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Joseph A. DiMicco and Dmitry V.

Zaretsky
Am J Physiol Regulatory Integrative Comp Physiol 292:47-63, 2007. First published Sep 7, 2006;
doi:10.1152/ajpregu.00498.2006

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The cold path to BAT
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Am J Physiol Regul Integr Comp Physiol 292: R47–R63, 2007.
First published September 7, 2006; doi:10.1152/ajpregu.00498.2006. Invited Review

CALL FOR PAPERS Physiology and Pharmacology of Temperature Regulation

The dorsomedial hypothalamus: a new player in thermoregulation


Joseph A. DiMicco and Dmitry V. Zaretsky
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana
Submitted 14 July 2006; accepted in final form 1 September 2006

DiMicco, Joseph A., and Dmitry V. Zaretsky. The dorsomedial hypothalamus: a new
player in thermoregulation. Am J Physiol Regul Integr Comp Physiol 292: R47–R63, 2007.
First published September 7, 2006; doi:10.1152/ajpregu.00498.2006.—Neurons in the
dorsomedial hypothalamus (DMH) play key roles in physiological responses to extero-
ceptive (“emotional”) stress in rats, including tachycardia. Tachycardia evoked from the
DMH or seen in experimental stress in rats is blocked by microinjection of the GABAA
receptor agonist muscimol into the rostral raphe pallidus (rRP), an important thermo-
regulatory site in the brain stem, where disinhibition elicits sympathetically mediated

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activation of brown adipose tissue (BAT) and cutaneous vasoconstriction in the tail.
Disinhibition of neurons in the DMH also elevates core temperature in conscious rats
and sympathetic activity to least significant difference interscapular BAT (IBAT) and
IBAT temperature in anesthetized preparations. The latter effects are blocked by
microinjection of muscimol into the rRP, while microinjection of muscimol into either
the rRP or DMH suppresses increases in sympathetic nerve activity to IBAT, IBAT
temperature, and core body temperature elicited either by microinjection of PGE2 into
the preoptic area (an experimental model for fever), or central administration of
fentanyl. Neurons concentrated in the dorsal region of the DMH project directly to the
rRP, a location corresponding to that of neurons transsynaptically labeled from IBAT.
Thus these neurons control nonshivering thermogenesis in rats, and their activation
signals its recruitment in diverse experimental paradigms. Evidence also points to a role
for neurons in the DMH in thermoregulatory cutaneous vasoconstriction, shivering, and
endocrine adjustments. These directions provide intriguing avenues for future explo-
ration that may expand our understanding of the DMH as an important hypothalamic
site for the integration of autonomic, endocrine, and behavioral responses to diverse
challenges.
brown fat; sympathetic nervous system; body temperature; fever; raphe pallidus

THERMOREGULATION IN MAMMALS is a vital process orchestrated by (see also Ref. 7), and cutaneous vasoconstriction, a mechanism
the central nervous system through endocrine, autonomic, and used by both these species, as well as other mammals. These
behavioral mechanisms. One of the first regions of the brain to be effects that serve to generate body heat and regulate heat loss,
linked with this process was the preoptic area (POA), an area that respectively, are sympathetically mediated and accompanied by
is not only the location of temperature sensitive neurons but adrenergic cardiac stimulation (35, 63, 125, 194), which is thought
receives and integrates input from ascending neural pathways to aid in the distribution of heat generated in thermogenic regions
carrying information derived from sensory receptors in the pe- (i.e., brown fat) and by contraction in skeletal muscle (i.e.,
riphery (for reviews see refs. 21, 80, 112). The result is a shivering). In addition to these sympathetic actions that could be
coordinated array of adaptive changes that involve multiple sys- viewed as constituting rapid adjustments, exposure to cold results
tems and are aimed at maintaining and stabilizing body temper- also in characteristic endocrine effects in mammals. These include
alterations of thyroid function (15, 61) and activation of the
ature. Although the POA plays a similar role in virtually all
hypothalamo-pituitary-adrenal axis to increase circulating glu-
mammals, the specific means through which normothermia is
cocorticoids (106, 153, 190, 206), actions, which together pro-
attained may vary in different species. In rats, normothermia in a mote an array of metabolic effects in support of the increased
cold environment is maintained in part through metabolic activa- thermogenic needs of the organism. Finally, somatic motor nerves
tion of brown adipose tissue (BAT) (105; for a review, see Ref. promote the generation of heat by skeletal muscle through shiv-
27), a tissue whose existence and significance in adult humans has ering (23, 39, 180, 190).
been the subject recently of considerable controversy and interest Over the past half century, a number of brain regions have
been implicated in the circuitry downstream from the POA that
Address for reprint requests and other correspondence: J. A. DiMicco,
Indiana Univ. School of Medicine, Dept. of Pharmacology and Toxicology, The costs of publication of this article were defrayed in part by the payment
635 Barnhill Dr., Rm. MS A417, Indianapolis, IN 46202 (e-mail: of page charges. The article must therefore be hereby marked “advertisement”
jdimicco@iupui.edu). in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

http://www.ajpregu.org 0363-6119/07 $8.00 Copyright © 2007 the American Physiological Society R47
Invited Review
R48 THE DORSOMEDIAL HYPOTHALAMUS AND THERMOREGULATION

might be involved in these various components of the system IBAT temperature in a later report (62), precludes a clear
outlined above. In recent years, the dorsomedial hypothalamus interpretation of the data. Indeed, a thorough understanding of
(DMH) has rapidly emerged as an area of considerable interest precisely which neural elements are activated by intracerebral
with regard to certain of these thermoregulatory mechanisms. electrical stimulation, as well as the exact mechanism for this
In this review, we summarize the evidence in support of a role activation, has proven elusive for decades (see Ref. 158). This
for the DMH in thermoregulation and dysregulation in mam- and the possibility of effects resulting from spread or diffusion
mals, principally, with respect to thermoregulatory mecha- of microinjected drugs to adjacent regions (see below) under-
nisms that are sympathetically mediated. However, we will mine the rationale for this earlier conclusion that activation of
also briefly consider evidence that dimly, but intriguingly, neurons in the VMH results in nonshivering thermogenesis.
illuminates the possibility of a role for neurons in the same In spite of the uncertainty regarding the interpretation of the
region in thermoregulatory adjustments that involve endocrine results of electrically stimulating and lesioning specific sites in
and somatomotor effects. As we will use the term, the thermo- the brain, experiments using these approaches provided the
regulatory DMH indicates a region of the hypothalamus that first indication that neurons in the DMH might play a role in
includes the dorsomedial hypothalamic nucleus (DMN) but thermoregulation. Historically, the DMH had been implicated
also extends into adjoining areas, particularly dorsal and per- in feeding and metabolic regulation associated with ingestive
haps posterior to the nucleus itself, as defined in the current behavior (for a review, see Ref. 12), phenomena closely linked
standard atlas (154). Indeed, as we will suggest below, the to thermoregulation for decades (70, 105, 169). Consequently,
specific neurons that may be relevant to thermoregulation the finding that IBAT weight was significantly reduced in rats
probably do not correspond precisely to any of the classically with lesions of the DMH (13) was interpreted only in this

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delineated hypothalamic nuclei or regions. context. In fact, increases in BAT mass are known to reflect
thermogenic accommodation to a cold environment that is
Search for a Hypothalamic “Thermogenic Center” sympathetically mediated (133, 164). A more direct link be-
tween the DMH and thermogenesis in BAT was posed by
Three decades ago, the notion of a hypothalamic region studies in which electrical stimulation of the VMH had no
distinct from the POA had not been integrated into the “black effect on IBAT temperature, while stimulation of the DMH (as
box” model of the brain in thermoregulation (see Refs. 24 and well as several other hypothalamic regions) increased it (62).
75). Nevertheless, it soon became clear that additional compo- Active sites of stimulation seemed to represent a continuous
nents linking temperature-sensitive neurons in the POA to band extending caudally from the preoptic area through the
appropriate effector outputs were needed to provide a cogent anterior hypothalamus, hypothalamic paraventricular nucleus
operational framework. The first hypothalamic region to re- (PVN) and DMH. Consequently, the authors surmised that
ceive serious consideration in this regard was the ventromedial observed thermogenic effects resulted from activation of fibers
hypothalamus (VMH). Electrical stimulation of the VMH was of passage emanating caudally from the preoptic area. (Curi-
found to elicit increased norepinephrine turnover and thermo- ously, however, they suggested that this pathway was inhibi-
genesis in IBAT (79, 88, 95, 157, 171, 215) and to increase tory to brain stem thermogenic mechanisms, a conclusion
markedly and specifically blood flow in this tissue (90). Con- seemingly at odds with their results.)
versely, electrolytic lesion of the VMH abolished cold-induced The potential for stimulation of fibers of passage was, in
increases in sympathetic nerve activity to IBAT (142), while fact, largely responsible for the abandonment of electrical
microinjection of the local anesthetic lidocaine into the region stimulation in favor of chemical stimulation, generally
of the VMH reduced the increase in IBAT temperature evoked achieved by local microinjection of highly concentrated solu-
by cooling or stimulation of the POA (90). Within this body of tions of glutamate or other excitatory amino acids (68). Studies
literature, the hypothesis that the VMH comprises a second using this approach reported that microinjection of glutamate
hypothalamic “thermogenic center” seems to have been estab- into either the VMH, the PVN, or the PH—regions virtually
lished by earlier reports, and this notion clearly influenced the surrounding the DMH—increased IBAT temperature in anes-
interpretation of the results of many of the studies that fol- thetized rats (2– 4, 71). Amir (4) also reported that similar
lowed. For example, when electrical stimulation of either the microinjection of the GABAA receptor antagonist bicuculline
VMH or the DMH was found to elevate IBAT temperature, methiodide (BMI) 50 ng, or ⬃100 pmol, into the PH increased
attention was focused on the VMH, nonetheless (95). Simi- core and IBAT temperature. Assuming that the results of these
larly, Thornhill and colleagues (204) found that microinjection studies represent actions of glutamate or BMI on neurons as
of lidocaine into either the VMH or the nearby posterior opposed to fibers of passage, they clearly suggested that
hypothalamus (PH) reduced the increase in IBAT temperature activation of hypothalamic neurons located outside of the
evoked from the POA in anesthetized rats, calling into question preoptic area could elicit sympathetically mediated activation
the relevant site of action for the microinjected agent, and of BAT. However, without appropriate anatomic controls and
neither report using lidocaine in this manner addressed the given the ambiguity regarding the exact delineation of PH vs.
potential for affecting fibers of passage with this approach. DMH (see below and Ref. 184), the precise location of the
Furthermore, the increases in IBAT temperature that were relevant neurons remained unclear. Even less illuminating
produced by electrical stimulation of the VMH in many of were the results of Yoshimatsu and colleagues (219), who
these studies were typically preceded by small, but consistent, studied the effects of microinjections of glutamate into several
decreases, a fact that seems to have been often, but not always hypothalamic regions on sympathetic nerve activity to IBAT in
(see Refs. 212 and 213) ignored. The biphasic nature of the anesthetized rats. They reported a confusing array of stimula-
temperature response in this study, as well as the failure of tory, inhibitory, and biphasic responses, and that the predom-
electrical stimulation of the VMH to evoke any increase in inant response evoked from the DMH was inhibitory, a finding
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THE DORSOMEDIAL HYPOTHALAMUS AND THERMOREGULATION R49
that appears contradictory in light of more recent results role for the DMH in thermoregulation. The rRP, a midline
detailed below. An explanation may lie in the fact that micro- longitudinal region at the base of the medulla between the
injection of highly concentrated solutions of excitatory amino pyramids, as well as the adjacent parapyramidal area and
acids to excite local neurons may have just the opposite effect perhaps raphe magnus, was revealed to be an important loca-
(111), probably owing to depolarizing blockade. Accordingly, tion of sympathetic premotor neurons in circuits innervating
microinjection of NMDA into the DMH at doses in the range BAT and thermoregulatory cutaneous blood vessels from the
of 0.68 to 6.8 pmol evokes marked dose-related tachycardia in results of transsynaptic neuronal tracing studies (for a review
anesthetized rats, but doses only slightly higher (20 pmol) of the technique, see Refs. 10, 29, 137, 183, 186). Moreover,
produce a lower response, and doses higher still (60 pmol) had functional studies had clearly demonstrated that activation— or
little or no effect on heart rate (184). Thus the relevant disinhibition— of neurons in the rRP by local microinjection of
sympathoexcitatory neurons in the DMH may be unusually BMI resulted in dramatic increases in sympathetic nerve ac-
sensitive to glutamate receptor agonists so that microinjection tivity to IBAT and increases in IBAT temperature and metab-
of excitatory amino acids at the millimolar concentrations olism, as well as in anesthetized rats (128, 129, 132). However,
typically used fail to evoke increased activity (see also ref. 49). it was also noted that these effects were accompanied by
Therefore, studies using the technique of microinjection of tachycardia and modest increases in blood pressure (132),
glutamate did little to clarify the specific location of the replicating the pattern of cardiovascular changes evoked by
hypothalamic neurons controlling sympathetic activity to BAT activation of the DMH or by stress in this species.
or to suggest that DMH might be a prime candidate in this Subsequent studies provided support for the notion that key
regard. However, microinjection of calcitonin gene-related sympathoexcitatory effects of activating neurons in the DMH

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peptide (CGRP) into the either the DMH or the VMH in were in fact mediated through neuronal activity in the rRP and
urethane-anesthetized rats evoked sharp increases in IBAT and that a direct projection from neurons in the former region to the
core body temperature, oxygen consumption, and heart rate latter might be involved. The sympathetically mediated tachy-
(101). The authors demonstrated a degree of anatomical spec- cardia that could be evoked by microinjection of BMI into the
ificity for the effect—similar injections into the POA or the DMH was mimicked by similar disinhibition of neurons in the
PVN were ineffective— but failed to resolve the region further rRP (30, 166) and was suppressed by 30 – 60% after microin-
or to pursue the suggestion that the DMH might represent a jection of muscimol into the latter region (30, 81, 172). Fur-
hypothalamic thermogenic region of some significance. In- thermore, specific sites in the DMH shown to be most sensitive
stead, the bias toward a focus on the VMH is evident in both to the tachycardic effects of “nanoinjections” of BMI at a
the design of their studies, the results selected for representa- reduced dose (2 pmol) and volume (5 nl) corresponded closely
tion, and the tenor of the discussion in this work. Nevertheless, to the area where neurons projecting to the rRP were most
the DMH was now added to the list of hypothalamic regions highly concentrated (173; see Fig. 1). Thus sympathetically
that might represent upstream sites involved in the control of mediated tachycardia seen in stress may be mediated, at least in
nonshivering thermogenesis in rats (135). part, through excitatory projections from the DMH to the rRP,
a pathway originating principally from a dense collection of
DMH Emerges as a Key Hypothalamic neurons in the dorsal area of the former region that had already
Sympathoexcitatory Region been well described and characterized anatomically (85– 87).
However, given the recent elucidation of the rRP as a key
The search for the precise location of one or more hypotha- medullary site for sympathetic control of BAT and cutaneous
lamic sympathetic thermogenic areas was thus set against the vasoconstriction, these findings also suggested that neurons in
backdrop of a confusing array of data, suggesting a wide the DMH might constitute the hypothalamic thermoregulatory
number of possibilities that principally included the PVN, the site whose existence had been suggested more than two de-
PH, and the VMH. As indicated above, however, these three cades earlier.
areas together bracket and surround the DMH, a region that by
the end of the last century had emerged as a major integrative DMH and Thermoregulatory Mechanisms: Sympathetic
site for the classic defense reaction and responses to experi- Activation of Brown Fat
mental exteroceptive stress (for a review, see Ref. 50). Thus, in
conscious rats, disinhibition of neurons in the DMH by local Zaretskaia and colleagues (221) provided the first clear
microinjection of BMI—at doses less than one-tenth of the evidence that activation of neurons in the DMH could dramat-
dose used by Amir (4) to evoke thermogenesis in the PH ically alter body temperature through a classic thermoregula-
— evokes an array of autonomic, behavioral, and endocrine tory mechanism. They demonstrated that, in addition to auto-
response, typically seen in stress, among these being marked nomic, endocrine, and behavioral effects already described,
sympathetically mediated tachycardia (9, 45, 184). Conversely, microinjection of BMI into the DMH markedly elevated core
local microinjection of muscimol, an inhibitor of the vast body temperature in conscious freely moving rats at room
majority of mammalian neurons by virtue of its agonist prop- temperature (Fig. 2). In urethane-anesthetized rats, similar
erties at GABAA receptors, virtually abolished the sympathet- microinjections evoked rapid and dramatic increases in IBAT
ically mediated increases in heart rate seen in experimental air temperature that preceded and exceeded the responses in core
jet stress (191, 192). temperature (Fig. 3), suggesting that the former was at least
Most importantly, the brain stem pathway mediating DMH- partly responsible for the latter. Most importantly, a dose of 10
evoked cardiac stimulation was subsequently found to involve pmol of BMI in 100 nl was used— one-tenth the dose and less
the region of the rostral raphe pallidus (rRP) in the medulla than half the volume injected by Amir and colleagues into the
(172), a discovery that provided the first strong indication of a PH as discussed above—and identical microinjections into the
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Fig. 1. Photomicrograph (above) and schematic diagrams (below) depicting coronal sections of rat brains through the dorsomedial hypothalamus (DMH) from
different studies. A: fluorescence micrograph depicting neurons in the DMH transsynaptically infected with pseudorabies virus (PRV) injected into interscapular
brown adipose tissue. LH, lateral hypothalamic area; DMD, dorsomedial hypothalamic nucleus, dorsal; VMH, ventromedial hypothalamic nucleus. Calibration
bar ⫽ 100 ␮m. B: cold-induced fos expression in same region of DMH in a different rat. C: schematic depicting distribution of neurons transsynaptically labeled
(PRV) in a representative experiment; open squares represent one infected neuron, and solid squares indicate five labeled neurons. PH, posterior hypothalamic
area; LHA, lateral hypothalamic area; ARC, arcuate nucleus; PAA, periarcuate area. D: schematic coronal section depicting on the left the distribution of neurons
retrogradely labeled from the rostral raphe pallidus in a representative experiment on the left (each solid circle representing a single labeled neuron), and on the
right a series of injection sites compiled from different experiments in anesthetized rats coded to represent the magnitude of the increase in heart rate evoked
by microinjection of bicuculline methiodide (BMI) 2 pmol in 5 nl at each site: solid circles, more than 50 beats/min; shaded squares ⫾25– 49 beats/min; open
triangles, less than 25 beats/min. mt, mammillothalamic tract, f, fornix. [A and B from Cano et al. (29), C from Yoshida et al. (217), D from Samuels et al. (173)]

VMH or the PVN failed to affect either core or IBAT temper- DMH (33). Microinjection of kynurenate, a nonselective an-
ature. Thus inclusion of the appropriate anatomical control data tagonist of all ionotropic glutamate receptors, rapidly (i.e.,
that were missing from earlier studies ruled out the possibility within 5 min of injection) and completely abolished BMI-
that the effects noted may have been a consequence of spread induced increases in sympathetic nerve activity to IBAT and
or diffusion of BMI to either region. attenuated the accompanying increases in IBAT temperature
Subsequently, Cao and colleagues (31) performed detailed without affecting increases in heart rate, arterial pressure, and
experiments in anesthetized animals that confirmed and extended renal sympathetic nerve activity. Injection of AP5 or of CNQX,
these findings by characterizing further the thermogenic response antagonists with the capacity for relative selectivity against
to disinhibition of the DMH and establishing the role of the rRP NMDA vs. non-NMDA subtypes of ionotropic glutamate re-
in these changes. Microinjection of BMI (60 pmol) into the DMH ceptors, respectively, elicited effects similar to those of kynure-
dramatically elevated IBAT, renal, and cardiac sympathetic nerve nate. These findings thus suggest that DMH-induced sympa-
activity, as well as heart rate and blood pressure, and these thetic activation of BAT is mediated at least, in part, through
elevations were associated with marked increases in IBAT tem- stimulation of ionotropic glutamate receptors in the rRP.
perature and expired CO2, a reflection of increased metabolic A close examination of the results of published anatomic
activity in BAT and, perhaps, the heart as well (Fig. 4). DMH- tracing studies provides supporting evidence that neurons in
evoked increases in IBAT temperature, IBAT sympathetic nerve the DMH are contributors to sympathetic activation of BAT
activity, and metabolism were greatly attenuated or abolished by and thus play a role in thermoregulation. Most relevant are
microinjection of muscimol into the rRP, implying that activation those studies in which the transneuronal tracing technique
of sympathetic premotor neurons in the latter region played a based upon sequential transsynaptic infection by pseudorabies
dominant role in these changes. On the other hand, although peak virus (PRV) was applied to elucidate central pathways project-
increases in heart rate were significantly reduced, increases in ing to IBAT, all of which reported labeling in the DMH (10,
renal or cardiac sympathetic nerve activity and in blood pressure 29, 31, 137, 147, 217). In fact, the results shown in one such
were unaffected. The marked effect of microinjection of musci- report indicate a particularly dense collection of PRV-infected
mol into the rRP on IBAT temperature and sympathetic nerve neurons in the region of the DMH just dorsal to the DMN and
activity clearly points to a critical role for neuronal activity in the extending somewhat ventrally into the latter nucleus itself
region in the thermogenic response. (217; Fig. 1). This distribution, suggested by the authors as
More recently, Cao and Morrison have provided insight into being in the PH, closely matches that of neurons retrogradely
the nature of the excitatory signaling through which disinhibi- labeled directly from the rRP, in what was previously identified
tion of neurons in the DMH activates thermogenic mechanisms as the dorsal hypothalamic area (77, 85, 143, 173), as well as
in the rRP. In anesthetized rats, they explored the effect of that of sites most sensitive to the cardiac sympathoexcitatory
microinjection of glutamate receptor antagonists into the rRP effect of microinjected BMI (173; Fig. 1). Together, these
with respect to responses to microinjection of BMI into the results indicate that neurons that project directly to the rRP and
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THE DORSOMEDIAL HYPOTHALAMUS AND THERMOREGULATION R51
(44) studied the effect of inhibiting neurons in the cPAG on
responses evoked from the DMH in conscious rats. Microin-
jection of muscimol into the cPAG not only reduced the
DMH-induced increases in heart rate and locomotor activity
but also suppressed the associated increases in body tempera-
ture (Fig. 5). Although de Menezes and colleagues targeted a
different subregion of the cPAG than did Chen and coworkers
(36, 37) (i.e., the lateral/dorsolateral vs. the lateral/ventrolateral
PAG), it seems likely that, given the anatomic resolution
possible with the microinjection techniques used, the same
neurons were involved in all effects described. Interestingly,
neurons retrogradely labeled from the cPAG were found in the
area of the dorsal DMH corresponding to that where rRP-
projecting neurons are concentrated, and these same neurons
were shown to express fos in response to exposure to a cold
environment (10°C; 218). These results suggest that neurons in
the same region of the DMH project to the rRP both directly
and indirectly through a neuronal relay in the cPAG and that
thermogenesis in BAT may be a consequence of activating either

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pathway. Whether the same hypothalamic neurons project to both
downstream thermogenic regions is currently unknown.
Just as neurons in the DMH are positioned to signal
sympathetic premotor neurons in the rRP that regulate the
activity of BAT through these efferent pathways, they are
also known to receive afferent input from regions that may
be relevant to thermoregulation (for a review, see Ref. 202).
Principal among these is the POA, a region of prime
importance with regard to thermoregulation. In tracing stud-
ies, the POA has been identified as the region containing the
largest number of neurons retrogradely labeled from the
DMH (202). Many neurons in the POA are known to be
GABAergic (146), and those that are relevant to thermoreg-
ulation are thought to exert tonic inhibition of downstream
elements important for activation of BAT (36). As discussed
Fig. 2. Effect of unilateral microinjection of BMI 10 pmol/100 nl (n ⫽ 6) and
above, microinjection of BMI, a GABAA receptor antago-
saline (n ⫽ 6) into the DMH on core body temperature, heart rate, blood nist, is an efficient means of evoking activation of neurons
pressure, plasma ACTH, and locomotor activity in conscious rats. Bars and in the DMH that are involved in sympathetic control of
asterisks indicate significant differences between BMI and saline treatment by IBAT, suggesting that these neurons are restrained by tonic
repeated measures ANOVA and Fisher’s least significant difference test. [from GABAergic inhibition under normal circumstances. Re-
Zaretskaia et al. (221)]
cently, neurons in the DMH retrogradely labeled from the
rRP were found to receive GABAergic projections originat-
polysynaptically to IBAT are found in the same region of the ing in the POA (138). Thus GABAergic neurons in the POA
DMH—a region to which various labels have been appended. are likely to provide a key source of the tonic inhibitory
Thus both anatomic and functional experiments support the input to sympathoexcitatory neurons in the DMH that was
existence of direct projections from the DMH to the rRP, the first implied by experimental findings two decades ago (47).
activation of which results in sympathetically mediated ther-
mogenesis in BAT. Clearly, much of our knowledge regarding DMH and Thermoregulatory Mechanisms: Sympathetic
the role of the DMH in thermoregulation is framed in the Cutaneous Vasoconstriction
functional context of these projections, and this notion has
already served to illuminate new paths for exploration as The clear evidence that neuronal activation in the DMH
detailed below. However, more recent studies suggest an al- elicits sympathetic thermogenesis through activation of BAT
ternative efferent pathway through which the DMH may exert and that this effect is mediated through the medullary rRP
significant thermogenic effects. Like neurons in the dorsal invites the possibility that cutaneous vasoconstriction, the other
DMH, neurons in the caudal periaqueductal gray (cPAG) are major sympathetic thermoregulatory mechanism apparently
retrogradely labeled from the rRP (77, 143), transsynaptically controlled from this region, might also be under similar de-
labeled from IBAT (10, 29, 217), and express fos after expo- scending control from the DMH. Cutaneous vasoconstriction
sure to cold (29). Chen and coworkers (37) reported that and vasodilation serve to conserve or dissipate body heat,
electrical or chemical stimulation of neurons in this region respectively, and so represent important thermoregulatory ad-
increases IBAT temperature in anesthetized rats, suggesting justments in mammals. The particular cutaneous region prin-
that neurons in the cPAG are interposed in neural circuits that cipally involved in this function may vary according to species.
can stimulate the activity of BAT. De Menezes and colleagues In rabbits, the cutaneous circulation of the pinna is of primary
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Fig. 3. Left: effect of unilateral microinjection of BMI 10 pmol/50 nl into the DMH (solid symbols), the paraventricular nucleus (PVN; open symbols), or the
VMH (shaded symbols) on core (triangles) and interscapular brown adipose tissue (IBAT; squares) temperature, heart rate, and blood pressure in
urethane-anesthetized rats. Right: schematic coronal sections representing two levels of the DMH and depicting eight of the injection sites in the DMH and all
six injection sites into the VMH from the experiments at left. Solid circles denote an increase in both core and IBAT temperature accompanied by increases in
heart rate of at least 40 beats/min; open circles denote no effect on temperature and increase in heart rate of less than 40 beats/min; open triangles denote no
effect on temperature or heart rate. Numbers indicate distance from bregma in millimeters. [from Zaretskaia et al. (221)]

importance (98, 197), while in rats, blood flow to the tail serves blood flow in the pinna by more than 80% but mesenteric blood
this purpose (43, 74, 159, 193). As with sympathetic innerva- flow was reduced only by 50%. More importantly, the reduction
tion of BAT, the rRP appears to represent the brain stem in blood flow to the ear induced by hypothalamic stimulation was
location of sympathetic premotor neurons that specifically completely abolished by prior injection of muscimol into the rRP,
regulate these anatomically distinct but functionally analogous while the decrease in mesenteric blood flow was unaffected. This
circulations in these two species, i.e., the tail in rats (20, 137, finding suggests that a pinna-specific vasoconstrictor pathway
149, 151, 152, 160, 161, 183, 196) and the pinna in rabbits (17, from the DMH to the rRP may exist in rabbits. However, the
19, 140, 149, 150). limitations regarding the interpretation of results from electrical
The hypothesis that neurons in the DMH play a role in ther- stimulation studies discussed above make a connection with
moregulatory vasoconstriction mediated through the rRP has not neurons in the DMH tenuous. Thus a likely possibility—and one
been explicitly examined, but recent reports provide some sup- ripe for investigation—is that, in rats, activation of neurons pro-
portive evidence. In a transsynaptic retrograde tracing study in jecting from the DMH to the rRP elicits cutaneous vasoconstric-
rats, substantial labeling was consistently seen in the DMH—and tion in the tail and that this pathway participates in thermoregu-
more specifically in the dorsal hypothalamic area and, to a lation.
somewhat lesser degree, in the DMN—7 days after injection of
pseudorabies virus into the wall of the rat tail artery (183). DMH and Thermoregulatory Mechanisms: Beyond the
Electrical stimulation of the DMH was subsequently reported to Sympathetic Nervous System?
decrease blood flow in the ear of anesthetized rabbits (97, 148).
Nalivaiko and Blessing (139) found that electrical stimulation of Although sympathetic innervation of brown fat and the
the region of the DMH in anesthetized paralyzed rabbits reduced cutaneous blood flow to the tail play a key role in rapid
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THE DORSOMEDIAL HYPOTHALAMUS AND THERMOREGULATION R53

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Fig. 4. Effect of microinjection of muscimol into the rostral raphe pallidus (RPa) on responses evoked by microinjection of bicuculline (BIC) into the DMH in
anesthetized rats. A: microinjection of bicuculline into DMH (dashed vertical line) elicits marked increases in IBAT sympathetic nerve activity (iBAT SNA) and
temperature (BAT Temp), as well as expired CO2 (Exp CO2), reflecting increased metabolic activity, cardiac sympathetic nerve activity (iCSNA), heart rate (HR),
renal sympathetic nerve activity (iRSNA), and mean arterial pressure (MAP) in a representative experiment. B: similar injection of BMI after microinjection of
muscimol into the RPa in the same experiment fails to increase IBAT SNA or temperature or to increase expired CO2, while the effects on cardiac indices are
modestly reduced, and renal SNA and MAP are unaffected. C: Data from 4 –9 experiments averaged over time. [from Cao et al. (31)]

thermoregulatory responses in the rat, other systems are also thought to be through neurons in the hypothalamic PVN (for
involved in the maintenance of body temperature. This is reviews, see Refs. 58, 76, 175). The parvocellular PVN, the
particularly true in humans where, in adults, the significance of principal location of neurons that contain corticotrophin-releasing
brown fat is currently a subject of some debate (see Refs. 7 and hormone and so control the secretion of ACTH, represents a
27). What other systems, then, are considered “thermogenic” in principal hypothalamic target for efferent projections from the
our own species? DMH in the rat (200, 201), and some of these projections are
First, endocrine mechanisms are known to play at least a known to contact thyrotropin-releasing hormone-containing neu-
supporting metabolic role in thermoregulatory responses. These rons in this region (121). Disinhibition of the DMH results in
mechanisms include the adrenal cortex, where secretion of glu- increased fos expression in the PVN and elevated plasma ACTH
cocorticoids has wide-ranging metabolic effects, and the thyroid (9, 48, 221; see Fig. 2 of this article), whereas inhibition of
gland, the hormones of which are thought to increase the meta- neurons in the DMH suppresses the increases in plasma ACTH
bolic rate in general and are specifically permissive for heat and in fos expression in the parvocellular PVN seen in experi-
generation through the induction of uncoupling protein 1 in BAT mental (air jet) stress in rats (127, 192). Thus the activation of the
and perhaps other tissues (15, 106, 108, 195). The activity of both PVN that occurs in this stress paradigm appears to be signaled
glands is under central control by neurons that regulate the release from neurons in the DMH. Accordingly, experimental stress
of the pituitary trophic hormones ACTH and thyrotropin, respec- increases fos expression in neurons in the DMH that are retro-
tively, and the final common pathway controlling their release is gradely labeled from the PVN (42, 110). Intravenous administra-
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R54 THE DORSOMEDIAL HYPOTHALAMUS AND THERMOREGULATION

gram was recorded while body temperature was permitted to


fall, and the resulting activity was usually (but not always)
abolished by microinjection of muscimol into the DMH, the
adjacent dorsal hypothalamus, and the dorsomedial region of
the adjoining PH (195). Although a more precise location of
the relevant neurons was unclear from the results presented, the
reactive region clearly included the same area of the DA/DMH
where putative thermoregulatory neurons projecting to the rRP
and to the PAG are found. Even more recently, the increase in
the activity of fusimotor fibers to the gastrocnemius elicited by
cooling of the trunk skin in anesthetized rats—a response
thought to be the mechanism responsible for thermoregulatory
shivering—was blocked by microinjection of the inhibitory
amino acid glycine into the rRP (197). This finding indicated
that, in addition to its well-established role in sympathetic
thermoregulatory mechanisms, neurons in the rRP may func-
tion in nonsympathetic thermoregulatory responses as well.
That the same may be true of neurons in the DMH that project

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to the rRP has been recently suggested by the report of an
intriguing neuroanatomic link between the DMH and somato-
motor function. In a dual PRV transsynaptic tracing study from
the adrenal gland, a sympathetic component well known to be
activated in cold exposure (28, 46, 64, 84, 209), and the
sympathectomized gastrocnemius muscle in rats, double-la-
beled neurons were evident in only a few brain regions, and,
among these, were the DMH and cPAG (96). Thus neurons in
the DMH that project to the rRP are appropriately interposed in
anatomic circuits that could elicit shivering under appropriate
conditions, making this another appealing area for further
investigation.
Fig. 5. Effect of identical microinjection of BMI 10 pmol into the DMH on
body temperature (TEMP) and heart rate (HR) after microinjection of either
saline or muscimol (MUS) 100 pmol into ipsilateral sites in the caudal Involvement of DMH in Physiological and Pathophysiological
periaqueductal grey (cPAG; injection sites shown in schematics below) in the Thermoregulatory Phenomena: Cold Defense and Fever
same conscious rats. *Significant differences between muscimol and saline
treatments. d, dorsal; dl, dorsolateral; l, lateral; vl, ventrolateral. [from de Thus disinhibition of neurons in the region of the DMH
Menezes et al. (44)]
results in increases in body temperature at least, in part,
through 1) neuronal activity in the rRP and 2) sympathetically
tion of LPS, a powerful stimulus for activation of the PVN and mediated activation of BAT. In the brief period since the
release of plasma ACTH (for a review, see Ref. 11), also increases recognition of a potential role for neurons in the DMH in the
fos expression in neurons in the DMH that are retrogradely control of core body temperature, evidence has appeared for
labeled from the PVN (55). The latter finding indicates that their participation in thermoregulatory responses in several
neurons projecting from the DMH to the PVN are activated in this different settings where activation of BAT and/or cutaneous
model for fever. Whether this activation might play a role in the vasoconstriction has been implicated.
thermoregulatory mobilization of these hormonal systems under One such circumstance is cold defense, or the recruitment of
these or any other circumstances remains another unexplored but mechanisms that both generate and conserve body heat in a
intriguing direction for future study. cold environment. In rats, these include activation of BAT and
In addition to autonomic and endocrine mechanisms, hu- cutaneous vasoconstriction in the tail. Under such conditions,
mans and other mammals may also recruit the somatic motor increased fos expression, and so presumably neuronal activa-
outflow to generate heat through shivering. Neurons in the tion, has been reported in the DMH (8, 29, 119, 216). In
hypothalamus have been implicated in the generation of ther- urethane-anesthetized rats, intense fos expression was noted in
moregulatory shivering for decades (see Ref. 39), and earlier the DMH of rats kept at an ambient temperature of 5°C but not
electrical stimulation studies suggested that shivering could be at 23°C (119). In conscious rats, marked fos expression was
evoked from the VMH in conscious rabbits (126) and from the also noted specifically in the dorsal DMH, the same region
PH— but not the VMH—in anesthetized rats (72, 203). Other where neurons projecting to the rRP are known to be most
studies over the years have attempted to characterize the densely concentrated, after exposure to either 10°C (97) or 5°C
efferent pathway from the POA that mediates shivering using (216). Furthermore, the cold-induced fos expression in the
localized knife cuts and lesions (92, 93). Only recently, how- DMH was dramatically suppressed by warming of the POA
ever, has clear evidence appeared that neuronal activity in a (216), an observation consistent with the idea that temperature-
specific hypothalamic region downstream from the POA may sensitive neurons in the POA exert tonic inhibitory control over
play a role in shivering. In anesthetized rats, an electromyo- thermoregulatory neurons in the DMH (see Ref. 138).
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THE DORSOMEDIAL HYPOTHALAMUS AND THERMOREGULATION R55
Although these results suggest that neurons in the DMH are including the bacterial cell wall component LPS, trigger the
activated in exposure to cold, no study to date has shown that release of endogenous pyrogenic cytokines (see Ref. 53), and
this activation occurs specifically in neurons in the region that 2) these cytokines (and perhaps the exogenous pyrogens as
project to the rRP. However, Cano and coworkers (29) reported well) initiate increases in body temperature through an action
that in rats exposed to 4°C for 4 h, fos expression was clearly that ultimately involves generation of PGE2, acting in the
evident in the same region of the dorsal DMH, where neurons region of the POA (see Refs. 16, 41, 53, 168). Consequently,
transsynaptically labeled from IBAT are concentrated (Fig. 1). systemic administration of LPS replicates many of the features
Thus, not only are neurons that project directly to the rRP and of the acute phase response, including fever and so has become
polysynaptically to IBAT found in the same region of the a widely employed experimental paradigm in rats. Another
DMH but neurons in this region appear to be activated in cold well-accepted model for fever based upon the mechanism
exposure. Because of this finding, Cano and coworkers (29) proposed above is the central administration of PGE2, which
suggested that these neurons might play a key role in cold- reliably and markedly increases body temperature in rats when
induced thermogenesis. Evidence for their hypothesis has given either by intracerebroventricular infusion or microin-
emerged in the preliminary finding of Almeida and colleagues jected directly into the POA (5, 116, 127, 136, 144).
that rats with electrolytic lesions of the DMH are unable to The results of experiments that used this latter experimental
maintain normal body temperature in a cold environment (1). paradigm first suggested that the DMH might be involved in
However, given that such lesions destroy local fibers of pas- fever two decades ago. Zabawska and colleagues (220) at-
sage, as well as neurons, the hypothesis remains to be tested tempted to localize the central site of a putative cholinergic link
directly in appropriate functional studies. in the generation of hyperthermia elicited by microinjection of

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Another setting in which evidence of a role for the recruit- PGE2 into the POA. In conscious control rats, rectal tempera-
ment of thermogenic mechanisms through activation of the ture was elevated by more than 1.5°C 15 min after microin-
DMH has now appeared is fever. Fever, a regulated increase in jection of PGE2, and this effect was essentially abolished after
body temperature achieved by increasing the thermostatic set- microinjection of atropine sulfate into either the dorsal or
point, is a salient component of a host response to bacterial dorsomedial hypothalamus (fig. 6). The dose of atropine in-
infection that in mammals includes immunologic, autonomic, jected (5 ␮g, or ⬃7 nmol) was sufficiently high to call into
endocrine, and behavioral adjustments (for reviews, see Refs. question the pharmacological specificity of this effect, thus
73, 102, 115, 176). In rats, sympathetic activation of BAT and undermining the stated purpose of the study. Nevertheless,
cutaneous vasoconstriction play primary roles in the increases anatomic specificity was apparent since identical microinjec-
in temperature seen in experimental fever (65, 92, 166). Al- tions of atropine into the VMH or the thalamus dorsal to the
though there is agreement regarding many mechanistic aspects DMH failed to influence PGE2-induced hyperthermia.
of the febrile response and associated physiological changes, In contrast to the experiments of Zabawska and colleagues,
others remain the subject of debate today. Thus it is generally anatomic specificity appears to have been assumed in a subse-
acknowledged that 1) exogenous pyrogens of bacterial origin, quent study that used this same model for fever but focused on

Fig. 6. Left: effect of microinjection of


PGE2 (dashed lines) or saline (solid lines)
into the preoptic/anterior hypothalamic re-
gion (PO/AH) on rectal temperature mea-
sured at 15-min intervals in conscious rats
(n ⫽ 7 or 8/group) after treatment in the
DMH with saline vehicle (1 ␮l; circles) or
atropine (5 ␮g or ⬃7 nmol; triangles). Right:
schematic coronal section of the rat brain
depicting sites in the dorsal/dorsomedial hy-
pothalamic (DH; triangles) area, where mi-
croinjection of atropine blocked hyperther-
mia induced by injection of PGE2 into the
PO/AH in experiments at left. Also shown
are sites more dorsal, said to be in the thal-
amus (T; squares) and more ventral in the
ventromedial hypothalamus (VH; circles),
where identical microinjections of atropine
failed to influence PGE2-induced increases
in rectal temperature. [from Zabawska et al.
(220)]

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Invited Review
R56 THE DORSOMEDIAL HYPOTHALAMUS AND THERMOREGULATION

the VMH (5). Here, microinjection of muscimol into the VMH between sympathoexcitatory neurons in the DMH and those in
was reported to reduce markedly the increase in both IBAT the rRP (172). Together, these findings brought the potential
temperature and core temperature elicited by microinjection of role of the DMH in fever into focus.
PGE2 into the POA in anesthetized rats (5). However, in this In studies that paralleled those of the rRP, microinjection of
case, the site of action was simply assumed to be the VMH, muscimol into the DMH was indeed shown to suppress the
based upon the prevailing hypothesis that the VMH repre- febrile response evoked by microinjection of PGE2 into the
sented the primary hypothalamic site for sympathetic control of POA. Zaretskaia and colleagues (222) first showed that unilat-
BAT. In retrospect, this assumption clearly was clearly ill eral microinjection of muscimol into the DMH evoked an
conceived, especially given that the high dose of muscimol immediate suppression of the elevation in body temperature
(440 pmol) and large volume of injection in which it was elicited by injection of PGE2 into the ipsilateral POA in
delivered (500 nl) made it highly likely that neurons in sur- anesthetized rats. At the same time, injection of muscimol
rounding regions (such as the DMH) might be affected. produced a smaller, but significant, effect on the accompanying
Thus, although the report of Zabawska and colleagues, a increase in heart rate. This result was subsequently confirmed
study that included appropriate anatomic control experiments, in expanded studies by Madden and Morrison (116; fig. 7) and
was the first to implicate neurons in the region of the DMH in Nakamura and colleagues (138) who found that bilateral mi-
experimental fever, the idea was forgotten, in deference to croinjections of muscimol into the DMH during the plateau
prevailing dogma until the more recent convergence of new phase of the febrile response rapidly reversed the PGE2-
lines of evidence outlined above. Specifically, microinjection induced increases in IBAT sympathetic nerve activity, IBAT
of muscimol into the rRP was shown to block both the temperature, expired CO2, and heart rate. Most importantly,

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increases in core body temperature, IBAT temperature, and identical microinjection of muscimol into the lateral hypothal-
sympathetic nerve activity to IBAT caused by microinjection amus, another hypothalamic area where disinhibition has re-
of PGE2 into the POA in anesthetized rats (130, 136). The cently been shown to elicit thermogenesis (34), failed to
latter observations clearly implicated activation of the thermo- influence any of the PGE2-induced increases (138). Thus a
regulatory sympathetic premotor neurons in the rRP in this degree of anatomic specificity for the effect of microinjections
model of fever in rats. At the same time, a link had been forged into the DMH was clearly demonstrated. In one study, similar

Fig. 7. Results from two representative experiments depict-


ing sympathetic, thermogenic, and cardiovascular responses
after microinjection of PGE2 into the medial preoptic area
(MPA) and acute reversal elicited by microinjection of
muscimol (MUSC) into the DMH in anesthetized rats. Note
that injection of PGE2 elicits sustained increases in IBAT
temperature, expired CO2, heart rate, and arterial pressure
that are unaffected by bilateral microinjection of saline
vehicle (60 nl/side) into the DMH but rapidly reversed by
similar injection of MUSC (120 pmol/side). [from Madden
and Morrison (116)]

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THE DORSOMEDIAL HYPOTHALAMUS AND THERMOREGULATION R57
microinjection of the ionotropic glutamate receptor antagonist increases in body temperature, but the response is highly
kynurenate into the DMH also countered PGE2-induced changes. complex and may involve various modes of signaling the CNS
Thus, not only was neuronal excitation in the DMH largely (for reviews, see refs. 41, 167, 168). Numerous studies in rats
responsible for the activation of BAT and other accompanying have reported that systemic administration of LPS increases fos
sympathetic effects elicited by PGE2 acting in the POA, but expression in the DMH (56, 66, 103, 104, 158, 165, 224),
this excitation appeared to rely on activation of excitatory indicating that neurons in the region are activated in this
glutamate receptors in the region. The latter finding paralleled model, and preliminary results suggest that this activation
the results of Soltis and DiMicco more than a decade earlier, involves neurons in the region that project to the rRP (174). To
demonstrating a role for activation of ionotropic glutamate date, however, no study that has systematically examined the
receptors in the DMH in stress-induced tachycardia (185), now effect of interventions in the DMH on the response to systemic
also known to be mediated largely through the rRP (223). LPS in rats has appeared.
These current findings invite a reappraisal of the results of
prior studies aimed at elucidating the hypothalamic circuitry Involvement of DMH in Physiological and Pathophysiological
mediating the febrile response. Past results seemed to point to Thermoregulatory Phenomena: Avenues for Future Exploration
the classic suspects as “downstream” mediators of fever
evoked from the POA, including the PVN (25, 83; also, see The finding that neurons in the DMH may signal the acti-
Ref. 57), the PH (123), and the VMH (124). In the case of each vation of premotor sympathetic neurons in the rRP that are
of these regions, the critical functional evidence supporting its aimed at elevating body temperature in cold defense and in
role was that lesioning or inhibiting local neurons was reported fever invites speculation regarding their potential roles in

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to attenuate experimentally induced fever. However, as dis- thermoregulatory responses in a variety of additional settings.
cussed above, once again, the proximity of each of these areas Among these settings are those associated with chemical
to the DMH presents the possibility that the effects noted in signals related to food intake and ingestive behavior, a hypo-
these studies might actually be mediated through neurons in the thalamic function that has long been linked with thermoregu-
latter region. For example, Monda and colleagues had reported lation (see Ref. 70). For example, leptin, a peptide best known
that the increases in sympathetic nerve activity to IBAT pro- for its effect on feeding behavior, also produces an increase in
duced by intracerebroventricular administration of PGE1 in body temperature in rats and mice (26, 156, 187, 188) and may
anesthetized rats were suppressed by microinjection of musci- play a role in the circadian rhythmicity of body temperature in
mol into the PH (123). However, the dose and volume in which humans (181). Leptin receptors are found in the DMH (109,
it was injected suggest that spread or diffusion to the relevant 120) and systemic administration of leptin results in fos ex-
thermoregulatory neurons in the DMH might account for the pression in the region (54), including the dorsal portion where
effect noted. Even more importantly, the stereotaxic coordi- neurons projecting to the rRP are concentrated. Microinjection
nates targeted in these experiments taken from the atlas of of leptin into the DMH— but not into the PVN or the VMH—
Pellegrino (155) correspond, in fact, more closely to the DMH, elevates heart rate in anesthetized rats (117), suggesting that
as the regions were subsequently delineated in a more current the peptide is capable of exciting cardiac sympathoexcitatory
reference work (154; see discussion in Ref. 184). Other reports rRP-projecting neurons in the region. Most importantly, Mor-
of a modest reduction in experimentally induced fever after rison has demonstrated that intravenous administration of lep-
chemical lesioning in either the VMH (124) or the PVN (25) tin elicits increases in sympathetic nerve activity to IBAT,
used the excitotoxin ibotenate, an agent thought to act through IBAT temperature, and heart rate in anesthetized rats, and that
stimulation of ionotropic glutamate receptors. Given the ap- these increases are suppressed by stimulation of serotonergic
parent sensitivity of sympathoexcitatory neurons in the DMH 5-HT1A receptors in the rRP (131). Thus the leptin-induced
to other ionotropic glutamate receptor agonists (see Search for activation of the rRP and resultant sympathetic thermogenic
a hypothalamic thermogenic center and Refs. 45 and 184) and response may well be a consequence of activation of excitatory
the fact that none of these studies included controls to establish projections originating in the DMH. If so, then Morrison’s
anatomic specificity for their interventions, the possibility of finding also indicates that manipulation of serotonergic recep-
excitotoxic damage to the DMH seems plausible here as well. tors in the rRP may be an effective means of blocking sympa-
It should be noted that in nearly all of these studies and thoexcitatory transmission from the DMH (see Chemical sig-
certainly in those that point directly to the participation of the naling in thermoregulatory pathways involving the DMH).
DMH in fever, the experimental model used involves the The role of the DMH in drug-induced thermoregulatory
central administration of PGE2 in anesthetized preparations. disturbances represents another relatively unexplored area ripe
However, anesthesia disrupts normal thermoregulation, so that for investigation. An example here is presented by the narcotic
artificial means are generally used to support basal body analgesics. Morphine itself, as well as other drugs and peptides
temperature in such experiments. Given this, it seems clear that acting at ␮-opioid receptors, elicits increases in body temper-
caution must be exercised when extrapolating the results from ature in rats (6, 38, 67, 177), perhaps by an action in the POA
studies in anesthetized preparations to physiological thermo- (163, 205, 207, 214), although a site of action in the periaq-
regulatory processes. Furthermore, as discussed above, the ueductal grey has also been proposed (178, 211). The hyper-
model itself is based upon current long-standing and perhaps thermia produced by systemic administration of morphine is
overly simplistic hypotheses regarding the central mechanisms accompanied by increased fos expression in the DMH (182),
and origins of the febrile response. Another model for fever suggesting that activation of thermogenic mechanisms in the
and one that is arguably more “physiological”, involves the region could be involved. Once again, studies by Morrison’s
systemic administration of LPS in an unanesthetized prepara- laboratory that focused principally on the regulation of sym-
tion. As with central administration of PGE2, LPS elicits pathetic nerve activity to BAT have provided key findings in
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Invited Review
R58 THE DORSOMEDIAL HYPOTHALAMUS AND THERMOREGULATION

support of this idea. Cao and Morrison (32) examined the regulated by synaptic inhibition and excitation mediated by
response evoked by the ␮-opioid receptor agonist fentanyl in GABAA receptors and ionotropic glutamate receptors, respec-
anesthetized rats. Given either intravenously or intracerebrov- tively (31, 33, 116, 132). However, little else is known about
entricularly, fentanyl evoked increases in renal and IBAT the potential for modulation of transmission in this key path-
sympathetic nerve activity, IBAT temperature, heart rate, and way by receptors for other neurotransmitters.
arterial pressure. The intracerebroventricular fentanyl-induced One direction that appears promising for future study is the
increases in IBAT sympathetic nerve activity, IBAT tempera- potential involvement of serotonin and serotonergic receptors
ture, and heart rate were virtually abolished by prior microin- in the circuit. Serotonin-containing neurons are found in the
jection of muscimol into the DMH, while fentanyl-evoked rRP, and these are known to project to sympathetic regions of
increases in arterial pressure and renal sympathetic nerve the spinal cord. Recent evidence links serotonergic neurons in
activity were unaffected. Thus neuronal activity in the DMH the rRP to thermoregulation (141). For many years, it has been
seems likely to play a role in the hyperthermia seen after appreciated that serotonergic drugs have significant effects on
systemic administration of narcotic analgesics that act through body temperature (for a review, see Ref. 40). This is particu-
␮-opioid receptors in rats. larly true for agents that act to stimulate 5HT1A receptors,
Returning full circle, the role of the DMH-to-rRP circuit in which are well known to evoke pronounced hypothermia (78,
the hyperthermia typically seen in experimental stress repre- 122), perhaps by acting in the rRP (14, 199). Horiuchi and
sents another promising research avenue. As discussed above, coworkers (82) found that the increases in heart rate, arterial
evidence has accrued over the past decade supporting a role for pressure, and renal sympathetic nerve activity evoked by dis-
neuronal activity in the DMH in a wide range of physiological inhibition of the DMH in anesthetized rats could be virtually

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responses associated with experimental stress in rats. Stress abolished by systemically or intracisternally administered
hyperthermia is an often ignored but well-documented phe- 8-OH-DPAT, a prototypical 5HT1A receptor agonist. Blessing
nomenon known to occur in rats and other mammals (22, 100, first reported that systemic administration of this agent could
113, 114, 208), including humans (59, 69, 162), and has been prevent the increases in body temperature and decreased blood
proposed to play a role in physiological thermoregulation in flow to the pinna evoked by systemic administration of LPS in
some mammals in the wild (134). In the laboratory, the ability rabbits, and that this effect was reversed by the 5HT1A
of even the mild stress associated with experimental manipu- receptor antagonist WAY 100635 (18). Subsequently, micro-
lation to elevate body temperature often necessitates careful injection of 8-OH-DPAT into the rRP in conscious rabbits was
consideration in the design of studies of the febrile response in reported to suppress the sympathetically mediated tachycardia
conscious animals (e.g, Refs. 166 and 189). Similarities (22, evoked by stress or by LPS (140). As discussed above, acti-
113, 114, 208) and differences (89) between stress hyperther- vation of BAT evoked by systemic leptin in anesthetized rats
mia and more conventional fevers have been posited, but the can be suppressed by stimulation of 5HT1A receptors in the
central mechanisms and neural pathways that mediate the rRP (131). Together, these findings suggest that sympathoex-
former remain less well studied than those responsible for the citatory transmission from the DMH to the rRP—including that
latter (for a review see Ref. 145). Because sympathetically which is relevant to thermoregulation— can be inhibited by
mediated activation of BAT seems to be involved in stress- stimulation of 5HT1A receptors in the latter region. Given that
induced hyperthermia in the rat (179), a role for activation of stress-induced hyperthermia is likely to be signaled through the
excitatory projections from the DMH to the rRP seems highly circuit from the DMH to the rRP, a report that 8-OH-DPAT
likely, and our preliminary results support this idea. We have suppresses this phenomenon in mice (107) provides additional
found that in conscious rats, microinjection of saline into the support for both hypotheses.
DMH or the PVN in control experiments typically results in an
increase in body temperature, likely resulting from the mild Perspectives
stress of experimental manipulation. Similar increases in tem-
perature were also apparent after microinjection of muscimol Thus the DMH has suddenly come to light as a hypothalamic
into the PVN but were entirely absent after otherwise identical region interposed between classic thermoregulatory neurons in
microinjection of muscimol into the DMH (Hunt JL, Zaretsky the POA and downstream neurons that ultimately control a
DV, Sarkar S, DiMicco JA, unpublished observations). These variety of mechanisms relevant to body temperature in rats.
findings suggest that inhibition of activity in the DMH can Evidence for this idea is strongest with regard to projections to
suppress stress-induced hyperthermia and so support a role for sympathetic premotor neurons in the rRP—and perhaps the
neurons in the region in this phenomenon. cPAG—that regulate BAT. Further insights into signaling
related to thermoregulation through projections from the DMH
Chemical Signaling in Thermoregulatory Pathways Involving to these downstream regions will undoubtedly emerge from
DMH: Another Unexplored Frontier characterization of the phenotype of the specific neurons that
contribute to these pathways. However, the literature also hints
The forgoing provides ample evidence, suggesting an im- at the participation of neurons in the DMH in thermoregulatory
portant role for neurons in the DMH—and specifically for endocrine adjustments, somatomotor activity, and even behav-
those in the region that project to the medullary rRP—in the ior (see Ref. 118). If these possibilities are borne out by the
control of sympathetic thermoregulatory mechanisms in a va- results of future studies, then the DMH may assume the role of
riety of settings. Now, important questions can be addressed a key hypothalamic site responsible for integrating the control
with regard to the neuropharmacology of this anatomically and coordination of multiple effector systems that mediate
defined pathway. Clearly, activity of relevant thermoregulatory thermoregulation in mammals. How this new function for the
neurons at both the hypothalamic and the brain stem level is region might relate to its better established role in physiolog-
AJP-Regul Integr Comp Physiol • VOL 292 • JANUARY 2007 • www.ajpregu.org
Invited Review
THE DORSOMEDIAL HYPOTHALAMUS AND THERMOREGULATION R59
ical and behavioral responses to exteroceptive stress (for re- 16. Blatteis CM, Li S, Li Z, Feleder C, and Perlik V. Cytokines, PGE2 and
views, see Refs. 50 and 51) is an issue that invites numerous endotoxic fever: a re-assessment. Prostaglandins Other Lipid Mediators
76: 1–18, 2005.
questions. For example, responses to stress resemble in many 17. Blessing WW. Lower brainstem pathways regulating sympathetically
ways the physiological changes seen in exposure to cold (i.e., mediated changes in cutaneous blood flow. Cell Mol Neurobiol 23:
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cutaneous vasoconstriction and fever associated with the acute inflam-
stances recruit a slightly different subset of neurons in the
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support from Research Facilities Improvement Program Grant Number C06 paraventricular nucleus abolishes fever induced by endotoxin and bra-
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