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To maintain core body temperature in mammals, the CNS thermoregulatory networks respond to cold exposure by increasing brown adipose tissue and shivering thermogenesis. However, in hibernation or torpor, this normal thermoregulatory response is supplanted by “thermoregulatory inversion”, an altered homeostatic state in which cold exposure causes inhibition of thermogenesis and warm exposure stimulates thermogenesis. Here we demonstrate the existence of a novel, dynorphinergic thermoregulatory reflex pathway between the dorsolateral parabrachial nucleus and the dorsomedial hypothalamus that bypasses the normal thermoregulatory integrator in the hypothalamic preoptic area to play a critical role in mediating the inhibition of thermogenesis during thermoregulatory inversion. Our results indicate the existence of a neural circuit mechanism for thermoregulatory inversion within the CNS thermoregulatory pathways and support the potential for inducing a homeostatically-regulated, therapeutic hypothermia in non-hibernating species, including humans.

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Hyperphosphorylated Tau protein (PPTau) is the hallmark of tauopathic neurodegeneration. During “synthetic torpor” (ST), a transient hypothermic state which can be induced in rats by the local pharmacological inhibition of the Raphe Pallidus, a reversible brain Tau hyperphosphorylation occurs. The aim of the present study was to elucidate the – as yet unknown – molecular mechanisms underlying this process, at both a cellular and systemic level. Different phosphorylated forms of Tau and the main cellular factors involved in Tau phospho-regulation were assessed by western blot in the parietal cortex and hippocampus of rats induced in ST, at either the hypothermic nadir or after the recovery of euthermia. Pro- and anti-apoptotic markers, as well as different systemic factors which are involved in natural torpor, were also assessed. Finally, the degree of microglia activation was determined through morphometry. Overall, the results show that ST triggers a regulated biochemical process which can counteract PPTau formation starting, unexpectedly even for a non-hibernator, from the hypothermic nadir. In particular, at the nadir, the glycogen synthase kinase-β was largely inhibited in both regions, the antiapoptotic factor AKT was significantly activated in the hippocampus, and melatonin plasma levels were significantly increased, while a transient neuroinflammation was observed during the recovery period. Together, the present data suggest that ST can trigger a previously undescribed latent and regulated physiological process, that is able to cope with brain PPTau formation.Graphical abstract

open 5 si This research was supported by National Institutes of Health Grants NS040987 and NS091066 (SFM); NS099234 and Rita Levi Montalcini Program (DT); NS099234 and OD010996 (GC) Within the central neural circuitry for thermoregulation, the balance between excitatory and inhibitory inputs to the dorsomedial hypothalamus (DMH) determines the level of activation of brown adipose tissue (BAT) thermogenesis. We employed neuroanatomical and in vivo electrophysiological techniques to identify a source of excitation to thermogenesis-promoting neurons in the DMH that is required for cold defense and fever. Inhibition of median preoptic area (MnPO) neurons blocked the BAT thermogenic responses during both PGE2-induced fever and cold exposure. Disinhibition or direct activation of MnPO neurons induced a BAT thermogenic response in warm rats. Blockade of ionotropic glutamate receptors in the DMH, or brain transection rostral to DMH, blocked cold-evoked or NMDA in MnPO-evoked BAT thermogenesis. RNAscope technique identified a glutamatergic population of MnPO neurons that projects to the DMH and expresses c-Fos following cold exposure. These discoveries relative to the glutamatergic drive to BAT sympathoexcitatory neurons in DMH augment our understanding of the central thermoregulatory circuitry in non-torpid mammals. Our data will contribute to the development of novel therapeutic approaches to induce therapeutic hypothermia for treating drug-resistant fever, and for improving glucose and energy homeostasis. open da Conceicao E.P.S.; Morrison S.F.; Cano G.; Chiavetta P.; Tupone D. da Conceicao E.P.S.; Morrison S.F.; Cano G.; Chiavetta P.; Tupone D.

The parabrachial nucleus (PBN) has long been recognized as a sensory relay receiving an array of interoceptive and exteroceptive inputs relevant to taste and ingestive behavior, pain, and multiple aspects of autonomic control, including respiration, blood pressure, water balance, and thermoregulation. Outputs are known to be similarly widespread and complex. How sensory information is handled in PBN and used to inform different outputs to maintain homeostasis and promote survival is only now being elucidated. With a focus on taste and ingestive behaviors, pain, and thermoregulation, this review is intended to provide a context for analysis of PBN circuits involved in aversion and avoidance, and consider how information of various modalities, interoceptive and exteroceptive, is processed within PBN and transmitted to distinct targets to signal challenge, and to engage appropriate behavioral and physiological responses to maintain homeostasis.

Neurogenic fever (NF) after subarachnoid hemorrhage (SAH) is a major cause of morbidity that is associated with poor outcomes and prolonged stay in the neurointensive care unit (NICU). Though SAH is a much more common cause of fever than sepsis in the NICU, it is often a diagnosis of exclusion, requiring significant effort to rule out an infectious source. NF does not respond to standard anti-pyretic medications such as COX inhibitors, and lack of good medical therapy has led to the introduction of external cooling systems that have their own associated problems. In a rodent model of SAH, we measured the effects of injecting whole blood, blood plasma, or erythrocytes on the sympathetic nerve activity to brown adipose tissue and on febrile thermogenesis. We demonstrate that following SAH the acute activation of brown adipose tissue leading to NF, is not dependent on PGE2, that subarachnoid space injection of whole blood or erythrocytes, but not plasma alone, is sufficient to trigger brown adipose tissue thermogenesis, and that activation of adenosine A1 receptors in the CNS can block the brown adipose tissue thermogenic component contributing to NF after SAH. These findings point to a distinct thermogenic mechanism for generating NF, compared to those due to infectious causes, and will hopefully lead to new therapies.

Torpor is a peculiar mammalian behaviour, characterized by the active reduction of metabolic rate, followed by a drop in body temperature. To enter torpor, the activation of all thermogenic organs that could potentially defend body temperature must be prevented. Most of these organs, such as the brown adipose tissue, are controlled by the key thermoregulatory region of the Raphe Pallidus (RPa). Currently, it is not known which brain areas mediate the entrance into torpor. To identify these areas, the expression of the early gene c-Fos at torpor onset was assessed in different brain regions in mice injected with a retrograde tracer (Cholera Toxin subunit b, CTb) into the RPa region. The results show a network of hypothalamic neurons that are specifically activated at torpor onset and a direct torpor-specific projection from the Dorsomedial Hypothalamus to the RPa that could putatively mediate the suppression of thermogenesis during torpor.

Tau protein is of primary importance for many physiological processes in neurons, where it affects the dynamics of the microtubule system. When hyperphosphorylated (PP-Tau), Tau monomers detach from microtubules and tend to aggregate firstly in oligomers, and then in neurofibrillary tangles, as it occurs in a group of neurodegenerative disorders named thauopathies. A hypothermia-related accumulation of PP-Tau, which is quickly reversed after the return to normothermia, has been shown to occur in the brain of hibernators during torpor. Since, recently, in our lab, a hypothermic torpor-like condition (synthetic torpor, ST) was pharmacologically induced in the rat, a non-hibernator, the aim of the present work was to assess whether ST can lead to a reversible PP-Tau accumulation in the rat brain. PP-Tau was immunohistochemically assessed by staining for AT8 (phosphorylated Tau) and Tau-1 (non-phosphorylated Tau) in 19 brain structures, which were chosen mostly due to their involvement in the regulation of autonomic and cognitive functions in relation to behavioral states. During ST, AT8 staining was strongly expressed throughout the brain, while Tau-1 staining was reduced compared to control conditions. During the following recovery period, AT8 staining progressively reduced close to zero after 6 h from ST. However, Tau-1 staining remained low even after 38 h from ST. Thus, overall, these results show that ST induced an accumulation of PP-Tau that was, apparently, only partially reversed to normal during the recovery period. While the accumulation of PP-Tau may only depend on the physicochemical characteristics of the enzymes regulating Tau phosphorylation, the reverse process of dephosphorylation should be actively regulated, also in non-hibernators. In conclusion, in this work a reversible and widespread PP-Tau accumulation has been induced through a procedure that leads a non-hibernator to a degree of reversible hypothermia, which is comparable to that observed in hibernators. Therefore, the physiological mechanism involved in this process can sustain an adaptive neuronal response to extreme conditions, which may however lead to neurodegeneration when particular intensities and durations are exceeded.

Torpor is a peculiar mammalian behaviour, characterized by the active reduction of metabolic rate, followed by a drop in body temperature. To enter torpor, the activation of all thermogenic organs that could potentially defend body temperature must be prevented. Most of these organs, such as the brown adipose tissue, are controlled by the key thermoregulatory region of the Raphe Pallidus (RPa). Currently, it is not known which brain areas mediate the entrance into torpor. To identify these areas, the expression of the early gene c-Fos at torpor onset was assessed in different brain regions in mice injected with a retrograde tracer (Cholera Toxin subunit b, CTb) into the RPa region. The results show a network of hypothalamic neurons that are specifically activated at torpor onset and a direct torpor-specific projection from the Dorsomedial Hypothalamus to the RPa that could putatively mediate the suppression of thermogenesis during torpor.

A cellular degeneration of two thalamic nuclei belonging to the "limbic thalamus", i.e., the anteroventral (AV) and mediodorsal (MD) nuclei, has been shown in patients suffering from Fatal Familial Insomnia (FFI), a lethal prion disease characterized by autonomic activation and severe insomnia. To better assess the physiological role of these nuclei in autonomic and sleep regulation, c-Fos expression was measured in rats during a prolonged exposure to low ambient temperature (Ta, -10°C) and in the first hours of the subsequent recovery period at normal laboratory Ta (25°C). Under this protocol, the thermoregulatory and autonomic activation led to a tonic increase in waking and to a reciprocal depression in sleep occurrence, which was more evident for REM sleep. These effects were followed by a clear REM sleep rebound and by a rebound of Delta power during non-REM sleep in the following recovery period. In the anterior thalamic nuclei, c-Fos expression was (1) larger during the activity rather than the rest period in the baseline; (2) clamped at a level in-between the normal daily variation during cold exposure; (3) not significantly affected during the recovery period in comparison to the time-matched baseline. No significant changes were observed in either the MD or the paraventricular thalamic nucleus, which is also part of the limbic thalamus. The observed changes in the activity of the anterior thalamic nuclei appear, therefore, to be more specifically related to behavioral activation than to autonomic or sleep regulation.

To maintain body core temperature (TCORE) in mammals, the central nervous system thermoregulatory networks respond to skin cooling by increasing brown adipose tissue (BAT) and shivering thermogenes...

The regulation of energy balance involves complex processes in the brain, including coordination by hypothalamic neurons that contain pro-opiomelanocortin (POMC). We previously demonstrated that central bone morphogenetic protein (BMP) 7 reduced appetite. Now we show that a type 1 BMP receptor, BMPR1A, is colocalized with POMC neurons and that POMC-BMPR1A-knockout (KO) mice are hyperphagic, revealing physiological involvement of BMP signaling in anorectic POMC neurons in the regulation of appetite. Surprisingly, the hyperphagic POMC-BMPR1A-KO mice exhibited a lack of obesity, even on a 45% high-fat diet. This is because the brown adipose tissue (BAT) of KO animals exhibited increased sympathetic activation and greater thermogenic capacity owing to a reestablishment of energy balance, most likely stemming from a compensatory increase of BMPR1A in the whole hypothalamus of KO mice. Indeed, control animals given central BMP7 displayed increased energy expenditure and a specific increase in sympathetic nerve activity (SNA) in BAT. In these animals, pharmacological blockade of BMPR1A-SMAD signaling blunted the ability of BMP7 to increase energy expenditure or BAT SNA. Together, we demonstrated an important role for hypothalamic BMP signaling in the regulation of energy balance, including BMPR1A-mediated appetite regulation in POMC neurons as well as hypothalamic BMP-SMAD regulation of the sympathetic drive to BAT for thermogenesis.

To maintain core body temperature in mammals, the normal central nervous system (CNS) thermoregulatory reflex networks produce an increase in brown adipose tissue (BAT) thermogenesis in response to skin cooling and an inhibition of the sympathetic outflow to BAT during skin rewarming. In contrast, these normal thermoregulatory reflexes appear to be inverted in hibernation/torpor; thermogenesis is inhibited during exposure to a cold environment, allowing dramatic reductions in core temperature and metabolism, and thermogenesis is activated during skin rewarming, contributing to a return of normal body temperature. Here, we describe two unrelated experimental paradigms in which rats, a nonhibernating/torpid species, exhibit a “thermoregulatory inversion,” which is characterized by an inhibition of BAT thermogenesis in response to skin cooling, and a switch in the gain of the skin cooling reflex transfer function from negative to positive values. Either transection of the neuraxis immediately rostral to the dorsomedial hypothalamus in anesthetized rats or activation of A1 adenosine receptors within the CNS of free-behaving rats produces a state of thermoregulatory inversion in which skin cooling inhibits BAT thermogenesis, leading to hypothermia, and skin warming activates BAT, supporting an increase in core temperature. These results reflect the existence of a novel neural circuit that mediates inverted thermoregulatory reflexes and suggests a pharmacological mechanism through which a deeply hypothermic state can be achieved in nonhibernating/torpid mammals, possibly including humans.

The rostral ventromedial medulla (RVM) has a well-documented role in pain modulation and exerts antinociceptive and pronociceptive influences mediated by 2 distinct classes of neurons, OFF-cells and ON-cells. OFF-cells are defined by a sudden pause in firing in response to nociceptive inputs, whereas ON-cells are characterized by a "burst" of activity. Although these reflex-related changes in ON- and OFF-cell firing are critical to their pain-modulating function, the pathways mediating these responses have not been identified. The present experiments were designed to test the hypothesis that nociceptive input to the RVM is relayed through the parabrachial complex (PB). In electrophysiological studies, ON- and OFF-cells were recorded in the RVM of lightly anesthetized male rats before and after an infusion of lidocaine or muscimol into PB. The ON-cell burst and OFF-cell pause evoked by noxious heat or mechanical probing were substantially attenuated by inactivation of the lateral, but not medial, parabrachial area. Retrograde tracing studies showed that neurons projecting to the RVM were scattered throughout PB. Few of these neurons expressed calcitonin gene-related peptide, suggesting that the RVM projection from PB is distinct from that to the amygdala. These data show that a substantial component of "bottom-up" nociceptive drive to RVM pain-modulating neurons is relayed through the PB. While the PB is well known as an important relay for ascending nociceptive information, its functional connection with the RVM allows the spinoparabrachial pathway to access descending control systems as part of a recurrent circuit.

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The dependence of BAT thermogenesis on the availability of metabolic substrates suggests that metabolic signals from the viscera could influence the sympathetic outflow driving BAT thermogenesis. Viscerosensory afferents in the proximal end of the sectioned left cervical vagus nerve were activated with electrical stimulation in anesthetized, ventilated rats while recording the SNA to the contralateral interscapular BAT pad. Paired-pulse VNS delivered once every 5 sec evoked excitatory evoked potentials in BAT SNA with a peak latency of ~ 180 ms, followed by a ~2 s period of quiescent BAT SNA. Within a few seconds of stimulus onset, continuous, single-pulse VNS at 2 Hz produced a complete inhibition of cold-evoked BAT SNA that was sustained for at least 2 hrs of maintained VNS. Similarly, activation of neurons in the intermediate nucleus of the solitary tract (iNTS), at the level of the area postrema, with nanoinjections (60 pmol) of bicuculline also inhibits the VNS-evoked excitation of BAT SNA. Inhibitio...

Thermogenesis, the production of heat energy, is the specific, neurally regulated, metabolic function of brown adipose tissue (BAT) and contributes to the maintenance of body temperature during cold exposure and to the elevated core temperature during several behavioral states, including wakefulness, the acute phase response (fever), and stress. BAT energy expenditure requires metabolic fuel availability and contributes to energy balance. This review summarizes the functional organization and neurochemical influences within the CNS networks governing the level of BAT sympathetic nerve activity to produce the thermoregulatory and metabolically driven alterations in BAT thermogenesis and energy expenditure that contribute to overall energy homeostasis. � 2014 Elsevier Inc.

Activation of central adenosine A1 receptors in the rat, a non-hibernating species, mimics the physiological characteristics of torpor and could thus represent a basis for the development of pharmacological approaches to induce therapeutic hypothermia in pathologies such as brain hemorrhage and ischemia, and to facilitate long-term space travel.

Thermoregulatory responses to temperature changes are not operant during REM sleep (REMS), but fully operant in non-REM sleep and wakefulness. The specificity of the relationship between REMS and the impairment of thermoregulation was tested by eliciting the reflex release of Thyrotropin Releasing Hormone (TRH), which is integrated at hypothalamic level. By inducing the sequential secretion of Thyroid Stimulating Hormone (TSH) and Thyroid Hormone, TRH intervenes in the regulation of obligatory and non-shivering thermogenesis. Experiments were performed on male albino rats implanted with epidural electrodes for EEG recording and 2 silver-copper wire thermodes, bilaterally placed in the preoptic-hypothalamic area (POA) and connected to small thermoelectric heat pumps driven by a low-voltage high current DC power supply. In preliminary experiments, a thermistor was added in order to measure hypothalamic temperature. The activation of TRH hypophysiotropic neurons by the thermode cooling of POA was indirectly assessed, in conditions in which thermoregulation was either fully operant (wakefulness) or not operant (REMS), by a radioimmunoassay determination of plasmatic levels of TSH. Different POA cooling were performed for 120 s or 40 s at current intensities of 80 mA and 125 mA, respectively. At both current intensities, POA cooling elicited, with respect to control values (no cooling current), a significant increase in plasmatic TSH levels in wakefulness, but not during REMS. These results confirm the inactivation of POA thermal sensitivity during REMS and show, for the first time, that this inactivation concerns also the fundamental endocrine control of non-shivering thermogenesis.

From mouse to man, brown adipose tissue (BAT) is a significant source of thermogenesis contributing to the maintenance of the body temperature homeostasis during the challenge of low environmental temperature. In rodents, BAT thermogenesis also contributes to the febrile increase in core temperature during the immune response. BAT sympathetic nerve activity controlling BAT thermogenesis is regulated by CNS neural networks which respond reflexively to thermal afferent signals from cutaneous and body core thermoreceptors, as well as to alterations in the discharge of central neurons with intrinsic thermosensitivity. Superimposed on the core thermoregulatory circuit for the activation of BAT thermogenesis, is the permissive, modulatory influence of central neural networks controlling metabolic aspects of energy homeostasis. The recent confirmation of the presence of BAT in human and its function as an energy consuming organ have stimulated interest in the potential for the pharmacological activation of BAT to reduce adiposity in the obese. In contrast, the inhibition of BAT thermogenesis could facilitate the induction of therapeutic hypothermia for fever reduction or to improve outcomes in stroke or cardiac ischemia by reducing infarct size through a lowering of metabolic oxygen demand. This review summarizes the central circuits for the autonomic control of BAT thermogenesis and highlights the potential clinical relevance of the pharmacological inhibition or activation of BAT thermogenesis. � 2014 Tupone, Madden and Morrison.

Since central activation of A1 adenosine receptors (A1ARs) plays an important role in the induction of the hypothermic and hypometabolic torpid state in hibernating mammals, we investigated the potential for the A1AR agonist N6-cyclohexyladenosine to induce a hypothermic, torpor-like state in the (nonhibernating) rat. Core and brown adipose tissue temperatures, EEG, heart rate, and arterial pressure were recorded in free-behaving rats, and c-fos expression in the brain was analyzed, following central administration of N6-cyclohexyladenosine. Additionally, we recorded the sympathetic nerve activity to brown adipose tissue; expiratory CO2and skin, core, and brown adipose tissue temperatures; and shivering EMGs in anesthetized rats following central and localized, nucleus of the solitary tract, administration of N6-cyclohexyladenosine. In rats exposed to a cool (15°C) ambient temperature, central A1AR stimulation produced a torpor-like state similar to that in hibernating species and characterized by a marked fall in body temperature due to an inhibition of brown adipose tissue and shivering thermogenesis that is mediated by neurons in the nucleus of the solitary tract. During the induced hypothermia, EEG amplitude and heart rate were markedly reduced. Skipped heartbeats and transient bradycardias occurring during the hypothermia were vagally mediated since they were eliminated by systemic muscarinic receptor blockade. These findings demonstrate that a deeply hypothermic, torpor-like state can be pharmacologically induced in a nonhibernating mammal and that recovery of normothermic homeostasis ensues upon rewarming. These results support the potential for central activation of A1ARs to be used in the induction of a hypothermic, therapeutically beneficial state in humans.

Sleep restriction leads to metabolism dysregulation and to weight gain, which is apparently the consequence of an excessive caloric intake. On the other hand, obesity is associated with excessive daytime sleepiness in humans and promotes sleep in different rodent models of obesity. Since no consistent data on the wake-sleep (WS) pattern in diet-induced obesity rats are available, in the present study the effects on the WS cycle of the prolonged delivery of a high-fat hypercaloric (HC) diet leading to obesity were studied in Sprague-Dawley rats. The main findings are that animals kept under a HC diet for either four or eight weeks showed an overall decrease of time spent in wakefulness (Wake) and a clear Wake fragmentation when compared to animals kept under a normocaloric diet. The development of obesity was also accompanied with the occurrence of a larger daily amount of REM sleep (REMS). However, the capacity of HC animals to respond to a "Continuous darkness" exposure condition (obtained by extending the Dark period of the Light-Dark cycle to the following Light period) with an increase of Sequential REMS was dampened. The results of the present study indicate that if, on one hand, sleep curtailment promotes an excess of energy accumulation; on the other hand an over-exceeding energy accumulation depresses Wake. Thus, processes underlying energy homeostasis possibly interact with those underlying WS behavior, in order to optimize energy storage.

The possibility of inducing a suspended animation state similar to natural torpor would be greatly beneficial in medical science, since it would avoid the adverse consequence of the powerful autonomic activation evoked by external cooling. Previous attempts to systemically inhibit metabolism were successful in mice, but practically ineffective in nonhibernators. Here we show that the selective pharmacological inhibition of key neurons in the central pathways for thermoregulatory cold defense is sufficient to induce a suspended animation state, resembling natural torpor, in a nonhibernator. In rats kept at an ambient temperature of 15°C and under continuous darkness, the prolonged inhibition (6 h) of the rostral ventromedial medulla, a key area of the central nervous pathways for thermoregulatory cold defense, by means of repeated microinjections (100 nl) of the GABAAagonist muscimol (1 mm), induced the following: (1) a massive cutaneous vasodilation; (2) drastic drops in deep brain temperature (reaching a nadir of 22.44 ± 0.74°C), heart rate (from 440 ± 13 to 207 ± 12 bpm), and electroencephalography (EEG) power; (3) a modest decrease in mean arterial pressure; and (4) a progressive shift of the EEG power spectrum toward slow frequencies. After the hypothermic bout, all animals showed a massive increase in NREM sleep Delta power, similarly to that occurring in natural torpor. No behavioral abnormalities were observed in the days following the treatment. Our results strengthen the potential role of the CNS in the induction of hibernation/torpor, since CNS-driven changes in organ physiology have been shown to be sufficient to induce and maintain a suspended animation state.

The positive outcome that hypothermia contributes to neuroprotection following brain ischemia has stimulated recent clinical interest in the development of techniques to induce a hypothermic and hypometabolic state. As demonstrated in hibernating animals, we recently showed that hypothermia and a torpor-like state can be induced in rat by central activation of A1AR. Both the reduction in metabolism and the reduced cortical function (i.e., lower EEG amplitude) are of interest in the application of a pharmacological approach to induce hypothermia to ameliorate the outcomes of ischemic stroke. The central activation of A1AR in rat is, however, accompanied by cardiovascular events, such as skipped beats and transient deep bradycardia associated with strong neck muscle activation. Similar events have been reported during naturally occurring torpor. Here we tested the hypothesis that these events arise from vagal input to the heart, by determining the effect of the muscarinic antagonist, atropine. Wistar male rats were implanted with a telemetric probe for the recording of the arterial pressure, with a thermistor located in the mediastinic cavity for the recording of core temperature and electrodes for the recording of the EEG and nuchal EMG. Following a day of baseline recording, rats were placed in an ambient temperature of 15 °C and treated with N6-Cyclohexyladenosine (CHA, 1 mM, 10 μL, ICV) to induce hypothermia. One hour after the injection, animals were treated with intraperitoneal injection of atropine or saline. Our preliminary result showed that atropine prevented the occurrence of the transient bradycardic events and skipped beats, but not the muscular contraction. This result suggests a role of cardiac vagal transmission in driving these cardiovascular events. Our conclusion that treatment with a cholinergic blocker could eliminate this cardiovascular side effect during a deep hypothermic state will support the translational potential of this approach for induction of hypothermia for human use following ischemic stroke.

�2 adrenergic receptor (�2-AR) agonists have been used as antihypertensive agents, in the management of drug withdrawal, and as sedative analgesics. Since �2-AR agonists also influence the regulation of body temperature, we explored their potential as antipyretic agents. This study delineates the central neural substrate for the inhibition of rat brown adipose tissue (BAT) and shivering thermogenesis by �2-AR agonists. Nanoinjection of the �2-AR agonist clonidine (1.2 nmol) into the rostral raphe pallidus area (rRPa) inhibited BAT sympathetic nerve activity (SNA) and BAT thermogenesis. Subsequent nanoinjection of the �2-AR antagonist idazoxan (6 nmol) into the rRPa reversed the clonidine-evoked inhibition of BAT SNA and BAT thermogenesis. Systemic administration of the �2-AR agonists dexmedetomidine (25 �g/kg, i.v.) and clonidine (100 �g/kg, i.v.) inhibited shivering EMGs, BAT SNA, and BAT thermogenesis, effects that were reversed by nanoinjection of idazoxan (6 nmol) into the rRPa. Dexmedetomidine (100 �g/kg, i.p.) prevented and reversed lipopolysaccharide-evoked (10 �g/kg, i.p.) thermogenesis in free-behaving rats. Cholera toxin subunit b retrograde tracing from rRPa and pseudorabies virus transynaptic retrograde tracing from BAT combined with immunohistochemistry for catecholaminergic biosynthetic enzymes revealed the ventrolateral medulla as the source of catecholaminergic input to the rRPa and demonstrated that these catecholaminergic neurons are synaptically connected to BAT. Photostimulation of ventrolateral medulla neurons expressing the PRSx8- ChR2-mCherry lentiviral vector inhibited BAT SNA via activation of 2-ARs in the rRPa. These results indicate a potent inhibition of BAT and shivering thermogenesis by �2-AR activation in the rRPa, and suggest a therapeutic potential of �2-AR agonists for reducing potentially lethal elevations in body temperature during excessive fever. � 2013 the authors.

Non-shivering thermogenesis in brown adipose tissue (BAT) plays an important role in thermoregulation. In addition, activations of BAT have important implications for energy homeostasis due to the metabolic consumption of energy reserves entailed in the production of heat in this tissue. In this conceptual overview, we describe the role of orexins/hypocretins within the central nervous system in the modulation of thermogenesis in BAT under several physiological conditions. Within this framework, we consider potential neural mechanisms underlying the pathological conditions associated with the absence of the central orexinergic modulation of BAT thermogenesis and energy expenditure. Overall, the experimental basis for our understanding of the role of central orexin in regulating body temperature and energy homeostasis provides an illustrative example that highlights several general principles and caveats that should help guide future investigations of the neurochemical regulation of thermogenesis and metabolism.

Non-shivering thermogenesis in brown adipose tissue (BAT) plays an important role in thermoregulatory cold-defense and, through its metabolic consumption of energy reserves to produce heat, can affect the long-term regulation of adiposity. An orexinergic pathway from the perifornical lateral hypothalamus (PeF/LH) to the rostral raphe pallidus (rRPa) has been demonstrated to increase the gain of the excitatory drives to medullary sympathetic premotor neurons controlling BAT sympathetic outflow and BAT thermogenesis. With this background, we consider neural mechanisms that could underlie orexin’s modulation of the excitability of BAT sympathetic premotor neurons in rRPa and the potential role of altered BAT thermogenesis in pathological conditions associated with the absence of the central orexin system. Overall, these new data enhance our understanding of the role of central orexin in regulating body temperature and energy homeostasis and provide further insight into the neurochemical regulation of BAT thermogenesis and metabolism.

Thermogenesis, the production of heat energy, is an essential component of the homeostatic repertoire to maintain body temperature during the challenge of low environmental temperature and plays a key role in elevating body temperature during the febrile response to infection. Mitochondrial oxidation in brown adipose tissue (BAT) is a significant source of neurally regulated metabolic heat production in many species from mouse to man. BAT thermogenesis is regulated by neural networks in the central nervous system which responds to feedforward afferent signals from cutaneous and core body thermoreceptors and to feedback signals from brain thermosensitive neurons to activate BAT sympathetic nerve activity. This review summarizes the research leading to a model of the feedforward reflex pathway through which environmental cold stimulates BAT thermogenesis and includes the influence on this thermoregulatory network of the pyrogenic mediator, prostaglandin E2, to increase body temperature during fever. The cold thermal afferent circuit from cutaneous thermal receptors, through secondorder thermosensory neurons in the dorsal horn of the spinal cord ascends to activate neurons in the lateral parabrachial nucleus which drive GABAergic interneurons in the preoptic area (POA) to inhibit warmsensitive, inhibitory output neurons of the POA. The resulting disinhibition of BAT thermogenesispromoting neurons in the dorsomedial hypothalamus activates BAT sympathetic premotor neurons in the rostral ventromedial medulla, including the rostral raphe pallidus, which provide excitatory, and possibly disinhibitory, inputs to spinal sympathetic circuits to drive BAT thermogenesis. Other recently recognized central sites influencing BAT thermogenesis and energy expenditure are also described. � 2012 Morrison, Madden and Tupone.

Wake-sleep (W-S) states are affected by thermoregulation. In particular, REM sleep (REMS) is reduced in homeotherms under a thermal load, due to an impairment of hypothalamic regulation of body temperature. The aim of this work was to assess whether osmoregulation, which is regulated at a hypothalamic level, but, unlike thermoregulation, is maintained across the different W-S states, could influence W-S occurrence. Sprague-Dawley rats, kept at an ambient temperature of 24°C and under a 12 h∶12 h light-dark cycle, were exposed to a prolonged osmotic challenge of three days of water deprivation (WD) and two days of recovery in which free access to water was restored. Two sets of parameters were determined in order to assess: i) the maintenance of osmotic homeostasis (water and food consumption; changes in body weight and fluid composition); ii) the effects of the osmotic challenge on behavioral states (hypothalamic temperature (Thy), motor activity, and W-S states). The first set of parameters changed in WD as expected and control levels were restored on the second day of recovery, with the exception of urinary Ca(++) that almost disappeared in WD, and increased to a high level in recovery. As far as the second set is concerned, WD was characterized by the maintenance of the daily oscillation of Thy and by a decrease in activity during the dark periods. Changes in W-S states were small and mainly confined to the dark period: i) REMS slightly decreased at the end of WD and increased in recovery; ii) non-REM sleep (NREMS) increased in both WD and recovery, but EEG delta power, a sign of NREMS intensity, decreased in WD and increased in recovery. Our data suggest that osmoregulation interferes with the regulation of W-S states to a much lesser extent than thermoregulation.

Orexin (hypocretin) neurons, located exclusively in the PeF-LH, which includes the perifornical area (PeF), the lateral hypothalamus (LH), and lateral portions of the medial hypothalamus, have widespread projections and influence many physiological functions, including the autonomic regulation of body temperature and energy metabolism. Narcolepsy is characterized by the loss of orexin neurons and by disrupted sleep, but also by dysregulation of body temperature and by a strong tendency for obesity. Heat production (thermogenesis) in brown adipose tissue (BAT) contributes to the maintenance of body temperature and, through energy consumption, to body weight regulation. We identified a neural substrate for the influence of orexin neurons on BAT thermogenesis in rat. Nanoinjection of orexin-A (12 pmol) into the rostral raphe pallidus (rRPa), the site of BAT sympathetic premotor neurons, produced large, sustained increases in BAT sympathetic outflow and in BAT thermogenesis. Activation of neurons in the PeF-LH also enhanced BAT thermogenesis over a long time course. Combining viral retrograde tracing from BAT, or cholera toxin subunit b tracing from rRPa, with orexin immunohistochemistry revealed synaptic connections to BAT from orexin neurons in PeF-LH and from rRPa neurons with closely apposed, varicose orexin fibers, as well as a direct, orexinergic projection from PeF-LH to rRPa. These results indicate a potent modulation of BAT thermogenesis by orexin released from the terminals of orexin neurons in PeF-LH directly into the rRPa and provide a potential mechanism contributing to the disrupted regulation of body temperature and energy metabolism in the absence of orexin. � 2011 the authors.