into
neuronal activity codes) and that these codes of local temperatures
are then integrated by a separate network (that consists
of several neurons with different roles) into some mean temperature.
The location of the integrating network was unclear
(8a). Nevertheless, it was often assumed that this integrating
network also compares the integrated temperature with an
external or internal reference signal and, based on such a
comparison, somehow generates individual orders to thermoef-
fectors.
Kobayashi and colleagues proposed a different scenario (56,
58, 83). According to them, a sensory neuron is wired through
a number of neurons to an effector cell. When the temperature
to which the temperature-sensitive part of a sensory neuron is
exposed reaches the activation threshold of this neuron, the
neuron fires and, through its connections, sends a signal to the
effector cell. If a large number of sensory neurons sends
signals to their effector cells, a thermoeffector response occurs.
In this model, a decision to trigger an effector is made “automatically”
(principally, by sensory neurons) and involves neither
a separate decision-making network nor operations with
temperature codes (computation of a mean Tb). According to
this model, a sensation is a “side product” of the activation of
those neurons that are wired to cause certain effector responses
(i.e., feeling cold means having activated those neurons that
trigger cold-defense responses). The same principle is used by
Kobayashi and colleagues (58) to explain how we sense other
modalities as well.
Kobayashi’s model also explains how deep Tbs and peripheral
(e.g., skin) Tbs contribute to thermoregulation. Deep Tbs
are regulated variables, and they are very stable. From the point
of view of the control theory, they serve as feedback signals.
Peripheral Tbs, on the other hand, are not regulated; they are
highly variable (97). They are feedforward signals that, according
to the control theory, allow the body to respond to a
thermal load “in advance,” that is, before deep Tbs start
changing. In Kobayashi’s model, both deep and peripheral Tbs
drive effector responses in a similar way. Which central and
peripheral sensory neurons are wired to a particular thermoeffector
determines which combinations of core and shell Tbs
activate this effector (see Thermoeffector Loops).
Despite its conceptual strength, Kobayashi’s model has not
become widely accepted yet, perhaps because the author favors
rather drastic terminological changes: he proposes to call
sensors thermostats (or comparators). Kobayashi is certainly
right that, from the engineering point of view, the role of
thermoreceptors in his model is that of thermostats, and not of
sensors. However, in the minds of the majority of medical and
biological scientists and students, the current terms (sensor,
thermosensor, sensory, somatosensory, etc.) are associated
with no particular engineering analog. Hence, biologists feel no
urge whatsoever to get rid of the entire family of widely used
biological terms or to start translating them to the engineering
language. (Later in this review, I will discuss a different term,
set point, which is associated with a false idea in the minds of
most biologists and physicians and, therefore, must be replaced.)
In the case of thermosensors, a more productive
approach might be to save the term, but to provide it with a
different meaning.
THERMOEFFECTORS
Effectors
Your textbook is likely to name various autonomic thermoeffectors
and possibly some behavioral ones, to discuss
their anatomy, mechanisms of physiological control, and effects
on heat balance. Various aspects of thermoregulatory skin
vasoconstriction (29, 118) and vasodilation (4, 55, 71, 127),
thermogenesis in brown adipose tissue (BAT) (79), shivering
(62), and thermoregulatory behavior (41) have been addressed
in the present Call for Papers. Some interactions between
thermogenesis, energy metabolism, and body temperature regulation
have been analyzed in several original articles (37, 45,
49, 124), two editorials (112, 113), and the invited review by
Diepvens et al. (31). I would also like to refer the reader to the
fundamental review on BAT by Cannon and Nedergaard (17)
published in Physiological Reviews. What your textbook is
unlikely to cover is the efferent neuronal pathways to ther-
moeffectors.
Efferent Pathways
Autonomic effectors. Efferent pathways to thermoeffectors
have not been well characterized in humans, although this topic
has recently started receiving attention (34). Even in the rat, the
most studied laboratory species, not all thermoeffector pathways
have been mapped. Some of the neuronal circuitries
connecting the warm-sensitive hypothalamic neurons to autonomic
thermoeffectors in the rat, particularly the BAT and
skeletal muscles (heat-production effectors) and the vasculature
of the tail (a specialized heat-exchange organ), have been
characterized during the past decade (Fig. 3). Studies of these
pathways have been propelled by the development of transsynaptic
retrograde tracing techniques using pseudorabies virus,
along with the refinement of techniques for discrete lesioning
and pharmacological stimulation and inhibition of neural structures.
The revealed pathways appeared complex, and their
detailed description is beyond the scope of the present paper;
see the invited review by DiMicco and Zaretsky (32) in the
present issue, as well as the reviews by Nagashima et al. (78)
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and Morrison (75) published elsewhere. However, a few points
deserve elaboration.
As shown in Fig. 3, both the BAT and skin vasculature are
controlled by sympathetic ganglia, with the bodies of preganglionic
neurons located in the intermediolateral column of the
spinal cord. These spinal neurons receive direct input from
cells located primarily in the raphe´/peripyramidal area of the
medulla. These medullary cells are under the control of hypothalamic
(dorsomedial and paraventricular nuclei), midbrain
(periaqueductal gray matter, retrorubral field, and ventral tegmental
area), and possibly pontine (locus coeruleus) neurons
that receive input from warm-sensitive POA cells (8, 18, 84).
Although the efferent pathways for skin vasomotor tone and
nonshivering thermogenesis have some similarities, they are
not identical, and both differ substantially from the pathway
controlling shivering. Within the shivering pathway, ␥ and ␣
motoneurons of the ventral horn receive direct and indirect
inputs from the midbrain and brain stem, including the raphe´/
peripyramidal area of the medulla (116). Axons of the midbrain
neurons descend the spinal cord with the reticulospinal
and rubrospinal tracts. These midbrain neurons are under
control of posterior hypothalamic neurons, which, in turn,
receive inhibitory input from warm-sensitive POA cells.
The efferent pathways described are to a large extent inhibitory.
Consequently, thermoeffector activation involves disinhibition
of tonically inhibited neurons. Importantly, thermoeffectors
are controlled relatively independently of each other
(69, 78), and certain portions of the pathways may be recruited
in a thermoregulatory response in a stimulus-specific fashion.
The latter speculation is supported by findings that the paraventricular
nucleus (16, 47, 67) and locus coeruleus (3) seem to
mediate a thermogenic response to bacterial lipopolysaccharide
or prostaglandin E2 but not cold-induced thermogenesis or a
nocturnal Tb rise in rodents. In the present Call for Papers,
neural circuitries of autonomic thermoeffector responses have
been subjects of original articles by Nakamura and Morrison
(79), Ootsuka and McAllen (85), Tanaka and McAllen (115)
and editorial foci by DiMicco and Zaretsky (33) and McAllen
(68a).
Behavioral effectors. Evidence (mostly from stimulation
experiments) suggests that different thermoregulatory behaviors
in the rat (e.g., relaxed postural extension, thermoregulatory
grooming, and locomotion) use distinct neural circuitries
(92). However, the neuroanatomic substrate of no thermoregulatory
behavior has been studied extensively, and little is
known about the neuroanatomy of behavioral thermoregulation
(78). This situation is likely to change, as behavioral thermoregulation
is becoming a subject of keen attention (1, 2, 59, 60,
68). In the present issue, Konishi et al. (59) report that neurons
in the median preoptic nucleus are involved in the intensification
of an operant thermoregulatory behavior (moving to a
reward zone during heat exposure to trigger a breeze of cold
air) caused by hypertonic saline. For a different behavioral
response (moving to a cold environment during bacterial lipopolysaccharide-induced
shock), two other substrates have
been recently identified by Almeida et al. (2): neurons of the
dorsomedial hypothalamic nucleus and fibers passing through
the paraventricular hypothalamic nucleus. By studying
warmth- and cold-seeking behaviors of rats in six different
tests, Almeida et al. (2) also showed that these behaviors do not
require an intact POA, whereas autonomic thermoregulatory
responses do.
FUNCTIONAL ARCHITECTURE OF THE
THERMOREGULATORY SYSTEM
“Think simple” as my old master used to say—meaning
reduce the whole of its parts into the simplest terms, getting
back to first principles.
—Frank Lloyd Wright (1868–1959)
“The ability to simplify means to eliminate the unnecessary
so that the necessary may speak.”
—Hans Hofmann (1880–1966)
Fig. 3. Efferent neuronal pathways for control
of skin vasomotor tone, nonshivering
thermogenesis in brown adipose tissue, and
shivering in the rat. The concept was taken
from Nagashima et al. (78); the figure was
substantially modified and published in Romanovsky
(93) by permission from Elsevier.
The Romanovsky (93) version is reproduced
here with a minor modification and by permission
from both Elsevier and Blackwell
Publishing. DMH, dorsomedial hypothalamus;
IML, intermediolateral column; PAG,
periaqueductal gray matter; cPAG, caudal
PAG; rPAG, rostral PAG; PH, posterior hypothalamus;
PVN, paraventricular nucleus;
RF, reticular formation; RPA, raphe´/peripyramidal
area; RRF, retrorubral field; SG,
sympathetic ganglia; VH, ventral horn;
VMH, ventromedial hypothalamus; VTA,
ventral tegmental area.
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Thermoeffector Loops
Thermoregulatory pathways form distinct thermoeffector
loops. The efferent parts of the loops clearly differ, because
each effector has its own efferent pathway (Fig. 3); the article
by Ootsuka and McAllen (85) in this Call for Papers provides
further support for this thesis. The afferent parts are also not
identical, as each effector receives a unique combination of
signals from peripheral and central thermosensors. The question
as to which temperatures (thermosensors in which parts of
the body) trigger which effectors has been recently revisited in
several studies (14, 116), including the one by Nakamura and
Morrison (79) in the present issue.
In general (although fully realizing that generalization may
not be the best approach in this particular case), behavioral
responses depend more on signals from peripheral thermosensors
(shell temperatures) than central thermosensors (core temperature)
(92), whereas deep Tb is relatively more important
for triggering autonomic responses (52, 103). Such an organization
reflects the fact that behavioral responses are often
aimed at escaping the forthcoming thermal insult. In contrast,
autonomic cold-defense responses (energetically expensive)
and heat-defense responses (water-consuming) are often recruited
only when deep Tb starts changing because behavioral
mechanisms were ineffective or could not be used (e.g., due to
competing behavioral demands). Even within the autonomic
responses, different thermoeffector responses are triggered by
different combinations of peripheral and central Tbs. Because
peripheral thermosensors are mostly cold sensors, information
from peripheral sensors is relatively more important for triggering
cold-defense effectors (14, 79, 103, 116) than heatdefense
ones (103). Because central thermosensors are mostly
warm sensors, information from central sensors is relatively
more important for triggering heat-defense responses (103).
Combinations of shell and core Tbs that trigger the same
thermoeffector response in different species are also likely to
differ. The great thermal inertia of large animals makes transient
thermal exposures less threatening, which decreases the
importance of feedforward regulation. Indeed, peripheral thermosensitivity
is relatively more important in smaller animals,
whereas central thermosensitivity is relatively more important
in larger animals (72). Therefore, caution should be exercised
while extrapolating results obtained in rats (this section of the
present review is based primarily on such results) to human
thermophysiology.
Thermoeffector Coordination
Usually, the recruitment of thermoeffectors into a thermoregulatory
response looks like a highly coordinated event.
Those effectors that affect heat balance in the opposite directions
are typically not activated simultaneously. Energetically
expensive and water-consuming responses are typically triggered
after those that do not consume a lot of energy or water.
For a long time, such coordination between thermoeffectors
was explained with the help of a complex neuronal network
(coordinator) within a single integrated system, the same (or a
similar) network that was thought to be responsible for the
formation of thermal sensations (see Thermosensors or Thermostats?).
However, the coordinator has never been found
experimentally. Furthermore, each effector was found to be
controlled by a distinct group of neurons (see Thermoeffector
Loops).
It is also accepted now that the anatomically distinct thermoeffectors
function largely independently (105), and a body
of experimental data has been accumulated showing that different
effectors sometimes defend drastically different levels of
Tb (for a review, see Ref. 94). An example of differential
responses of thermoeffectors is endotoxin shock: it is accompanied
by a large (2°C) decrease in the threshold hypothalamic
temperature for activation of cold-induced thermogenesis, but
a small (a few tenths of a degree) or no decrease in the
threshold hypothalamic temperature for triggering tail skin
vasodilation (98). Data showing independent effector responses
are often questioned (e.g., Refs. 15 and 19) based on
the fact that a thermoeffector can be recruited by another
homeostatic system to meet a competing demand and, hence,
can become unavailable for thermoregulation. In the example
with endotoxin shock (98), skin vasoconstriction is needed to
maintain blood pressure, thus preventing thermoregulatory
skin vasodilation. The real question, however, is not whether
an “unusual” thermoeffector response has a compelling teleological
explanation, but whether the thresholds of different
thermoeffectors can change independently of each other. The
data accumulated (reviewed in Ref. 94) clearly show that
thermoeffector thresholds often change independently, and this
is a rather strong argument against a unified model of the
thermoregulatory system with a single controller. Models of
the thermoregulation system with multiple controllers (relatively
independent thermoeffector loops) to replace the unified
system have been proposed (e.g., Ref. 53).
Furthermore, it has been realized that any regulatory system
can exist, using the words of Partridge (86), as a group of
relatively autonomous controllers, acting in a common environment
with generally compatible rules, but at any particular
time, operating with only limited active coordinating linkages,
and at no time acting as a unified system with a single
controller. In fact, almost any regulated variable in the body,
for example, arterial blood pressure (39), is likely to be an
emergent product of a decentralized control system.
Coming back to the thermoregulatory system, basic coordination
between thermoeffectors is likely to be achieved
through their dependence on a common variable: Tb. Such
coordination can be explained, in a simplified way, as follows.
When one thermoeffector is activated, its activity changes Tb,
which changes the position of Tb relative to the thresholds of
other thermoeffectors, which, in turn, triggers activation or
cessation of other thermoeffector mechanisms (for a more
detailed description, see Ref. 93).
What To Do with the Term Set Point?
On a related issue, there has been a recent upsurge of interest
in the term set point (12, 15, 19, 93, 94, 96). The original
meaning of the term—a physical (thermal, electric, etc.), externally
originated reference signal in a unified control system—is
now considered invalid almost unanimously. However,
the term is still used widely, mostly in the following three
meanings. First, it is used to designate some internal property
of the unified thermoregulatory system that substitutes for an
external reference signal. Needless to say, such a usage is
obviously wrong as it refers to the same unified system.
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Second, it is used to designate some internal characteristics
(usually thresholds) of individual thermoeffector loops or their
subcomponents (e.g., Kobayashi’s “thermostats” or individual
thermoTRP channels). There is nothing wrong with such a
usage of the term, except that it creates confusion: this usage
refers to a set point as a property of an individual component,
whereas all definitions of thermoregulatory responses (see next
paragraph) use the term set point while referring to the entire
system.
Third, many colleagues use this term to designate a regulated
level of Tb (e.g., Refs. 12, 15, 19). Such a usage is in
accordance with the most recent thermophysiological glossary
(25), and many definitions of thermoregulatory responses (fever,
anapyrexia, hypothermia, hyperthermia) are built upon this
definition of the set point. However, in the minds of biologists,
physicians, and students, the term set point is strongly, perhaps
inseparably, associated with the reference signal of a unified
thermoregulatory system. Even today, it is not unusual for
scientists outside the thermoregulation field to talk about the
set point temperature (117) or about neurons that detect the
error signal (26). Even for scientists within the thermoregulation
field, it is rather typical to seemingly accept the relative
mutual independence of individual thermoeffector loops, but to
use (whether intentionally or not) the unified model with a
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
point of a unified thermoregulation system (12).
In other words, the intrinsic association of the term set point
with nonexistent physical signals (a computed mean Tb and
reference Tb) within the nonexistent unified thermoregulatory
system complicates the usage of this term. It provides reference
to the engineering analogies that are more misleading than
informative. To eliminate this often unintended reference, I
have proposed to use the term balance point when talking about
the regulated level of Tb (93, 94, 96). The balance point-based
definitions work for all cases where the set point-based definitions
of thermoregulatory responses work (25). More importantly,
they also work for all cases where the set point-based
definitions may not work (94). As an added benefit of such a
substitution, the term balance point redirects the scientific
search from looking for the location of the set point (or
building a new model of it) to studying the multiple feedback,
feedforward, and open-loop components that contribute to
thermal balance in the thermoregulatory system operating as a
federation of independent thermoeffector loops. Interestingly,
many scientists in the field are already avoiding using the term
set point altogether or replacing it with different terms (e.g.,
Ref. 10). In his editorial about the regulation of body fat
content, Wade (122) suggests to put the notions of lipostats and
set points behind us and to move on. Applying Wade’s suggestion
to Tb regulation, it is time to free the thermophysiological
terminology of remnants of the unified control system
and to focus our research on studying independent thermoeffector
loops.
INSTEAD OF CONCLUSIONS
In this review, I have tried to make a point that thermoeffectors
can coordinate their activities and regulate Tb while
functioning within relatively independent loops, without a
unified control system. To understand how thermoeffector
loops work, we need to study, among other things, thermosensors
(including the thermoTRP channels; Fig. 1), as well as the
afferent (Fig. 2) and efferent (Fig. 3) portions of thermoeffector
loops. Figures 1–3 represent an attempt to summarize the
recent progress achieved in these three areas. I invite the
readers to use these figures in the classroom to complement the
thermoregulation chapter they are currently using. I encourage
viewing these figures as drafts and asking your students to
correct and update them. A major shortcoming of these figures
is that they follow the organization of the same unified thermoregulatory
system that is extensively criticized in this review.
Although the central controller is eliminated, different
thermoeffectors loops are cut across to represent the same level
of all loops in each cross section: sensors, afferent pathways,
and efferent pathways. To correct this shortcoming would
require constructing a figure for each thermoeffector that
would represent the entire loop. Inspirational examples of such
constructs can be found in the article of Nakamura and Morrison
(79) in the present issue. Investigations of the roles of
individual thermoTRP channels in the control of different
thermoeffectors have just been started, for example, by
Almeida et al. (1, 2), who used TRPV1 and TRPM8 agonists to
cause thermoregulatory locomotion.
ACKNOWLEDGMENTS
I thank all of the past and present members of my laboratory, especially Drs.
Alexandre A. Steiner, Victoria F. Turek, and M. Camila Almeida, for helping
me with the work on which the current review was partially built, for educating
me on various aspects of thermoregulation, and for discussing with me early
drafts of this manuscript and the figures. My views on how Tb is regulated have
been influenced by enlightening discussions with Drs. Kazuyuki Kanosue and
the late Lloyd D. Partridge. A draft of Fig. 3 was discussed with Drs. Shaun F.
Morrison and Christopher J. Madden. Dr. Thomas M. Hamm and F. E. Farmer
read an early version of this review and provided important feedback.
This review closes the Special Call for Papers on Physiology and Pharmacology
of Temperature Regulation of the American Journal of Physiology—
Regulatory, Integrative and Comparative Physiology (volumes 288–292,
2005–2007). As Guest Editor for this Call, I thank Dr. Pontus B. Persson,
Editor-in-Chief, for accepting the proposal for this project. I also thank the
authors of the more than 100 manuscripts submitted in response to this Call, as
well as the many colleagues in the field who expertly reviewed these submissions.
Special thanks go to Olivia Kaferly, Assistant to the Editor-in-Chief.
Like a good mother takes care of her children, Olivia took an excellent care of
the editors, authors, and referees involved. She successfully led us through the
project and made sure we would not fall in various organizational, technical,
ethical, and other potholes.
GRANTS
The author’s research reviewed in this paper has been supported by grants
from the National Institute of Neurological Disorders and Stroke (NS41233),
Arizona Biomedical Research Commission (8016), and St. Joseph’s Founda-
tion.
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