Dimicco Zaretsky 07 DMH in Thermoregulation

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

Joseph A. DiMicco and Dmitry V. Zaretsky

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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. ZaretskyDepartment 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 newplayer 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 thedorsomedial hypothalamus (DMH) play key roles in physiological responses to extero-ceptive (“emotional”) stress in rats, including tachycardia. Tachycardia evoked from theDMH 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 mediatedactivation of brown adipose tissue (BAT) and cutaneous vasoconstriction in the tail.Disinhibition of neurons in the DMH also elevates core temperature in conscious ratsand sympathetic activity to least significant difference interscapular BAT (IBAT) andIBAT temperature in anesthetized preparations. The latter effects are blocked bymicroinjection of muscimol into the rRP, while microinjection of muscimol into eitherthe rRP or DMH suppresses increases in sympathetic nerve activity to IBAT, IBATtemperature, and core body temperature elicited either by microinjection of PGE2 intothe preoptic area (an experimental model for fever), or central administration offentanyl. Neurons concentrated in the dorsal region of the DMH project directly to therRP, a location corresponding to that of neurons transsynaptically labeled from IBAT.Thus these neurons control nonshivering thermogenesis in rats, and their activationsignals its recruitment in diverse experimental paradigms. Evidence also points to a rolefor neurons in the DMH in thermoregulatory cutaneous vasoconstriction, shivering, andendocrine adjustments. These directions provide intriguing avenues for future explo-ration that may expand our understanding of the DMH as an important hypothalamicsite for the integration of autonomic, endocrine, and behavioral responses to diversechallenges.

brown fat; sympathetic nervous system; body temperature; fever; raphe pallidus

THERMOREGULATION IN MAMMALS is a vital process orchestrated bythe central nervous system through endocrine, autonomic, andbehavioral mechanisms. One of the first regions of the brain to belinked with this process was the preoptic area (POA), an area thatis not only the location of temperature sensitive neurons butreceives and integrates input from ascending neural pathwayscarrying information derived from sensory receptors in the pe-riphery (for reviews see refs. 21, 80, 112). The result is acoordinated array of adaptive changes that involve multiple sys-tems and are aimed at maintaining and stabilizing body temper-ature. Although the POA plays a similar role in virtually allmammals, the specific means through which normothermia isattained may vary in different species. In rats, normothermia in acold environment is maintained in part through metabolic activa-tion of brown adipose tissue (BAT) (105; for a review, see Ref.27), a tissue whose existence and significance in adult humans hasbeen the subject recently of considerable controversy and interest

(see also Ref. 7), and cutaneous vasoconstriction, a mechanismused by both these species, as well as other mammals. Theseeffects that serve to generate body heat and regulate heat loss,respectively, are sympathetically mediated and accompanied byadrenergic cardiac stimulation (35, 63, 125, 194), which is thoughtto aid in the distribution of heat generated in thermogenic regions(i.e., brown fat) and by contraction in skeletal muscle (i.e.,shivering). In addition to these sympathetic actions that could beviewed as constituting rapid adjustments, exposure to cold resultsalso in characteristic endocrine effects in mammals. These includealterations of thyroid function (15, 61) and activation of thehypothalamo-pituitary-adrenal axis to increase circulating glu-cocorticoids (106, 153, 190, 206), actions, which together pro-mote an array of metabolic effects in support of the increasedthermogenic needs of the organism. Finally, somatic motor nervespromote the generation of heat by skeletal muscle through shiv-ering (23, 39, 180, 190).

Over the past half century, a number of brain regions havebeen 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,635 Barnhill Dr., Rm. MS A417, Indianapolis, IN 46202 (e-mail:[email protected]).

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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.

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might be involved in these various components of the systemoutlined above. In recent years, the dorsomedial hypothalamus(DMH) has rapidly emerged as an area of considerable interestwith regard to certain of these thermoregulatory mechanisms.In this review, we summarize the evidence in support of a rolefor the DMH in thermoregulation and dysregulation in mam-mals, principally, with respect to thermoregulatory mecha-nisms that are sympathetically mediated. However, we willalso briefly consider evidence that dimly, but intriguingly,illuminates the possibility of a role for neurons in the sameregion in thermoregulatory adjustments that involve endocrineand somatomotor effects. As we will use the term, the thermo-regulatory DMH indicates a region of the hypothalamus thatincludes the dorsomedial hypothalamic nucleus (DMN) butalso extends into adjoining areas, particularly dorsal and per-haps posterior to the nucleus itself, as defined in the currentstandard atlas (154). Indeed, as we will suggest below, thespecific neurons that may be relevant to thermoregulationprobably do not correspond precisely to any of the classicallydelineated hypothalamic nuclei or regions.

Search for a Hypothalamic “Thermogenic Center”

Three decades ago, the notion of a hypothalamic regiondistinct from the POA had not been integrated into the “blackbox” model of the brain in thermoregulation (see Refs. 24 and75). Nevertheless, it soon became clear that additional compo-nents linking temperature-sensitive neurons in the POA toappropriate effector outputs were needed to provide a cogentoperational framework. The first hypothalamic region to re-ceive serious consideration in this regard was the ventromedialhypothalamus (VMH). Electrical stimulation of the VMH wasfound to elicit increased norepinephrine turnover and thermo-genesis in IBAT (79, 88, 95, 157, 171, 215) and to increasemarkedly and specifically blood flow in this tissue (90). Con-versely, electrolytic lesion of the VMH abolished cold-inducedincreases in sympathetic nerve activity to IBAT (142), whilemicroinjection of the local anesthetic lidocaine into the regionof the VMH reduced the increase in IBAT temperature evokedby cooling or stimulation of the POA (90). Within this body ofliterature, the hypothesis that the VMH comprises a secondhypothalamic “thermogenic center” seems to have been estab-lished by earlier reports, and this notion clearly influenced theinterpretation of the results of many of the studies that fol-lowed. For example, when electrical stimulation of either theVMH or the DMH was found to elevate IBAT temperature,attention was focused on the VMH, nonetheless (95). Simi-larly, Thornhill and colleagues (204) found that microinjectionof lidocaine into either the VMH or the nearby posteriorhypothalamus (PH) reduced the increase in IBAT temperatureevoked from the POA in anesthetized rats, calling into questionthe relevant site of action for the microinjected agent, andneither report using lidocaine in this manner addressed thepotential for affecting fibers of passage with this approach.Furthermore, the increases in IBAT temperature that wereproduced by electrical stimulation of the VMH in many ofthese studies were typically preceded by small, but consistent,decreases, a fact that seems to have been often, but not always(see Refs. 212 and 213) ignored. The biphasic nature of thetemperature response in this study, as well as the failure ofelectrical stimulation of the VMH to evoke any increase in

IBAT temperature in a later report (62), precludes a clearinterpretation of the data. Indeed, a thorough understanding ofprecisely which neural elements are activated by intracerebralelectrical stimulation, as well as the exact mechanism for thisactivation, has proven elusive for decades (see Ref. 158). Thisand the possibility of effects resulting from spread or diffusionof microinjected drugs to adjacent regions (see below) under-mine the rationale for this earlier conclusion that activation ofneurons in the VMH results in nonshivering thermogenesis.

In spite of the uncertainty regarding the interpretation of theresults of electrically stimulating and lesioning specific sites inthe brain, experiments using these approaches provided thefirst indication that neurons in the DMH might play a role inthermoregulation. Historically, the DMH had been implicatedin feeding and metabolic regulation associated with ingestivebehavior (for a review, see Ref. 12), phenomena closely linkedto thermoregulation for decades (70, 105, 169). Consequently,the finding that IBAT weight was significantly reduced in ratswith lesions of the DMH (13) was interpreted only in thiscontext. In fact, increases in BAT mass are known to reflectthermogenic accommodation to a cold environment that issympathetically mediated (133, 164). A more direct link be-tween the DMH and thermogenesis in BAT was posed bystudies in which electrical stimulation of the VMH had noeffect on IBAT temperature, while stimulation of the DMH (aswell as several other hypothalamic regions) increased it (62).Active sites of stimulation seemed to represent a continuousband extending caudally from the preoptic area through theanterior hypothalamus, hypothalamic paraventricular nucleus(PVN) and DMH. Consequently, the authors surmised thatobserved thermogenic effects resulted from activation of fibersof passage emanating caudally from the preoptic area. (Curi-ously, however, they suggested that this pathway was inhibi-tory to brain stem thermogenic mechanisms, a conclusionseemingly at odds with their results.)

The potential for stimulation of fibers of passage was, infact, largely responsible for the abandonment of electricalstimulation in favor of chemical stimulation, generallyachieved by local microinjection of highly concentrated solu-tions of glutamate or other excitatory amino acids (68). Studiesusing this approach reported that microinjection of glutamateinto either the VMH, the PVN, or the PH—regions virtuallysurrounding the DMH—increased IBAT temperature in anes-thetized rats (2–4, 71). Amir (4) also reported that similarmicroinjection of the GABAA receptor antagonist bicucullinemethiodide (BMI) 50 ng, or �100 pmol, into the PH increasedcore and IBAT temperature. Assuming that the results of thesestudies represent actions of glutamate or BMI on neurons asopposed to fibers of passage, they clearly suggested thatactivation of hypothalamic neurons located outside of thepreoptic area could elicit sympathetically mediated activationof BAT. However, without appropriate anatomic controls andgiven the ambiguity regarding the exact delineation of PH vs.DMH (see below and Ref. 184), the precise location of therelevant neurons remained unclear. Even less illuminatingwere the results of Yoshimatsu and colleagues (219), whostudied the effects of microinjections of glutamate into severalhypothalamic regions on sympathetic nerve activity to IBAT inanesthetized rats. They reported a confusing array of stimula-tory, inhibitory, and biphasic responses, and that the predom-inant response evoked from the DMH was inhibitory, a finding

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that appears contradictory in light of more recent resultsdetailed below. An explanation may lie in the fact that micro-injection of highly concentrated solutions of excitatory aminoacids to excite local neurons may have just the opposite effect(111), probably owing to depolarizing blockade. Accordingly,microinjection of NMDA into the DMH at doses in the rangeof 0.68 to 6.8 pmol evokes marked dose-related tachycardia inanesthetized rats, but doses only slightly higher (20 pmol)produce a lower response, and doses higher still (60 pmol) hadlittle or no effect on heart rate (184). Thus the relevantsympathoexcitatory neurons in the DMH may be unusuallysensitive to glutamate receptor agonists so that microinjectionof excitatory amino acids at the millimolar concentrationstypically used fail to evoke increased activity (see also ref. 49).

Therefore, studies using the technique of microinjection ofglutamate did little to clarify the specific location of thehypothalamic neurons controlling sympathetic activity to BATor to suggest that DMH might be a prime candidate in thisregard. However, microinjection of calcitonin gene-relatedpeptide (CGRP) into the either the DMH or the VMH inurethane-anesthetized rats evoked sharp increases in IBAT andcore body temperature, oxygen consumption, and heart rate(101). The authors demonstrated a degree of anatomical spec-ificity for the effect—similar injections into the POA or thePVN were ineffective—but failed to resolve the region furtheror to pursue the suggestion that the DMH might represent ahypothalamic thermogenic region of some significance. In-stead, the bias toward a focus on the VMH is evident in boththe design of their studies, the results selected for representa-tion, and the tenor of the discussion in this work. Nevertheless,the DMH was now added to the list of hypothalamic regionsthat might represent upstream sites involved in the control ofnonshivering thermogenesis in rats (135).

DMH Emerges as a Key HypothalamicSympathoexcitatory Region

The search for the precise location of one or more hypotha-lamic sympathetic thermogenic areas was thus set against thebackdrop of a confusing array of data, suggesting a widenumber of possibilities that principally included the PVN, thePH, and the VMH. As indicated above, however, these threeareas together bracket and surround the DMH, a region that bythe end of the last century had emerged as a major integrativesite for the classic defense reaction and responses to experi-mental exteroceptive stress (for a review, see Ref. 50). Thus, inconscious rats, disinhibition of neurons in the DMH by localmicroinjection of BMI—at doses less than one-tenth of thedose used by Amir (4) to evoke thermogenesis in the PH—evokes an array of autonomic, behavioral, and endocrineresponse, typically seen in stress, among these being markedsympathetically mediated tachycardia (9, 45, 184). Conversely,local microinjection of muscimol, an inhibitor of the vastmajority of mammalian neurons by virtue of its agonist prop-erties at GABAA receptors, virtually abolished the sympathet-ically mediated increases in heart rate seen in experimental airjet stress (191, 192).

Most importantly, the brain stem pathway mediating DMH-evoked cardiac stimulation was subsequently found to involvethe region of the rostral raphe pallidus (rRP) in the medulla(172), a discovery that provided the first strong indication of a

role for the DMH in thermoregulation. The rRP, a midlinelongitudinal region at the base of the medulla between thepyramids, as well as the adjacent parapyramidal area andperhaps raphe magnus, was revealed to be an important loca-tion of sympathetic premotor neurons in circuits innervatingBAT and thermoregulatory cutaneous blood vessels from theresults of transsynaptic neuronal tracing studies (for a reviewof the technique, see Refs. 10, 29, 137, 183, 186). Moreover,functional studies had clearly demonstrated that activation—ordisinhibition—of neurons in the rRP by local microinjection ofBMI resulted in dramatic increases in sympathetic nerve ac-tivity to IBAT and increases in IBAT temperature and metab-olism, as well as in anesthetized rats (128, 129, 132). However,it was also noted that these effects were accompanied bytachycardia and modest increases in blood pressure (132),replicating the pattern of cardiovascular changes evoked byactivation of the DMH or by stress in this species.

Subsequent studies provided support for the notion that keysympathoexcitatory effects of activating neurons in the DMHwere in fact mediated through neuronal activity in the rRP andthat a direct projection from neurons in the former region to thelatter might be involved. The sympathetically mediated tachy-cardia that could be evoked by microinjection of BMI into theDMH was mimicked by similar disinhibition of neurons in therRP (30, 166) and was suppressed by 30–60% after microin-jection of muscimol into the latter region (30, 81, 172). Fur-thermore, specific sites in the DMH shown to be most sensitiveto the tachycardic effects of “nanoinjections” of BMI at areduced dose (2 pmol) and volume (5 nl) corresponded closelyto the area where neurons projecting to the rRP were mosthighly concentrated (173; see Fig. 1). Thus sympatheticallymediated tachycardia seen in stress may be mediated, at least inpart, through excitatory projections from the DMH to the rRP,a pathway originating principally from a dense collection ofneurons in the dorsal area of the former region that had alreadybeen well described and characterized anatomically (85–87).However, given the recent elucidation of the rRP as a keymedullary site for sympathetic control of BAT and cutaneousvasoconstriction, these findings also suggested that neurons inthe DMH might constitute the hypothalamic thermoregulatorysite whose existence had been suggested more than two de-cades earlier.

DMH and Thermoregulatory Mechanisms: SympatheticActivation of Brown Fat

Zaretskaia and colleagues (221) provided the first clearevidence that activation of neurons in the DMH could dramat-ically alter body temperature through a classic thermoregula-tory mechanism. They demonstrated that, in addition to auto-nomic, endocrine, and behavioral effects already described,microinjection of BMI into the DMH markedly elevated corebody temperature in conscious freely moving rats at roomtemperature (Fig. 2). In urethane-anesthetized rats, similarmicroinjections evoked rapid and dramatic increases in IBATtemperature that preceded and exceeded the responses in coretemperature (Fig. 3), suggesting that the former was at leastpartly responsible for the latter. Most importantly, a dose of 10pmol of BMI in 100 nl was used—one-tenth the dose and lessthan half the volume injected by Amir and colleagues into thePH as discussed above—and identical microinjections into the

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VMH or the PVN failed to affect either core or IBAT temper-ature. Thus inclusion of the appropriate anatomical control datathat were missing from earlier studies ruled out the possibilitythat the effects noted may have been a consequence of spreador diffusion of BMI to either region.

Subsequently, Cao and colleagues (31) performed detailedexperiments in anesthetized animals that confirmed and extendedthese findings by characterizing further the thermogenic responseto disinhibition of the DMH and establishing the role of the rRPin these changes. Microinjection of BMI (60 pmol) into the DMHdramatically elevated IBAT, renal, and cardiac sympathetic nerveactivity, as well as heart rate and blood pressure, and theseelevations were associated with marked increases in IBAT tem-perature and expired CO2, a reflection of increased metabolicactivity in BAT and, perhaps, the heart as well (Fig. 4). DMH-evoked increases in IBAT temperature, IBAT sympathetic nerveactivity, and metabolism were greatly attenuated or abolished bymicroinjection of muscimol into the rRP, implying that activationof sympathetic premotor neurons in the latter region played adominant role in these changes. On the other hand, although peakincreases in heart rate were significantly reduced, increases inrenal or cardiac sympathetic nerve activity and in blood pressurewere unaffected. The marked effect of microinjection of musci-mol into the rRP on IBAT temperature and sympathetic nerveactivity clearly points to a critical role for neuronal activity in theregion in the thermogenic response.

More recently, Cao and Morrison have provided insight intothe nature of the excitatory signaling through which disinhibi-tion of neurons in the DMH activates thermogenic mechanismsin the rRP. In anesthetized rats, they explored the effect ofmicroinjection of glutamate receptor antagonists into the rRPwith respect to responses to microinjection of BMI into the

DMH (33). Microinjection of kynurenate, a nonselective an-tagonist of all ionotropic glutamate receptors, rapidly (i.e.,within 5 min of injection) and completely abolished BMI-induced increases in sympathetic nerve activity to IBAT andattenuated the accompanying increases in IBAT temperaturewithout affecting increases in heart rate, arterial pressure, andrenal sympathetic nerve activity. Injection of AP5 or of CNQX,antagonists with the capacity for relative selectivity againstNMDA vs. non-NMDA subtypes of ionotropic glutamate re-ceptors, respectively, elicited effects similar to those of kynure-nate. These findings thus suggest that DMH-induced sympa-thetic activation of BAT is mediated at least, in part, throughstimulation of ionotropic glutamate receptors in the rRP.

A close examination of the results of published anatomictracing studies provides supporting evidence that neurons inthe DMH are contributors to sympathetic activation of BATand thus play a role in thermoregulation. Most relevant arethose studies in which the transneuronal tracing techniquebased upon sequential transsynaptic infection by pseudorabiesvirus (PRV) was applied to elucidate central pathways project-ing to IBAT, all of which reported labeling in the DMH (10,29, 31, 137, 147, 217). In fact, the results shown in one suchreport indicate a particularly dense collection of PRV-infectedneurons in the region of the DMH just dorsal to the DMN andextending somewhat ventrally into the latter nucleus itself(217; Fig. 1). This distribution, suggested by the authors asbeing in the PH, closely matches that of neurons retrogradelylabeled directly from the rRP, in what was previously identifiedas the dorsal hypothalamic area (77, 85, 143, 173), as well asthat of sites most sensitive to the cardiac sympathoexcitatoryeffect of microinjected BMI (173; Fig. 1). Together, theseresults indicate that neurons that project directly to the rRP and

Fig. 1. Photomicrograph (above) and schematic diagrams (below) depicting coronal sections of rat brains through the dorsomedial hypothalamus (DMH) fromdifferent studies. A: fluorescence micrograph depicting neurons in the DMH transsynaptically infected with pseudorabies virus (PRV) injected into interscapularbrown adipose tissue. LH, lateral hypothalamic area; DMD, dorsomedial hypothalamic nucleus, dorsal; VMH, ventromedial hypothalamic nucleus. Calibrationbar � 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 hypothalamicarea; LHA, lateral hypothalamic area; ARC, arcuate nucleus; PAA, periarcuate area. D: schematic coronal section depicting on the left the distribution of neuronsretrogradely labeled from the rostral raphe pallidus in a representative experiment on the left (each solid circle representing a single labeled neuron), and on theright a series of injection sites compiled from different experiments in anesthetized rats coded to represent the magnitude of the increase in heart rate evokedby 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; opentriangles, 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)]

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polysynaptically to IBAT are found in the same region of theDMH—a region to which various labels have been appended.

Thus both anatomic and functional experiments support theexistence of direct projections from the DMH to the rRP, theactivation of which results in sympathetically mediated ther-mogenesis in BAT. Clearly, much of our knowledge regardingthe role of the DMH in thermoregulation is framed in thefunctional context of these projections, and this notion hasalready served to illuminate new paths for exploration asdetailed below. However, more recent studies suggest an al-ternative efferent pathway through which the DMH may exertsignificant thermogenic effects. Like neurons in the dorsalDMH, neurons in the caudal periaqueductal gray (cPAG) areretrogradely labeled from the rRP (77, 143), transsynapticallylabeled from IBAT (10, 29, 217), and express fos after expo-sure to cold (29). Chen and coworkers (37) reported thatelectrical or chemical stimulation of neurons in this regionincreases IBAT temperature in anesthetized rats, suggestingthat neurons in the cPAG are interposed in neural circuits thatcan stimulate the activity of BAT. De Menezes and colleagues

(44) studied the effect of inhibiting neurons in the cPAG onresponses evoked from the DMH in conscious rats. Microin-jection of muscimol into the cPAG not only reduced theDMH-induced increases in heart rate and locomotor activitybut also suppressed the associated increases in body tempera-ture (Fig. 5). Although de Menezes and colleagues targeted adifferent subregion of the cPAG than did Chen and coworkers(36, 37) (i.e., the lateral/dorsolateral vs. the lateral/ventrolateralPAG), it seems likely that, given the anatomic resolutionpossible with the microinjection techniques used, the sameneurons were involved in all effects described. Interestingly,neurons retrogradely labeled from the cPAG were found in thearea of the dorsal DMH corresponding to that where rRP-projecting neurons are concentrated, and these same neuronswere shown to express fos in response to exposure to a coldenvironment (10°C; 218). These results suggest that neurons inthe same region of the DMH project to the rRP both directlyand indirectly through a neuronal relay in the cPAG and thatthermogenesis in BAT may be a consequence of activating eitherpathway. Whether the same hypothalamic neurons project to bothdownstream thermogenic regions is currently unknown.

Just as neurons in the DMH are positioned to signalsympathetic premotor neurons in the rRP that regulate theactivity of BAT through these efferent pathways, they arealso known to receive afferent input from regions that maybe relevant to thermoregulation (for a review, see Ref. 202).Principal among these is the POA, a region of primeimportance with regard to thermoregulation. In tracing stud-ies, the POA has been identified as the region containing thelargest number of neurons retrogradely labeled from theDMH (202). Many neurons in the POA are known to beGABAergic (146), and those that are relevant to thermoreg-ulation are thought to exert tonic inhibition of downstreamelements important for activation of BAT (36). As discussedabove, microinjection of BMI, a GABAA receptor antago-nist, is an efficient means of evoking activation of neuronsin the DMH that are involved in sympathetic control ofIBAT, suggesting that these neurons are restrained by tonicGABAergic inhibition under normal circumstances. Re-cently, neurons in the DMH retrogradely labeled from therRP were found to receive GABAergic projections originat-ing in the POA (138). Thus GABAergic neurons in the POAare likely to provide a key source of the tonic inhibitoryinput to sympathoexcitatory neurons in the DMH that wasfirst implied by experimental findings two decades ago (47).

DMH and Thermoregulatory Mechanisms: SympatheticCutaneous Vasoconstriction

The clear evidence that neuronal activation in the DMHelicits sympathetic thermogenesis through activation of BATand that this effect is mediated through the medullary rRPinvites the possibility that cutaneous vasoconstriction, the othermajor sympathetic thermoregulatory mechanism apparentlycontrolled from this region, might also be under similar de-scending control from the DMH. Cutaneous vasoconstrictionand vasodilation serve to conserve or dissipate body heat,respectively, and so represent important thermoregulatory ad-justments in mammals. The particular cutaneous region prin-cipally involved in this function may vary according to species.In rabbits, the cutaneous circulation of the pinna is of primary

Fig. 2. Effect of unilateral microinjection of BMI 10 pmol/100 nl (n � 6) andsaline (n � 6) into the DMH on core body temperature, heart rate, bloodpressure, plasma ACTH, and locomotor activity in conscious rats. Bars andasterisks indicate significant differences between BMI and saline treatment byrepeated measures ANOVA and Fisher’s least significant difference test. [fromZaretskaia et al. (221)]

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importance (98, 197), while in rats, blood flow to the tail servesthis purpose (43, 74, 159, 193). As with sympathetic innerva-tion of BAT, the rRP appears to represent the brain stemlocation of sympathetic premotor neurons that specificallyregulate these anatomically distinct but functionally analogouscirculations in these two species, i.e., the tail in rats (20, 137,149, 151, 152, 160, 161, 183, 196) and the pinna in rabbits (17,19, 140, 149, 150).

The hypothesis that neurons in the DMH play a role in ther-moregulatory vasoconstriction mediated through the rRP has notbeen explicitly examined, but recent reports provide some sup-portive evidence. In a transsynaptic retrograde tracing study inrats, substantial labeling was consistently seen in the DMH—andmore specifically in the dorsal hypothalamic area and, to asomewhat lesser degree, in the DMN—7 days after injection ofpseudorabies virus into the wall of the rat tail artery (183).Electrical stimulation of the DMH was subsequently reported todecrease blood flow in the ear of anesthetized rabbits (97, 148).Nalivaiko and Blessing (139) found that electrical stimulation ofthe region of the DMH in anesthetized paralyzed rabbits reduced

blood flow in the pinna by more than 80% but mesenteric bloodflow was reduced only by 50%. More importantly, the reductionin blood flow to the ear induced by hypothalamic stimulation wascompletely abolished by prior injection of muscimol into the rRP,while the decrease in mesenteric blood flow was unaffected. Thisfinding suggests that a pinna-specific vasoconstrictor pathwayfrom the DMH to the rRP may exist in rabbits. However, thelimitations regarding the interpretation of results from electricalstimulation studies discussed above make a connection withneurons in the DMH tenuous. Thus a likely possibility—and oneripe for investigation—is that, in rats, activation of neurons pro-jecting from the DMH to the rRP elicits cutaneous vasoconstric-tion in the tail and that this pathway participates in thermoregu-lation.

DMH and Thermoregulatory Mechanisms: Beyond theSympathetic Nervous System?

Although sympathetic innervation of brown fat and thecutaneous blood flow to the tail play a key role in rapid

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 theVMH (shaded symbols) on core (triangles) and interscapular brown adipose tissue (IBAT; squares) temperature, heart rate, and blood pressure inurethane-anesthetized rats. Right: schematic coronal sections representing two levels of the DMH and depicting eight of the injection sites in the DMH and allsix injection sites into the VMH from the experiments at left. Solid circles denote an increase in both core and IBAT temperature accompanied by increases inheart 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 noeffect on temperature or heart rate. Numbers indicate distance from bregma in millimeters. [from Zaretskaia et al. (221)]

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thermoregulatory responses in the rat, other systems are alsoinvolved in the maintenance of body temperature. This isparticularly true in humans where, in adults, the significance ofbrown fat is currently a subject of some debate (see Refs. 7 and27). What other systems, then, are considered “thermogenic” inour own species?

First, endocrine mechanisms are known to play at least asupporting metabolic role in thermoregulatory responses. Thesemechanisms include the adrenal cortex, where secretion of glu-cocorticoids has wide-ranging metabolic effects, and the thyroidgland, the hormones of which are thought to increase the meta-bolic rate in general and are specifically permissive for heatgeneration through the induction of uncoupling protein 1 in BATand perhaps other tissues (15, 106, 108, 195). The activity of bothglands is under central control by neurons that regulate the releaseof the pituitary trophic hormones ACTH and thyrotropin, respec-tively, and the final common pathway controlling their release is

thought to be through neurons in the hypothalamic PVN (forreviews, see Refs. 58, 76, 175). The parvocellular PVN, theprincipal location of neurons that contain corticotrophin-releasinghormone and so control the secretion of ACTH, represents aprincipal hypothalamic target for efferent projections from theDMH in the rat (200, 201), and some of these projections areknown to contact thyrotropin-releasing hormone-containing neu-rons in this region (121). Disinhibition of the DMH results inincreased fos expression in the PVN and elevated plasma ACTH(9, 48, 221; see Fig. 2 of this article), whereas inhibition ofneurons in the DMH suppresses the increases in plasma ACTHand in fos expression in the parvocellular PVN seen in experi-mental (air jet) stress in rats (127, 192). Thus the activation of thePVN that occurs in this stress paradigm appears to be signaledfrom neurons in the DMH. Accordingly, experimental stressincreases fos expression in neurons in the DMH that are retro-gradely labeled from the PVN (42, 110). Intravenous administra-

Fig. 4. Effect of microinjection of muscimol into the rostral raphe pallidus (RPa) on responses evoked by microinjection of bicuculline (BIC) into the DMH inanesthetized rats. A: microinjection of bicuculline into DMH (dashed vertical line) elicits marked increases in IBAT sympathetic nerve activity (iBAT SNA) andtemperature (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 ofmuscimol 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 aremodestly reduced, and renal SNA and MAP are unaffected. C: Data from 4–9 experiments averaged over time. [from Cao et al. (31)]

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tion of LPS, a powerful stimulus for activation of the PVN andrelease of plasma ACTH (for a review, see Ref. 11), also increasesfos expression in neurons in the DMH that are retrogradelylabeled from the PVN (55). The latter finding indicates thatneurons projecting from the DMH to the PVN are activated in thismodel for fever. Whether this activation might play a role in thethermoregulatory mobilization of these hormonal systems underthese or any other circumstances remains another unexplored butintriguing direction for future study.

In addition to autonomic and endocrine mechanisms, hu-mans and other mammals may also recruit the somatic motoroutflow to generate heat through shivering. Neurons in thehypothalamus have been implicated in the generation of ther-moregulatory shivering for decades (see Ref. 39), and earlierelectrical stimulation studies suggested that shivering could beevoked from the VMH in conscious rabbits (126) and from thePH—but not the VMH—in anesthetized rats (72, 203). Otherstudies over the years have attempted to characterize theefferent pathway from the POA that mediates shivering usinglocalized knife cuts and lesions (92, 93). Only recently, how-ever, has clear evidence appeared that neuronal activity in aspecific hypothalamic region downstream from the POA mayplay a role in shivering. In anesthetized rats, an electromyo-

gram was recorded while body temperature was permitted tofall, and the resulting activity was usually (but not always)abolished by microinjection of muscimol into the DMH, theadjacent dorsal hypothalamus, and the dorsomedial region ofthe adjoining PH (195). Although a more precise location ofthe relevant neurons was unclear from the results presented, thereactive region clearly included the same area of the DA/DMHwhere putative thermoregulatory neurons projecting to the rRPand to the PAG are found. Even more recently, the increase inthe activity of fusimotor fibers to the gastrocnemius elicited bycooling of the trunk skin in anesthetized rats—a responsethought to be the mechanism responsible for thermoregulatoryshivering—was blocked by microinjection of the inhibitoryamino acid glycine into the rRP (197). This finding indicatedthat, in addition to its well-established role in sympatheticthermoregulatory 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 projectto the rRP has been recently suggested by the report of anintriguing neuroanatomic link between the DMH and somato-motor function. In a dual PRV transsynaptic tracing study fromthe adrenal gland, a sympathetic component well known to beactivated in cold exposure (28, 46, 64, 84, 209), and thesympathectomized 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 inthe DMH that project to the rRP are appropriately interposed inanatomic circuits that could elicit shivering under appropriateconditions, making this another appealing area for furtherinvestigation.

Involvement of DMH in Physiological and PathophysiologicalThermoregulatory Phenomena: Cold Defense and Fever

Thus disinhibition of neurons in the region of the DMHresults in increases in body temperature at least, in part,through 1) neuronal activity in the rRP and 2) sympatheticallymediated activation of BAT. In the brief period since therecognition of a potential role for neurons in the DMH in thecontrol of core body temperature, evidence has appeared fortheir participation in thermoregulatory responses in severaldifferent settings where activation of BAT and/or cutaneousvasoconstriction has been implicated.

One such circumstance is cold defense, or the recruitment ofmechanisms that both generate and conserve body heat in acold environment. In rats, these include activation of BAT andcutaneous vasoconstriction in the tail. Under such conditions,increased fos expression, and so presumably neuronal activa-tion, has been reported in the DMH (8, 29, 119, 216). Inurethane-anesthetized rats, intense fos expression was noted inthe DMH of rats kept at an ambient temperature of 5°C but notat 23°C (119). In conscious rats, marked fos expression wasalso noted specifically in the dorsal DMH, the same regionwhere neurons projecting to the rRP are known to be mostdensely concentrated, after exposure to either 10°C (97) or 5°C(216). Furthermore, the cold-induced fos expression in theDMH was dramatically suppressed by warming of the POA(216), an observation consistent with the idea that temperature-sensitive neurons in the POA exert tonic inhibitory control overthermoregulatory neurons in the DMH (see Ref. 138).

Fig. 5. Effect of identical microinjection of BMI 10 pmol into the DMH onbody temperature (TEMP) and heart rate (HR) after microinjection of eithersaline or muscimol (MUS) 100 pmol into ipsilateral sites in the caudalperiaqueductal grey (cPAG; injection sites shown in schematics below) in thesame conscious rats. *Significant differences between muscimol and salinetreatments. d, dorsal; dl, dorsolateral; l, lateral; vl, ventrolateral. [from deMenezes et al. (44)]

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Although these results suggest that neurons in the DMH areactivated in exposure to cold, no study to date has shown thatthis activation occurs specifically in neurons in the region thatproject to the rRP. However, Cano and coworkers (29) reportedthat in rats exposed to 4°C for 4 h, fos expression was clearlyevident in the same region of the dorsal DMH, where neuronstranssynaptically labeled from IBAT are concentrated (Fig. 1).Thus, not only are neurons that project directly to the rRP andpolysynaptically to IBAT found in the same region of theDMH but neurons in this region appear to be activated in coldexposure. Because of this finding, Cano and coworkers (29)suggested that these neurons might play a key role in cold-induced thermogenesis. Evidence for their hypothesis hasemerged in the preliminary finding of Almeida and colleaguesthat rats with electrolytic lesions of the DMH are unable tomaintain normal body temperature in a cold environment (1).However, given that such lesions destroy local fibers of pas-sage, as well as neurons, the hypothesis remains to be testeddirectly in appropriate functional studies.

Another setting in which evidence of a role for the recruit-ment of thermogenic mechanisms through activation of theDMH has now appeared is fever. Fever, a regulated increase inbody temperature achieved by increasing the thermostatic set-point, is a salient component of a host response to bacterialinfection that in mammals includes immunologic, autonomic,endocrine, and behavioral adjustments (for reviews, see Refs.73, 102, 115, 176). In rats, sympathetic activation of BAT andcutaneous vasoconstriction play primary roles in the increasesin temperature seen in experimental fever (65, 92, 166). Al-though there is agreement regarding many mechanistic aspectsof the febrile response and associated physiological changes,others remain the subject of debate today. Thus it is generallyacknowledged that 1) exogenous pyrogens of bacterial origin,

including the bacterial cell wall component LPS, trigger therelease of endogenous pyrogenic cytokines (see Ref. 53), and2) these cytokines (and perhaps the exogenous pyrogens aswell) initiate increases in body temperature through an actionthat ultimately involves generation of PGE2, acting in theregion of the POA (see Refs. 16, 41, 53, 168). Consequently,systemic administration of LPS replicates many of the featuresof the acute phase response, including fever and so has becomea widely employed experimental paradigm in rats. Anotherwell-accepted model for fever based upon the mechanismproposed above is the central administration of PGE2, whichreliably and markedly increases body temperature in rats whengiven either by intracerebroventricular infusion or microin-jected directly into the POA (5, 116, 127, 136, 144).

The results of experiments that used this latter experimentalparadigm first suggested that the DMH might be involved infever two decades ago. Zabawska and colleagues (220) at-tempted to localize the central site of a putative cholinergic linkin the generation of hyperthermia elicited by microinjection ofPGE2 into the POA. In conscious control rats, rectal tempera-ture was elevated by more than 1.5°C 15 min after microin-jection of PGE2, and this effect was essentially abolished aftermicroinjection of atropine sulfate into either the dorsal ordorsomedial hypothalamus (fig. 6). The dose of atropine in-jected (5 �g, or �7 nmol) was sufficiently high to call intoquestion the pharmacological specificity of this effect, thusundermining the stated purpose of the study. Nevertheless,anatomic specificity was apparent since identical microinjec-tions of atropine into the VMH or the thalamus dorsal to theDMH failed to influence PGE2-induced hyperthermia.

In contrast to the experiments of Zabawska and colleagues,anatomic specificity appears to have been assumed in a subse-quent study that used this same model for fever but focused on

Fig. 6. Left: effect of microinjection ofPGE2 (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 theDMH with saline vehicle (1 �l; circles) oratropine (5 �g or �7 nmol; triangles). Right:schematic coronal section of the rat braindepicting sites in the dorsal/dorsomedial hy-pothalamic (DH; triangles) area, where mi-croinjection of atropine blocked hyperther-mia induced by injection of PGE2 into thePO/AH in experiments at left. Also shownare sites more dorsal, said to be in the thal-amus (T; squares) and more ventral in theventromedial hypothalamus (VH; circles),where identical microinjections of atropinefailed to influence PGE2-induced increasesin rectal temperature. [from Zabawska et al.(220)]

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the VMH (5). Here, microinjection of muscimol into the VMHwas reported to reduce markedly the increase in both IBATtemperature and core temperature elicited by microinjection ofPGE2 into the POA in anesthetized rats (5). However, in thiscase, the site of action was simply assumed to be the VMH,based upon the prevailing hypothesis that the VMH repre-sented the primary hypothalamic site for sympathetic control ofBAT. In retrospect, this assumption clearly was clearly illconceived, especially given that the high dose of muscimol(440 pmol) and large volume of injection in which it wasdelivered (500 nl) made it highly likely that neurons in sur-rounding regions (such as the DMH) might be affected.

Thus, although the report of Zabawska and colleagues, astudy that included appropriate anatomic control experiments,was the first to implicate neurons in the region of the DMH inexperimental fever, the idea was forgotten, in deference toprevailing dogma until the more recent convergence of newlines of evidence outlined above. Specifically, microinjectionof muscimol into the rRP was shown to block both theincreases in core body temperature, IBAT temperature, andsympathetic nerve activity to IBAT caused by microinjectionof PGE2 into the POA in anesthetized rats (130, 136). Thelatter observations clearly implicated activation of the thermo-regulatory sympathetic premotor neurons in the rRP in thismodel of fever in rats. At the same time, a link had been forged

between sympathoexcitatory neurons in the DMH and those inthe rRP (172). Together, these findings brought the potentialrole of the DMH in fever into focus.

In studies that paralleled those of the rRP, microinjection ofmuscimol into the DMH was indeed shown to suppress thefebrile response evoked by microinjection of PGE2 into thePOA. Zaretskaia and colleagues (222) first showed that unilat-eral microinjection of muscimol into the DMH evoked animmediate suppression of the elevation in body temperatureelicited by injection of PGE2 into the ipsilateral POA inanesthetized rats. At the same time, injection of muscimolproduced a smaller, but significant, effect on the accompanyingincrease in heart rate. This result was subsequently confirmedin expanded studies by Madden and Morrison (116; fig. 7) andNakamura and colleagues (138) who found that bilateral mi-croinjections of muscimol into the DMH during the plateauphase of the febrile response rapidly reversed the PGE2-induced increases in IBAT sympathetic nerve activity, IBATtemperature, expired CO2, and heart rate. Most importantly,identical microinjection of muscimol into the lateral hypothal-amus, another hypothalamic area where disinhibition has re-cently been shown to elicit thermogenesis (34), failed toinfluence any of the PGE2-induced increases (138). Thus adegree of anatomic specificity for the effect of microinjectionsinto the DMH was clearly demonstrated. In one study, similar

Fig. 7. Results from two representative experiments depict-ing sympathetic, thermogenic, and cardiovascular responsesafter microinjection of PGE2 into the medial preoptic area(MPA) and acute reversal elicited by microinjection ofmuscimol (MUSC) into the DMH in anesthetized rats. Notethat injection of PGE2 elicits sustained increases in IBATtemperature, expired CO2, heart rate, and arterial pressurethat are unaffected by bilateral microinjection of salinevehicle (60 nl/side) into the DMH but rapidly reversed bysimilar injection of MUSC (120 pmol/side). [from Maddenand Morrison (116)]

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microinjection of the ionotropic glutamate receptor antagonistkynurenate into the DMH also countered PGE2-induced changes.Thus, not only was neuronal excitation in the DMH largelyresponsible for the activation of BAT and other accompanyingsympathetic effects elicited by PGE2 acting in the POA, butthis excitation appeared to rely on activation of excitatoryglutamate receptors in the region. The latter finding paralleledthe results of Soltis and DiMicco more than a decade earlier,demonstrating a role for activation of ionotropic glutamatereceptors in the DMH in stress-induced tachycardia (185), nowalso known to be mediated largely through the rRP (223).

These current findings invite a reappraisal of the results ofprior studies aimed at elucidating the hypothalamic circuitrymediating the febrile response. Past results seemed to point tothe classic suspects as “downstream” mediators of feverevoked from the POA, including the PVN (25, 83; also, seeRef. 57), the PH (123), and the VMH (124). In the case of eachof these regions, the critical functional evidence supporting itsrole was that lesioning or inhibiting local neurons was reportedto attenuate experimentally induced fever. However, as dis-cussed above, once again, the proximity of each of these areasto the DMH presents the possibility that the effects noted inthese studies might actually be mediated through neurons in thelatter region. For example, Monda and colleagues had reportedthat the increases in sympathetic nerve activity to IBAT pro-duced by intracerebroventricular administration of PGE1 inanesthetized rats were suppressed by microinjection of musci-mol into the PH (123). However, the dose and volume in whichit was injected suggest that spread or diffusion to the relevantthermoregulatory neurons in the DMH might account for theeffect noted. Even more importantly, the stereotaxic coordi-nates targeted in these experiments taken from the atlas ofPellegrino (155) correspond, in fact, more closely to the DMH,as the regions were subsequently delineated in a more currentreference work (154; see discussion in Ref. 184). Other reportsof a modest reduction in experimentally induced fever afterchemical lesioning in either the VMH (124) or the PVN (25)used the excitotoxin ibotenate, an agent thought to act throughstimulation of ionotropic glutamate receptors. Given the ap-parent sensitivity of sympathoexcitatory neurons in the DMHto other ionotropic glutamate receptor agonists (see Search fora hypothalamic thermogenic center and Refs. 45 and 184) andthe fact that none of these studies included controls to establishanatomic specificity for their interventions, the possibility ofexcitotoxic damage to the DMH seems plausible here as well.

It should be noted that in nearly all of these studies andcertainly in those that point directly to the participation of theDMH in fever, the experimental model used involves thecentral administration of PGE2 in anesthetized preparations.However, anesthesia disrupts normal thermoregulation, so thatartificial means are generally used to support basal bodytemperature in such experiments. Given this, it seems clear thatcaution must be exercised when extrapolating the results fromstudies in anesthetized preparations to physiological thermo-regulatory processes. Furthermore, as discussed above, themodel itself is based upon current long-standing and perhapsoverly simplistic hypotheses regarding the central mechanismsand origins of the febrile response. Another model for feverand one that is arguably more “physiological”, involves thesystemic administration of LPS in an unanesthetized prepara-tion. As with central administration of PGE2, LPS elicits

increases in body temperature, but the response is highlycomplex and may involve various modes of signaling the CNS(for reviews, see refs. 41, 167, 168). Numerous studies in ratshave reported that systemic administration of LPS increases fosexpression in the DMH (56, 66, 103, 104, 158, 165, 224),indicating that neurons in the region are activated in thismodel, and preliminary results suggest that this activationinvolves neurons in the region that project to the rRP (174). Todate, however, no study that has systematically examined theeffect of interventions in the DMH on the response to systemicLPS in rats has appeared.

Involvement of DMH in Physiological and PathophysiologicalThermoregulatory Phenomena: Avenues for Future Exploration

The finding that neurons in the DMH may signal the acti-vation of premotor sympathetic neurons in the rRP that areaimed at elevating body temperature in cold defense and infever invites speculation regarding their potential roles inthermoregulatory responses in a variety of additional settings.

Among these settings are those associated with chemicalsignals related to food intake and ingestive behavior, a hypo-thalamic function that has long been linked with thermoregu-lation (see Ref. 70). For example, leptin, a peptide best knownfor its effect on feeding behavior, also produces an increase inbody temperature in rats and mice (26, 156, 187, 188) and mayplay a role in the circadian rhythmicity of body temperature inhumans (181). Leptin receptors are found in the DMH (109,120) and systemic administration of leptin results in fos ex-pression in the region (54), including the dorsal portion whereneurons projecting to the rRP are concentrated. Microinjectionof leptin into the DMH—but not into the PVN or the VMH—elevates heart rate in anesthetized rats (117), suggesting thatthe peptide is capable of exciting cardiac sympathoexcitatoryrRP-projecting neurons in the region. Most importantly, Mor-rison has demonstrated that intravenous administration of lep-tin elicits increases in sympathetic nerve activity to IBAT,IBAT temperature, and heart rate in anesthetized rats, and thatthese increases are suppressed by stimulation of serotonergic5-HT1A receptors in the rRP (131). Thus the leptin-inducedactivation of the rRP and resultant sympathetic thermogenicresponse may well be a consequence of activation of excitatoryprojections originating in the DMH. If so, then Morrison’sfinding also indicates that manipulation of serotonergic recep-tors in the rRP may be an effective means of blocking sympa-thoexcitatory transmission from the DMH (see Chemical sig-naling in thermoregulatory pathways involving the DMH).

The role of the DMH in drug-induced thermoregulatorydisturbances represents another relatively unexplored area ripefor investigation. An example here is presented by the narcoticanalgesics. Morphine itself, as well as other drugs and peptidesacting at �-opioid receptors, elicits increases in body temper-ature in rats (6, 38, 67, 177), perhaps by an action in the POA(163, 205, 207, 214), although a site of action in the periaq-ueductal grey has also been proposed (178, 211). The hyper-thermia produced by systemic administration of morphine isaccompanied by increased fos expression in the DMH (182),suggesting that activation of thermogenic mechanisms in theregion could be involved. Once again, studies by Morrison’slaboratory that focused principally on the regulation of sym-pathetic nerve activity to BAT have provided key findings in

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support of this idea. Cao and Morrison (32) examined theresponse evoked by the �-opioid receptor agonist fentanyl inanesthetized rats. Given either intravenously or intracerebrov-entricularly, fentanyl evoked increases in renal and IBATsympathetic nerve activity, IBAT temperature, heart rate, andarterial pressure. The intracerebroventricular fentanyl-inducedincreases in IBAT sympathetic nerve activity, IBAT tempera-ture, and heart rate were virtually abolished by prior microin-jection of muscimol into the DMH, while fentanyl-evokedincreases in arterial pressure and renal sympathetic nerveactivity were unaffected. Thus neuronal activity in the DMHseems likely to play a role in the hyperthermia seen aftersystemic administration of narcotic analgesics that act through�-opioid receptors in rats.

Returning full circle, the role of the DMH-to-rRP circuit inthe hyperthermia typically seen in experimental stress repre-sents another promising research avenue. As discussed above,evidence has accrued over the past decade supporting a role forneuronal activity in the DMH in a wide range of physiologicalresponses associated with experimental stress in rats. Stresshyperthermia is an often ignored but well-documented phe-nomenon known to occur in rats and other mammals (22, 100,113, 114, 208), including humans (59, 69, 162), and has beenproposed to play a role in physiological thermoregulation insome mammals in the wild (134). In the laboratory, the abilityof even the mild stress associated with experimental manipu-lation to elevate body temperature often necessitates carefulconsideration in the design of studies of the febrile response inconscious animals (e.g, Refs. 166 and 189). Similarities (22,113, 114, 208) and differences (89) between stress hyperther-mia and more conventional fevers have been posited, but thecentral mechanisms and neural pathways that mediate theformer remain less well studied than those responsible for thelatter (for a review see Ref. 145). Because sympatheticallymediated activation of BAT seems to be involved in stress-induced hyperthermia in the rat (179), a role for activation ofexcitatory projections from the DMH to the rRP seems highlylikely, and our preliminary results support this idea. We havefound that in conscious rats, microinjection of saline into theDMH or the PVN in control experiments typically results in anincrease in body temperature, likely resulting from the mildstress of experimental manipulation. Similar increases in tem-perature were also apparent after microinjection of muscimolinto the PVN but were entirely absent after otherwise identicalmicroinjection of muscimol into the DMH (Hunt JL, ZaretskyDV, Sarkar S, DiMicco JA, unpublished observations). Thesefindings suggest that inhibition of activity in the DMH cansuppress stress-induced hyperthermia and so support a role forneurons in the region in this phenomenon.

Chemical Signaling in Thermoregulatory Pathways InvolvingDMH: Another Unexplored Frontier

The forgoing provides ample evidence, suggesting an im-portant role for neurons in the DMH—and specifically forthose in the region that project to the medullary rRP—in thecontrol of sympathetic thermoregulatory mechanisms in a va-riety of settings. Now, important questions can be addressedwith regard to the neuropharmacology of this anatomicallydefined pathway. Clearly, activity of relevant thermoregulatoryneurons at both the hypothalamic and the brain stem level is

regulated by synaptic inhibition and excitation mediated byGABAA receptors and ionotropic glutamate receptors, respec-tively (31, 33, 116, 132). However, little else is known aboutthe potential for modulation of transmission in this key path-way by receptors for other neurotransmitters.

One direction that appears promising for future study is thepotential involvement of serotonin and serotonergic receptorsin the circuit. Serotonin-containing neurons are found in therRP, and these are known to project to sympathetic regions ofthe spinal cord. Recent evidence links serotonergic neurons inthe rRP to thermoregulation (141). For many years, it has beenappreciated that serotonergic drugs have significant effects onbody temperature (for a review, see Ref. 40). This is particu-larly true for agents that act to stimulate 5HT1A receptors,which are well known to evoke pronounced hypothermia (78,122), perhaps by acting in the rRP (14, 199). Horiuchi andcoworkers (82) found that the increases in heart rate, arterialpressure, and renal sympathetic nerve activity evoked by dis-inhibition of the DMH in anesthetized rats could be virtuallyabolished by systemically or intracisternally administered8-OH-DPAT, a prototypical 5HT1A receptor agonist. Blessingfirst reported that systemic administration of this agent couldprevent the increases in body temperature and decreased bloodflow to the pinna evoked by systemic administration of LPS inrabbits, and that this effect was reversed by the 5HT1Areceptor antagonist WAY 100635 (18). Subsequently, micro-injection of 8-OH-DPAT into the rRP in conscious rabbits wasreported to suppress the sympathetically mediated tachycardiaevoked by stress or by LPS (140). As discussed above, acti-vation of BAT evoked by systemic leptin in anesthetized ratscan be suppressed by stimulation of 5HT1A receptors in therRP (131). Together, these findings suggest that sympathoex-citatory transmission from the DMH to the rRP—including thatwhich is relevant to thermoregulation—can be inhibited bystimulation of 5HT1A receptors in the latter region. Given thatstress-induced hyperthermia is likely to be signaled through thecircuit from the DMH to the rRP, a report that 8-OH-DPATsuppresses this phenomenon in mice (107) provides additionalsupport for both hypotheses.

Perspectives

Thus the DMH has suddenly come to light as a hypothalamicregion interposed between classic thermoregulatory neurons inthe POA and downstream neurons that ultimately control avariety of mechanisms relevant to body temperature in rats.Evidence for this idea is strongest with regard to projections tosympathetic premotor neurons in the rRP—and perhaps thecPAG—that regulate BAT. Further insights into signalingrelated to thermoregulation through projections from the DMHto these downstream regions will undoubtedly emerge fromcharacterization of the phenotype of the specific neurons thatcontribute to these pathways. However, the literature also hintsat the participation of neurons in the DMH in thermoregulatoryendocrine adjustments, somatomotor activity, and even behav-ior (see Ref. 118). If these possibilities are borne out by theresults of future studies, then the DMH may assume the role ofa key hypothalamic site responsible for integrating the controland coordination of multiple effector systems that mediatethermoregulation in mammals. How this new function for theregion might relate to its better established role in physiolog-

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ical and behavioral responses to exteroceptive stress (for re-views, see Refs. 50 and 51) is an issue that invites numerousquestions. For example, responses to stress resemble in manyways the physiological changes seen in exposure to cold (i.e.,“cold stress”) or accompanying the innate immune response,but the resemblance is not perfect. Do these different circum-stances recruit a slightly different subset of neurons in theDMH, or is the response shaped and modified by the involve-ment of other brain regions? Similarly, although the neuronscontrolling sympathetic nervous responses to BAT and theheart have been localized to a distinct subregion of the DMH,those responsible for the accompanying neuroendocrine andbehavioral effects have not. As the afferent and efferent neuralcircuitry relevant to these components becomes clear, the stagewill be set for studies that will likewise clarify the functionalneuroanatomy of the DMH.

GRANTS

This work was supported by U. S. Public Health Service Grants NS 19883and MH 65697. This investigation was conducted in a facility constructed withsupport from Research Facilities Improvement Program Grant Number C06RR015481–01 from the National Center for Research Resources, NationalInstitutes of Health.

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