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J Appl Physiol 110: 1137–1149, 2011.
First published January 26, 2011; doi:10.1152/japplphysiol.01227.2010.
Review
2010 Carl Ludwig Distinguished Lectureship of the APS Neural Control and
Autonomic Regulation Section: Central neural pathways for thermoregulatory
cold defense
Shaun F. Morrison
Department of Neurological Surgery, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd.,
Portland, Oregon
Submitted 19 October 2010; accepted in final form 13 January 2011
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Morrison SF. 2010 Carl Ludwig Distinguished Lectureship of the APS Neural
Control and Autonomic Regulation Section: Central neural pathways for thermoregulatory cold defense. J Appl Physiol 110: 1137–1149, 2011. First published
January 26, 2011; doi:10.1152/japplphysiol.01227.2010.—Central neural circuits
orchestrate the homeostatic repertoire to maintain body temperature during environmental temperature challenges and to alter body temperature during the inflammatory response. This review summarizes the research leading to a model representing our current understanding of the neural pathways through which cutaneous
thermal receptors alter thermoregulatory effectors: the cutaneous circulation for
control of heat loss, and brown adipose tissue, skeletal muscle, and the heart for
thermogenesis. The activation of these effectors is regulated by parallel but distinct,
effector-specific core efferent pathways within the central nervous system (CNS)
that share a common peripheral thermal sensory input. The thermal afferent circuit
from cutaneous thermal receptors includes neurons in the spinal dorsal horn
projecting to lateral parabrachial nucleus neurons that project to the medial aspect
of the preoptic area. Within the preoptic area, warm-sensitive, inhibitory output
neurons control heat production by reducing the discharge of thermogenesispromoting neurons in the dorsomedial hypothalamus. The rostral ventromedial
medulla, including the raphe pallidus, receives projections form the dorsomedial
hypothalamus and contains spinally projecting premotor neurons that provide the
excitatory drive to spinal circuits controlling the activity of thermogenic effectors.
A distinct population of warm-sensitive preoptic neurons controls heat loss through
an inhibitory input to raphe pallidus sympathetic premotor neurons controlling
cutaneous vasoconstriction. The model proposed for central thermoregulatory
control provides a platform for further understanding of the functional organization
of central thermoregulation.
homeostasis; sympathetic nervous system; brown adipose tissue; cutaneous vasoconstriction; shivering; thermogenesis
THE REGULATION OF BODY TEMPERATURE is one of the myriad of
interrelated functions essential to the maintenance of homeostasis that are controlled primarily through dedicated pathways
in the brain. Significant deviations in cellular temperature from
homeostatic values alter a variety of molecular properties,
including a reduction in enzyme efficiency and altered diffusion capacity and membrane fluidity, which, in turn, reduce
critical cellular functions, including cellular energy availability
and membrane ion fluxes. Such changes within the nervous and
organ systems of most mammals lead to organ system failure
and the inability to maintain homeostasis and to coordinate and
execute motor activities, followed by loss of consciousness and
eventual death. Hence, although not as immediately critical as
the availability of oxygen and glucose, the brain is highly
Address for reprint requests and other correspondence: S. Morrison, Dept. of
Neurological Surgery (RJH3371), Oregon Health and Science Univ., Mail
Code L-472, 3181 SW Sam Jackson Park Rd., Portland, OR 97239 (e-mail:
[email protected]).
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attentive to the potential for deviations from a homeostatic
brain and core body temperature. Anticipation of such deviations from environmental cues, such as changes in skin temperature, activates the brain’s central thermoregulatory circuits
and thermal effectors to sustain an optimal operating temperature for the immediate environment of its resident neurons and
for the many tissues on which it depends for survival.
This review of the central neural pathways for thermoregulation, focusing on those for cold defense, is based on the Carl
Ludwig Distinguished Lecture that I had the honor of delivering at the Experimental Biology 2010 meeting in Anaheim,
CA. It will describe the experimental basis for our current
understanding of the core central thermoregulatory network
(Fig. 1). This network comprises the fundamental pathways
through which changes in peripheral or central thermal sensation elicit changes in thermoregulatory effector tissues to
protect the brain and other critical tissues from temperature
deviations that would reduce cellular efficiency. The principal
nonbehavioral effector mechanisms for cold defense, recruited
8750-7587/11 Copyright © 2011 the American Physiological Society
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essential mechanism in cold defense and in the elevated body
temperature in fever in both experimental animals and in
humans (74, 84), the central neural mechanisms generating
shivering and the thermoregulatory circuits controlling shivering are almost entirely unknown.
In contrast to the ancillary nature of thermogenic shivering
in skeletal muscles that are normally used to produce movement and posture, thermogenesis in BAT is the specific metabolic function of this tissue, which is an important thermoregulatory effector not only in small mammals, but also in humans
(21, 26, 94, 96). BAT thermogenesis arises from the heatgenerating capacity of a significant proton leak across the
extensive mitochondrial membranes of the brown adipocytes
that is facilitated by the high expression of uncoupling protein-1 (UCP1) in BAT mitochondria. The levels of BAT
sympathetic nerve activity (SNA), norepinephrine release in
BAT, and ␤3-adrenergic receptor binding regulate both the
activity of lipases providing the immediate fuel molecules for
BAT mitochondria and the level of expression of BAT mitochondrial UCP1 (11).
The significance of the heat production from BAT and other
nonshivering thermogenic mechanisms relative to that from
shivering is likely dependent on species and on the thermal
challenge. Animals, including humans, with significant muscle
mass and basal metabolic heat production would likely have
the capacity to combat an acute, strong cold challenge by
generating more heat from shivering than from BAT. Nonetheless, the specific localization of BAT depots and of the BAT
circulation could allow BAT to provide the heat necessary to
sustain central and peripheral nervous system function in
extreme conditions. On the other hand, rodents in a sustained
cool environment would be more dependent on a maintained
heat production from BAT, rather than from shivering, for the
maintenance of their body temperature.
The stimuli to the central thermoregulatory network that
activate BAT and shivering thermogenesis also elicit a marked,
centrally evoked, sympathetically mediated increase in heart
rate. The tachycardia elicited under these conditions contributes to the maintenance of cardiac output during the significant,
metabolically driven dilation of BAT and skeletal muscle
blood vessels, thereby serving to distribute BAT- and shiver-
Fig. 1. Functional neuroanatomic and neurotransmitter model for the fundamental pathways providing the thermoregulatory control and pyrogenic activation of
cutaneous vasoconstriction (CVC), brown adipose tissue (BAT), and shivering thermogenesis. Cool and warm cutaneous thermal sensory receptors transmit
signals to respective primary sensory neurons in the dorsal root ganglia (DRG), which relay this information to second-order thermal sensory neurons in the dorsal
horn (DH). Cool and warm sensory DH neurons glutamate (GLU) to activate third-order sensory neurons in the external lateral subnucleus of the lateral
parabrachial nucleus (LPBel) and in the dorsal subnucleus of the lateral parabrachial nucleus (LPBd), respectively. The pathway from the DH to LPB is primarily
crossed (30), but the level of this decussation has not been described. Thermosensory signals from DH neurons are also relayed to the thalamus and then to the
cortex for conscious thermal perception and localization. Cool thermosensory signals are glutamatergically transmitted from the LPB to the preoptic area (POA)
where GABAergic interneurons in the median preoptic (MnPO) subnucleus inhibit the distinct populations of warm-sensitive (W-S) neurons in the medial
preoptic (MPO) subnucleus that control CVC, BAT, and shivering. In contrast, glutamatergic interneurons in the MnPO, postulated to be excited by glutamatergic
inputs from warm-activated neurons in LPBd, excite W-S neurons in MPO. Prostaglandin (PG) E2 binds to EP3 receptors on W-S neurons in the POA to inhibit
their activity. Preoptic W-S neurons controlling CVC inhibit CVC sympathetic premotor neurons in the rostral ventromedial medulla, including the rostral raphe
pallidus (rRPa), that project to CVC sympathetic preganglionic neurons in the spinal intermediolateral nucleus (IML). CVC premotor neurons can increase CVC
sympathetic tone by release of glutamate and/or serotonin (5-HT) within the IML. Preoptic W-S neurons controlling BAT thermogenesis inhibit BAT
sympathoexcitatory neurons in the dorsomedial hypothalamus (DMH) that, when disinhibited, excite BAT sympathetic premotor neurons in the rRPa that project
to BAT sympathetic preganglionic neurons in the IML. Some BAT premotor neurons, containing vesicular glutamate transporter 3 (VGLUT3), can release
glutamate to excite BAT sympathetic preganglionic neurons, while others can release 5-HT to interact with 5-HT1A receptors (R), potentially on spinal inhibitory
interneurons, to increase BAT sympathetic outflow and thermogenesis. Preoptic W-S neurons controlling skeletal muscle shivering responses inhibit
shivering-promoting neurons in the DMH, which are postulated to provide excitation to medial medullary shivering premotor neurons in the rRPa that project
to the ventral horn (VH) to excite alpha (␣) and gamma (␥) motoneurons during shivering. Also illustrated are some sources of tonic excitation to neuronal
populations in the core thermoregulatory pathways. NE, norepinephrine.
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in order of increasing energy costs, include cutaneous vasoconstriction (CVC) to conserve heat in the body core, nonshivering thermogenesis in brown adipose tissue (BAT) and the
heart, and shivering thermogenesis in skeletal muscle. Mechanisms for heat defense include cutaneous vasodilation to
facilitate heat loss and evaporative cooling through sweating,
saliva spreading, or panting, employed to differing degrees by
different species. The central neural pathways for the regulation of body temperature have been recently reviewed (47, 49,
50). A wide variety of nonthermal physiological parameters,
disease processes, neurochemicals, and drugs can influence the
central regulation of body temperature, and their effects are
hypothesized to result from an alteration of the activity within
this core neural circuits for thermoregulation.
Increased cutaneous blood flow brings metabolic heat to the
body surface where it is available for transfer to the environment. Sympathetic regulation of CVC determines whether
blood flow is routed centrally during cold exposure, to conserve heat with a low cutaneous blood flow, or peripherally
during heat exposure, to increase heat loss with a high cutaneous blood flow. In this manner, sympathetic regulation of
CVC contributes not only to the maintenance of body temperature, but also to an elevated body temperature during fever
and to drug-induced hyperthermia (47).
Since heat generation (thermogenesis) is a by-product of the
inefficiency of mitochondrial ATP production and of ATP
utilization, thermogenesis occurs to a greater or lesser extent in
all tissues during the derivation of cellular energy requirements
from the potential energy in the chemical bonds of food or
stored energy sources. During the rapid, repeated skeletal
muscle contractions of shivering, thermogenesis arises from
the inefficiency of energy utilization in cross-bridge cycling
and calcium ion sequestration and from mitochondrial membrane proton leak in the course of ATP production (33, 77, 80).
Shivering thermogenesis is the last cold-defense mechanism to
be activated as its thermal threshold is lower than those for
cutaneous vasoconstriction or BAT thermogenesis, in keeping
with the high metabolic energy cost of shivering and the
relative vulnerability of an animal during shivering, as escape
behavior would be more slowly mobilized. Although heat
generation through shivering has long been recognized as an
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ing-generated heat more efficiently and to increase the availability of energy substrates to activated BAT and skeletal
muscle. However, the inefficiency of cardiac energy utilization
in cross-bridge cycling and calcium ion sequestration suggests
that such dramatic increases in heart rate will also elicit a
significant cardiac thermogenesis. The fact that this tachycardia is driven in a feed-forward manner and that the resulting
thermogenesis contributes to cold-defense suggests that the
heart may also be considered among the thermoregulatory
effectors for cold defense.
CENTRAL NEURAL PATHWAYS FOR THERMOREGULATION
Fig. 2. Rat POA-projecting LPBel and LPBd neurons are activated in a cold or warm environment, respectively. A: Fos expression (black) in nuclei of LPB
neurons labeled with the retrograde tracer, cholera toxin b-subunit (CTb; injection sites in red, immunoreactivity in brown) injected into the MnPO and
dorsomedial MPO in rats exposed to 24°C (left panel), 4°C (middle panel), and 36°C (right panel). Note the CTb and Fos immunoreactivities in LPBel neurons
(middle panel, filled arrowheads) of the cold-exposed rats and in LPBd neurons (right panel, filled arrowheads) of the warm-exposed rats. B: skin warming-evoked
increases in the extracellular action potential frequency of an LPBd neuron antidromically activated from the MnPO are accompanied by decreases in BAT
sympathetic nerve activity (SNA). C: skin cooling-evoked increases in the extracellular action potential frequency of an LPBel neuron antidromically activated
from the MnPO are accompanied by increases in BAT SNA. 3V, third ventricle; ac, anterior commissure; IC, inferior colliculus; MnPO, median preoptic area;
MPO, medial preoptic area; ox, optic chiasm; scp, superior cerebellar peduncle. [Modified from Ref. 58 with permission from National Academy of Sciences;
and modified from Ref. 59 with permission from Nature Publishing Group.]
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Cutaneous thermal receptor afferent pathway. By sensing
changes in environmental temperature through thermoreceptors in primary sensory nerve endings distributed in the skin,
the central thermoregulatory system can defend the thermal
homeostasis of the brain and body from a variety of environmental thermal challenges. The molecular mechanisms of cutaneous thermoreception have been attributed to members of
the transient receptor potential (TRP) family of cation chan-
nels, including TRPM8 as the potential cold receptor (23, 44,
75) and TRPV3 and TRPV4 as potential warm receptor channels that are activated by innocuous warm temperatures (28,
76, 97). Although TRPV1 has been widely considered as a
temperature sensor involved in normal thermoregulation, studies with knockout animals and pharmacological antagonists
argue against its role in the processing of temperature signals
used for thermoregulation (82). Primary somatosensory fibers
deliver thermal information detected by cutaneous thermoreceptors to thermoreceptive-specific, lamina I spinal (or trigeminal) dorsal horn cells that respond linearly to graded, innocuous cooling or warming stimuli and are not activated further
in the noxious temperature range (2, 18, 20). In turn, spinal and
trigeminal lamina I neurons collateralize (31, 38) and innervate
the thalamus and the pontine lateral parabrachial nucleus
(LPB) (5, 16, 25), where the axonal swellings of dorsal horn
neurons are closely apposed to preoptic area (POA)-projecting
LPB neurons (59).
Functional neuroanatomic tracing experiments have revealed densely clustered neurons in the dorsal (LPBd) and
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external lateral (LPBel) subnuclei of the LPB that are activated
(Fos expression) following warm (36°C) or cold (4°C) exposure, respectively (9, 58, 59), and retrogradely labeled following tracer injections into the POA (58, 59) (Fig. 2A). The
greatest number of double-labeled LPBd and LPBel neurons
were found when the tracer injections were centered on the
midline subregion of the POA, including the median preoptic
nucleus (MnPO), suggesting that the warm and cool cutaneous
sensory signals from LPBd and LPBel neurons, respectively,
are transmitted mainly to the MnPO rather than the medial
(MPO) or lateral (LPO) POA (58, 59). These findings indicate
that LPBd and LPBel neurons can directly transmit cutaneous
warming and cooling signals, respectively, to the MnPO region.
Supporting the conclusions from these anatomic observations, in vivo electrophysiological recordings from single LPB
cells revealed that the firing rate of most neurons in the LPBd
and the LPBel that were antidromically identified as projecting
to the MnPO increased markedly in response to skin warming
(58) (Fig. 2B) and skin cooling (59) (Fig. 2C), respectively, and
then returned to the basal level following respective recooling
and rewarming of the skin. Most such LPB neurons were not
activated in response to noxious mechanical stimuli. These
LPB neuronal responses occurred in parallel with skin warming-evoked inhibitions and skin cooling-evoked activations,
respectively, of BAT SNA (58, 59). Thus the LPB contains
MnPO-projecting neurons that specifically mediate thermoregulatory afferent signaling and that are distinct from those
responding to nociceptive afferents.
In in vivo functional studies, glutamatergic stimulation of
LPBd or LPBel neurons with N-methyl-D-aspartate (NMDA)
evokes respective decreases or increases in BAT thermogenesis, metabolism, and heart rate that mimic skin warmingevoked or skin cooling-evoked physiological responses (58,
59). Further, either inhibition of local neurons or blockade of
their glutamate receptors in the LPBel eliminates skin coolingevoked cold-defense responses, including the activation of
BAT and shivering thermogenesis and increases in metabolism
(indicated by increases in expired CO2) and in heart rate (59)
(Fig. 3, A and B). Similarly, inhibition of local neurons or
blockade of their glutamate receptors in the LPBd eliminates
skin warming-evoked heat-defense responses, including the
inhibition of cutaneous vasoconstrictor SNA (mediating cutaneous vasodilation) (58) (Fig. 3C). Thus activations of LPBd
and LPBel neurons, likely by glutamatergic inputs from lamina
I neurons, driven, respectively, by cutaneous warming and
cooling signals, are essential for the transmission of the respective warm and cold cutaneous thermal afferent stimuli that
initiate heat defense and cold-defense responses to defend body
temperature during environmental thermal challenges (Fig. 1).
Consistent with these conclusions, rats that have bilateral
lesions of the LPB fail to maintain body temperature in a cool
environment (36).
Determining the pathways through which afferent fibers
from visceral and skeletal muscle cold and warm receptors
influence central thermoregulatory networks will contribute
significantly to an understanding of the integration of cutaneous thermosensory signals with those from the body core. The
classic spinothalamocortical pathway comprises lamina I neurons that directly synapse on neurons in the thalamus that
project to the primary somatosensory cortex and leads to
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Fig. 3. Inhibition of neuronal activity or blockade of ionotropic glutamate
receptors in the rat LPBel or LPBd reverses skin cooling-evoked cold-defense
and skin warming-evoked heat-defense responses, respectively. A: skin cooling-evoked increases in BAT SNA, BAT temperature (TBAT), expired CO2,
and heart rate (HR) are eliminated by bilateral nanoinjections (dashed lines) of
the GABAA receptor agonist, muscimol (MUSC), into the LPBel. AP, arterial
pressure. B: skin cooling-evoked increases in nuchal EMG are eliminated by
bilateral injections (dashed lines) of the glutamate receptor antagonists, AP5
and CNQX, into the LPBel. C: skin warming-evoked decreases in sural CVC
sympathetic discharge are eliminated by bilateral injections (dashed lines) of
AP5 and CNQX into the LPBd. SAL, saline. [Modified from Ref. 58 with
permission from National Academy of Sciences; and modified from Ref. 59
with permission from Nature Publishing Group.]
perception and discrimination of cutaneous temperature (18,
19). This pathway does not, however, play a significant role in
the triggering of involuntary thermoregulatory responses to
environmental cold challenges. This is demonstrated by the
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maintenance of sympathetic thermogenic responses to skin
cooling following elimination of the skin cooling-evoked
changes in primary somatosensory cortical EEG activity after
lesions of the thalamic regions that receive thermal spinothalamic projections (59). Elucidating the relative contributions of
the spinothalamic vs. spinoparabrachial pathways in initiating
thermoregulatory behaviors, the stereotypical somatic motor
acts directed primarily toward minimizing or optimizing heat
transfer from the body to the environment, may, however,
point to a thermoregulatory role for the spinothalamocortical
pathway.
Thermoregulatory sensorimotor integration in the POA. The
following observations support the significance of a glutamatergic input from LPBel neurons primarily to the MnPO subregion of the POA (Fig. 1) in the signaling of cutaneous
cooling to the central thermoregulatory network. First, the
projections from LPB neurons activated by skin cooling terminate mainly in the median part of the POA (59). Second,
glutamatergic stimulation of MnPO neurons, rather than those
in MPO or LPO, evokes thermogenic, metabolic, and tachycardic responses similar to those evoked during cold defense
(57). Third, cold-defense responses triggered either by LPBel
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Fig. 4. Blockade of glutamate receptors in the rat MnPO or
of GABAA receptors in the rat MPO blocks BAT thermogenic, metabolic, and cardiac responses. A: increases in BAT
SNA, expired CO2, and HR evoked by injection (dashed
line) of NMDA, but not saline (SAL), into the LPB are
prevented by prior injection (open circles and arrow in
insets) of the glutamate receptor antagonists, AP5 and
CNQX, into the MnPO. B: injection of AP5 and CNQX into
MnPO prevents skin warming-evoked inhibition of sural
sympathetic discharge and accompanying increases in tail
temperature (Ttail). C: injection of the GABAA receptor
antagonist, bicuculline, into MPO (filled circles and arrows
in insets) reverses skin cooling-evoked increases in BAT
SNA, BAT temperature, and expired CO2. [Modified from
Ref. 56; modified from Ref. 58 with permission from National Academy of Sciences; and modified from Ref. 59 with
permission from Nature Publishing Group.]
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the discharge of postganglionic sympathetic neurons innervating the rat tail (73) (Fig. 5C) and to eliminate shivering (33a)
(Fig. 5D) and that cooling of the local environment of POA
neurons evokes BAT and shivering thermogenesis (29, 32)
reveals a tonically active, local-warming-mediated mechanism
in the POA capable of driving a potent inhibition of colddefense effector activation. The POA neuronal substrate for
these effects may reside in the warm-responsive neurons that
have been characterized both in vivo (62) (Fig. 5E) and in vitro
(27, 89) (Fig. 5F) in the POA and anterior hypothalamus,
including the medial preoptic area (MPO) and the MnPO and
which are mostly GABAergic (39) (Fig 5F). The tonic discharge of POA warm-sensitive neurons is reduced by skin
cooling (8). Whether warm-sensitive POA neurons project
axons outside of the POA remains to be demonstrated.
BAT and shivering thermogenesis as well as increases in
metabolism and heart rate that are evoked by skin cooling are
blocked by antagonizing GABAA receptors in the MPO (56,
71) (Fig. 4C). Thus skin cooling-evoked responses are postulated to require a local circuit in the POA (Fig. 1) in which
cutaneous cool signals that are received by MnPO neurons
drive a GABAergic inhibition of inhibitory warm-sensitive,
MPO projection neurons (57). Together, these observations
support a model (Fig. 1) in which warm-sensitive, GABAergic
Fig. 5. Warm-sensitive POA projection neurons provide an inhibitory influence to CVC,
BAT, and shivering. A and B: transections of
the rat neuraxis caudal to the POA increase
rat-tail CVC activity and BAT and core (REC)
temperatures. MAP, mean arterial pressure;
PE, phenylephrine; H, hexamethonium. [Modified from Ref. 78; and modified from Ref. 17
with permission from Wiley.] C and D: POA
warming in the rat inhibits the sympathetic
nerve activity (TSNA) controlling rat tail CVC
and cooling-evoked shivering. Thy, hypothalamic temperature; R, right; L, left; IEMG,
integrated electromyogram. [Modified from
Ref. 33a; and modified from Ref.73 with permission from Wiley.] E: increasing local POA
temperature in the cat increases the discharge
frequency of a POA neuron recorded in vivo.
[Modified from Ref. 62.] F: increasing the
recording bath temperature increased the discharge frequency of a mouse GAD-67 green
fluorescent protein (GFP)-labeled POA neuron
recorded in vitro. [Modified from Ref. 39 with
permission from Society for Neuroscience.]
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stimulation (Fig. 4A) or by skin cooling are blocked by antagonizing glutamate receptors in the MnPO (57, 59). Thus
activation of MnPO neurons is an essential process in the
central mechanism for eliciting cold-defensive responses to
environmental cold challenges. Skin warming signaling, mediated via LPBd neurons, also appears to be transmitted preferentially to neurons in MnPO and in the rostral dorsomedial
portions of MPO, and blockade of glutamate receptors in this
region of the POA interrupts skin warming-evoked responses
(58) (Fig. 4B). Whether heat defense responses are mediated
via a glutamatergic interneuron in MnPO (hypothesized in Fig.
1) or via a direct glutamatergic drive to POA warm-sensitive
neurons (see below) from LPBd neurons remains to be determined.
The finding that transections of the neural pathways immediately caudal to the POA results in increases in BAT temperature (17) (Fig. 5B) and in the sympathetic nerve activity to the
rat tail (78) (Fig. 5A) and, similarly, that reducing the activity
of neurons in the MPO produces hyperthermia by stimulating
metabolism, shivering thermogenesis, and cutaneous vasoconstriction (1, 71, 88, 101), suggests that neurons in the POA
exert a tonic inhibitory influence on cold-defense-related thermogenic and heat conservation mechanisms. Further, the demonstration that local warming of the POA is sufficient to inhibit
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POA projection neurons integrate cutaneous and local thermal
information and are tonically active at thermoneutral temperatures to suppress, to varying degrees, shivering and nonshivering thermogenesis and cutaneous vasoconstriction. Different
populations of warm-sensitive, GABAergic POA projection
neurons, whose firing rates are a potentially significant determinant of the thermoregulatory “balance point” (81), are expected to control the activation of different thermal effectors,
thereby providing the substrate for the graded thermal thresh-
Fig. 6. Role of DMH neurons in rat thermoregulatory responses. A: injection of
the glutamate antagonist, kynurenic acid (KYN), into DMH reversed the increases
in BAT SNA, BAT temperature, expired CO2, and HR produced by injection of
PGE2 into the MPO. [Modified from Ref. 42.] B: disinhibition of neurons in the
DMH (arrowhead in inset) and dorsal hypothalamic area with injection of the
GABAA receptor antagonist, bicuculline (BIC), activates BAT SNA and increases
in BAT temperature and expired CO2. [Modified from Ref. 48 with permission
from Elsevier.] C: injection of the GABAA receptor agonist, muscimol (MUSC),
into the DMH did not affect either spontaneous, thermally stimulated CVC
neuronal activity to the rat tail or the increase in CVC neuronal discharge
following injection of PGE2 into MPO, indicating that activation of DMH neurons
is not required for thermoregulatory or febrile activation of CVC sympathetic
outflow. [Modified from Ref. 78.] To facilitate the observation of an effect of
PGE2 on tail CVC activity, ongoing tail CVC discharge was reduced reflexively by
elevating core temperature by warming the skin during the period marked with a
bracket.
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olds for the cold-defense activation of different thermal effectors.
Although PGE2 in the POA does not play a recognized role
in normal thermoregulation, its binding to EP3 receptors in the
POA plays an essential role in fever. The binding of PGE2 to
inhibitory EP3 receptors on POA inhibitory neurons that project to the dorsomedial hypothalamus (DMH) or to the rostral
raphe pallidus (rRPa) (61) could provide a substrate for the
disinhibitory activation of cold-defense effectors during fever
(42, 56, 60). However, the precise localization of the EP3
receptor-expressing POA neurons and the microcircuitry
within POA that mediate the febrile responses of the various
thermal effectors remain to be clarified. In this regard, EP3
receptors for PGE2 are found on neurons throughout the MnPO
(53) and, to a lesser extent, the MPO, that project either to the
DMH or to the rRPa (55, 61); the more rostrally located MnPO
area is highly sensitive to the injection of PGE2 (72), although
febrile responses can also be elicited from injection of slightly
higher doses of PGE2 into the more caudal MPO area (42, 55,
85); and genetic deletion of EP3 receptors (37) in MnPO or
blockade of GABAA receptors (70) in the MPO area eliminates
febrile responses.
Thermoregulatory effector drive from the dorsomedial
hypothalamus. The dorsal portion of the rostral DMH and the
dorsal hypothalamic area (DA) contain neurons required for
the BAT thermogenic and heart rate responses to skin cooling
and to injection of PGE2 into the POA (24, 42, 56, 60, 99)
(Fig. 6A). Activation with the glutamatergic agonist, NMDA,
or disinhibition with bicuculline, of neurons in this region of
the DMH elicits potent increases in BAT thermogenesis, heart
rate, and metabolism (13, 15, 24, 42, 83, 100) (Fig. 6B). In
contrast, DMH neurons do not mediate the cutaneous vasoconstriction stimulated by cooling or by intra-POA PGE2 (78)
(Fig. 6C), although activation of DMH neurons can increase
CVC sympathetic outflow (78, 90). These data are consistent
with a model (Fig. 1) in which skin cooling- and febrile-evoked
BAT and cardiac sympathoexcitatory and somatic shivering
excitatory signals are, respectively, transmitted to BAT and
cardiac sympathetic and somatic shivering premotor neurons in
the rRPa from those DMH neurons that are disinhibited following cold cutaneous or pyrogenic stimuli in the POA. In
contrast, the parallel activations of CVC sympathetic outflow
appear to be mediated by POA projection neurons that bypass
the DMH. Interestingly, although several POA neurons branch
to innervate both the DMH and the rRPa regions, almost none
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CNS PATHWAYS FOR COLD DEFENSE
neous heat loss are determined by the amplitudes and the
rhythmic bursting characteristics of BAT, cardiac, and CVC
SNAs and of skeletal muscle shivering EMGs. The latter are,
in turn, governed by the discharges of BAT, cardiac, and CVC
sympathetic preganglionic neurons, and those of alpha and
gamma motoneurons, respectively. The activities of these spinal output neurons are controlled, in turn, by their supraspinal
inputs and by the excitability of the network of spinal interneurons (10, 12, 22, 34) in which they are embedded. A significant
fraction of the BAT and CVC sympathetic and the somatic
shivering premotor neurons in the rRPa are glutamatergic
and/or serotonergic (Fig. 7G) neurons (12, 35, 54, 86, 87, 93,
98), giving rise to at least a portion of the 5-hydroxytryptamine
(5-HT)-containing and vesicular glutamate transporter 3
(VGLUT3)-containing terminals in the intermediolateral nucleus (IML) (3, 54, 87, 95).
Physiologically, spinal glutamate receptor activation in
the IML plays an important role in the control of BAT
thermogenesis (43, 54) (Fig. 8, A and B) and CVC (65) (Fig.
8C). However, activation of spinal 5-HT receptors elicits a
significant potentiation of the BAT SNA response to glutamate receptor stimulation in the IML (Fig. 8B), such that
even subthreshold doses of NMDA into the IML can increase BAT SNA in the presence of 5-HT (43). Further,
spinal 5-HT receptor activation contributes significantly to
Fig. 7. rRPa contains premotor neurons for BAT, shivering, and CVC that are essential for the cold-evoked activation of these thermal effectors in the rat. A–
C: inhibition of neurons in the rRPa reverses or prevents the skin cooling-evoked activation of BAT SNA, BAT temperature, expired CO2, HR, shivering EMG,
and rat-tail sympathetic discharge. [Modified from Ref. 56; and modified from Ref. 59 with permission from Nature Publishing Group.] D–F: disinhibition of
neurons in rRPa (arrow in inset) increases BAT SNA, BAT temperature, expired CO2, HR, EMG activity, and rat sural CVC sympathetic discharge. G: rRPa
contains neurons, some of which are serotonergic, that are retrogradely infected following pseudorabies virus injections into BAT. py, pyramidal tract. [Modified
from Ref. 12 with permission from Wiley.]
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of these express the EP3 receptor (61), suggesting that at least
the febrile activations of BAT and shivering thermogenesis and
of CVC are activated by relief of a tonic inhibition from
separate populations of POA neurons.
Rostral raphe pallidus area contains premotor neurons for
thermoregulatory effectors. Activation of neurons in the rRPa
is required for skin-cooling (Fig. 7, A–C) and febrile activations of BAT and shivering thermogenesis, of heart rate, and
of CVC heat retention (6, 41, 45, 55, 56, 66 – 68, 78, 91, 92).
Consistent with these effects, activation or disinhibition of
neurons in the rRPa (Fig. 7, D–F) elicits pronounced increases in BAT SNA, BAT thermogenesis, and shiveringlike EMGs, in heart rate and in CVC (6, 7, 14, 46, 52, 54,
63, 65, 69, 79, 102). The rRPa is a prominent site of neurons
that multisynaptically innervate BAT (Fig. 7G), skeletal
muscle, and cutaneous blood vessels (4, 12, 34, 35, 54, 64,
86, 93, 98). Together, these data indicate that neurons in the
rRPa and the immediately surrounding rostral ventromedial
medulla play a key role as sympathetic and somatic premotor neurons controlling BAT and shivering thermogenesis
and CVC—- providing essential excitatory drives to activate
spinal motor networks during cold defense and fever
(Fig. 1).
Spinal sympathetic mechanisms controlling thermal effectors. The
levels of BAT, cardiac, and shivering thermogenesis, and cuta-
1145
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1146
CNS PATHWAYS FOR COLD DEFENSE
the cold-evoked and rRPa stimulus-evoked increases in
BAT SNA and BAT thermogenesis (40) and in CVC sympathetic outflow (65), although with different 5-HT receptor
profiles, consistent with different synaptic mechanisms and
postsynaptic targets (Fig. 1) for the spinal 5-HT regulation
of different thermal effectors.
SUMMARY AND PERSPECTIVES
The principal thermoregulatory effectors for cold defense
are the cutaneous blood vessels for control of heat loss and the
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Fig. 8. Spinal glutamatergic and serotonergic neurotransmission play significant roles in the activation of rat BAT and CVC sympathetic outflows.
A: injection of the glutamate receptor antagonists, AP5 and CNQX, into the
spinal intermediolateral nucleus (IML) prevents the increase in BAT temperature evoked by disinhibition, with bicuculline injection, of neurons in the
rRPa. [Modified from Ref. 54 with permission from Society for Neuroscience.]
B: injection of serotonin (5-HT) into the IML produces a marked and longlasting potentiation of the activation of BAT SNA evoked by IML injection of
NMDA. [Modified from Ref. 43 with permission from Wiley.] Note the long
latency (⬃20 min) activation of BAT following the injection of 5-HT into the
IML, which was eliminated by methysergide injection into the IML (43).
C: application of the 5-HT2A receptor antagonist, SR46349B, to the dorsal
surface of the upper thoracic spinal cord reduces the amplitude of the potentials
evoked in the sympathetic nerve to the rabbit ear by electrical stimulation in
the RPa, and subsequent application of the glutamate receptor antagonist,
kynurenate, eliminated the remaining RPa-evoked sympathetic activation.
[Modified from Ref. 65.]
BAT and skeletal muscle for thermogenesis. The activation of
these effectors is strongly influenced by shared cutaneous
thermal afferent signals that drive parallel but distinct, effectorspecific efferent pathways (Fig. 1). Cutaneous thermal sensory
pathway includes synapses in the spinal dorsal horn leading to
glutamatergic activation of neurons in the lateral parabrachial
nucleus, where cool and warm afferent signals are processed
within anatomically distinct regions with projections to the
POA. Within the POA, different, effector-specific populations
of warm-sensitive, GABAergic projection neurons, provide the
substrate for the integration of local (sometimes called “core”)
temperature and of thermal sensory inputs, arriving via inputs
from LPB, to influence the activation of each type of thermoregulatory effector. Different thermal sensitivities among populations of temperature-sensitive POA neurons may allow
differential responsiveness of different effectors to changes in
cutaneous vs. brain temperatures. How these differing thermal
sensitivities may be altered under a variety of perturbing
alterations in the external or internal thermal and neurochemical environments remains unknown.
The core efferent pathway for thermoregulatory activation of
BAT thermogenesis and heart rate involves a tonically active
inhibitory input from the POA to sympathoexcitatory neurons
in the DMH, which project to sympathetic premotor neurons in
the rRPa, which, in turn, provide the excitatory drive to
sympathetic preganglionic neurons in the thoracic spinal cord
that is transmitted via sympathetic ganglion cells to brown
adipocytes and to cardiac pacemaker cells. A similarly organized core effector pathway is indicated for the control of
shivering thermogenesis, although additional experimentation
is necessary to define this circuit. The core efferent pathway for
CVC also involves a tonically active inhibition emanating from
the POA. However, these POA projection neurons send axons
to the rRPa where they influence the discharge of CVC sympathetic premotor neurons and, consequently, the level of
excitation to CVC sympathetic preganglionic neurons to elicit
cutaneous vasoconstriction. Identifying key structures within
each of these core thermoregulatory pathways provides a
framework for increased understanding of the sites and mechanisms through which body temperature regulation is influenced by a wide variety of neurotransmitters, peptides, cytokines, and genetic, nutritional, and perinatal (51) manipulations.
Within these core efferent pathways controlling thermoregulatory effectors, the sources and mechanisms responsible for
the tonic discharge of key neuronal populations and for the
synchronous bursting that characterizes the sympathetic outflows are unknown. Similarly puzzling is the neural basis for
the rapidly oscillating EMG signal during shivering. The sites
and mechanisms underlying the critical integration of thermogenesis with other homeostatic systems regulating oxygen and
fuel substrate availability, body water, salt appetite, and energy
balance remain to be investigated. The projection neurons
connecting important regions in the central thermogenic pathways have yet to be characterized, including the inhibitory
output neurons of the POA, the excitatory output neurons in the
DMH, and the sympathetic premotor neurons in the rRPa
region of the rostral ventromedial medulla. The marked differences in temperature response thresholds among thermoregulatory effectors suggests that significant differences should be
expected among the populations of warm-sensitive POA pro-
Review
CNS PATHWAYS FOR COLD DEFENSE
jection neurons that control these effectors. We expect that the
model circuit for central thermoregulatory control (Fig. 1) will
be embellished and corrected as we gain a further understanding of the functional organization of the central neural pathways that transmit ambient temperature signals, the hypothalamic networks that receive and integrate them with brain
temperature information, and the circuits through which the
various patterns of thermal effector responses are orchestrated
to sustain a homeostatic brain temperature.
GRANTS
The author is grateful for the institutional support of the research that
contributed to this review: National Institutes of Health Grants NS-40987 and
DK-57838.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
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