The neural pathway of the hyperthermic response to antagonists of the transient receptor potential vanilloid-1 channel.

We identified the neural pathway of the hyperthermic response to TRPV1 antagonists. We showed that hyperthermia induced by i.v. AMG0347, AMG 517, or AMG8163 did not occur in rats with abdominal sensory nerves desensitized by pretreatment with a low i.p. dose of resiniferatoxin (RTX, TRPV1 agonist). However, neither bilateral vagotomy nor bilateral transection of the greater splanchnic nerve attenuated AMG0347-induced hyperthermia. Yet, this hyperthermia was attenuated by bilateral high cervical transection of the spinal dorsolateral funiculus (DLF). To explain the extra-splanchnic, spinal mediation of TRPV1 antagonist-induced hyperthermia, we proposed that abdominal signals that drive this hyperthermia originate in skeletal muscles - not viscera. If so, in order to prevent TRPV1 antagonist-induced hyperthermia, the desensitization caused by i.p. RTX should spread into the abdominal-wall muscles. Indeed, we found that the local hypoperfusion response to capsaicin (TRPV1 agonist) in the abdominal-wall muscles was absent in i.p. RTX-desensitized rats. We then showed that the most upstream (lateral parabrachial, LPB) and the most downstream (rostral raphe pallidus) nuclei of the intrabrain pathway that controls autonomic cold defenses are also required for the hyperthermic response to i.v. AMG0347. Injection of muscimol (inhibitor of neuronal activity) into the LPB or injection of glycine (inhibitory neurotransmitter) into the raphe blocked the hyperthermic response to i.v. AMG0347, whereas i.v. AMG0347 increased the number of c-Fos cells in the raphe. We conclude that the neural pathway of TRPV1 antagonist-induced hyperthermia involves TRPV1-expressing sensory nerves in trunk muscles, the DLF, and the same LPB-raphe pathway that controls autonomic cold defenses.

Central sympathetic network for thermoregulatory responses to psychological stress.

In mammals, many types of psychological stressors elicit a variety of sympathoexcitatory responses paralleling the classic fight-or-flight response to a threat to survival, including increased body temperature via brown adipose tissue thermogenesis and cutaneous vasoconstriction, and increased skeletal muscle blood flow via tachycardia and visceral vasoconstriction. Although these responses are usually supportive for stress coping, aberrant sympathetic responses to stress can lead to clinical issues in psychosomatic medicine. Sympathetic stress responses are mediated mostly by sympathetic premotor drives from the rostral medullary raphe region (rMR) and partly by those from the rostral ventrolateral medulla (RVLM). Hypothalamomedullary descending pathways from the dorsomedial hypothalamus (DMH) to the rMR and RVLM mediate important, stress-driven sympathoexcitatory transmission to the premotor neurons to drive the thermal and cardiovascular responses. The DMH also likely sends an excitatory input to the paraventricular hypothalamic nucleus to stimulate stress hormone release. Neurons in the DMH receive a stress-related excitation from the dorsal peduncular cortex and dorsal tenia tecta (DP/DTT) in the ventromedial prefrontal cortex. By connecting the corticolimbic emotion circuit to the central sympathetic and somatic motor systems, the DP/DTT â†’ DMH pathway plays as the primary mediator of the psychosomatic signaling that drives a variety of sympathetic and behavioral stress responses. These brain regions together with other stress-related regions constitute a central neural network for physiological stress responses. This network model is relevant to understanding the central mechanisms by which stress and emotions affect autonomic regulations of homeostasis and to developing new therapeutic strategies for various stress-related disorders.

Dopaminergic input from the posterior hypothalamus to the raphe pallidus area inhibits brown adipose tissue thermogenesis.

Systemic administration of dopamine (DA) receptor agonists leads to falls in body temperature. However, the central thermoregulatory pathways modulated by DA have not been fully elucidated. Here we identified a source and site of action contributing to DA's hypothermic action by inhibition of brown adipose tissue (BAT) thermogenesis. Nanoinjection of the type 2 and type 3 DA receptor (D2R/D3R) agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), in the rostral raphe pallidus area (rRPa) inhibits the sympathetic activation of BAT evoked by cold exposure or by direct activation of N-methyl-d-aspartate (NMDA) receptors in the rRPa. Blockade of D2R/D3R in the rRPa with nanoinjection of SB-277011A increases BAT thermogenesis, consistent with a tonic release of DA in the rRPa contributing to inhibition of BAT thermogenesis. Accordingly, D2Rs are expressed in cold-activated and serotonergic neurons in the rRPa, and anatomical tracing studies revealed that neurons in the posterior hypothalamus (PH) are a source of dopaminergic input to the rRPa. Disinhibitory activation of PH neurons with nanoinjection of gabazine inhibits BAT thermogenesis, which is reduced by pretreatment of the rRPa with SB-277011A. In conclusion, the rRPa, the site of sympathetic premotor neurons for BAT, receives a tonically active, dopaminergic input from the PH that suppresses BAT thermogenesis.

Activation of Transient Receptor Potential Vanilloid 1 Channels in the Nucleus of the Solitary Tract and Activation of Dynorphin Input to the Median Preoptic Nucleus Contribute to Impaired BAT Thermogenesis in Diet-Induced Obesity.

The impairment of cold-evoked activation of brown adipose tissue (BAT) in rats fed a high-fat diet (HFD) requires the activity of a vagal afferent to the medial nucleus of the solitary tract (mNTS). We determined the role of transient receptor potential vanilloid 1 (TRPV1) activation in the mNTS, and of a dynorphin input to the median preoptic nucleus (MnPO) in the impaired BAT thermogenic response to cold in HFD-fed rats. The levels of some linoleic acid (LA) metabolites, which can act as endogenous TRPV1 agonists, were elevated in the NTS of HFD rats compared with chow-fed rats. In HFD rats, nanoinjections of the TRPV1 antagonist, capsazepine (CPZ) in the NTS rescued the impaired BAT sympathetic nerve activity (BAT SNA) and thermogenic responses to cold. In contrast, in chow-fed rats, cold-evoked BAT SNA and BAT thermogenesis were not changed by nanoinjections of CPZ into the NTS. Axon terminals of NTS neurons that project to the dorsal lateral parabrachial nucleus (LPBd) were closely apposed to LPBd neurons that project to the MnPO. Many of the neurons in the LPBd that expressed c-fos during cold challenge were dynorphinergic. In HFD rats, nanoinjections of the κ opioid receptor (KOR) antagonist, nor-binaltorphimine (nor-BNI), in the MnPO rescued the impaired BAT SNA and thermogenic responses to cold. These data suggest that HFD increases the content of endogenous ligands of TRPV1 in the NTS, which increases the drive to LPBd neurons that in turn release dynorphin in the MnPO to impair activation of BAT.

Median preoptic area neurons are required for the cooling and febrile activations of brown adipose tissue thermogenesis in rat.

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.

Systemic serotonin inhibits brown adipose tissue sympathetic nerve activity via a GABA input to the dorsomedial hypothalamus, not via 5HT1A receptor activation in raphe pallidus.

AIM: Serotonin (5-hydroxytryptamine, 5-HT), an important neurotransmitter and hormone, modulates many physiological functions including body temperature. We investigated neural mechanisms involved in the inhibition of brown adipose tissue (BAT) sympathetic nerve activity (SNA) and BAT thermogenesis evoked by 5-HT. METHODS: Electrophysiological recordings, intravenous (iv) injections and nanoinjections in the brains of anaesthetized rats. RESULTS: Cooling-evoked increases in BAT SNA were inhibited by the intra-rostral raphé pallidus (rRPa) and the iv administration of the 5-HT1A receptor agonist, 8-OH-DPAT or 5-HT. The intra-rRPa 5-HT, the intra-rRPa and the iv 8-OH-DPAT, but not the iv 5-HT-induced inhibition of BAT SNA were prevented by nanoinjection of a 5-HT1A receptor antagonist in the rRPa. The increase in BAT SNA evoked by nanoinjection of NMDA in the rRPa was not inhibited by iv 5-HT, indicating that iv 5-HT does not inhibit BAT SNA by acting in the rRPa or in the sympathetic pathway distal to the rRPa. In contrast, under a warm condition, blockade of 5HT1A receptors in the rRPa increased BAT SNA and BAT thermogenesis, suggesting that endogenous 5-HT in the rRPa contributes to the suppression of BAT SNA and BAT thermogenesis. The increases in BAT SNA and BAT thermogenesis evoked by nanoinjection of NMDA in the dorsomedial hypothalamus (DMH) were inhibited by iv 5-HT, but those following bicuculline nanoinjection in the DMH were not inhibited. CONCLUSIONS: The systemic 5-HT-induced inhibition of BAT SNA requires a GABAergic inhibition of BAT sympathoexcitatory neurones in the DMH. In addition, during warming, 5-HT released endogenously in rRPa inhibits BAT SNA.

Neurons in the rat ventral lateral preoptic area are essential for the warm-evoked inhibition of brown adipose tissue and shivering thermogenesis.

AIM: To determine the role of neurons in the ventral part of the lateral preoptic area (vLPO) in CNS thermoregulation. METHODS: In vivo electrophysiological and neuropharmacological were used to evaluate the contribution of neurons in the vLPO to the regulation of brown adipose tissue (BAT) thermogenesis and muscle shivering in urethane/chloralose-anaesthetized rats. RESULTS: Nanoinjections of NMDA targeting the medial preoptic area (MPA) and the vLPO suppressed the cold-evoked BAT sympathetic activity (SNA), reduced the BAT temperature (TBAT ), expired CO2 , mean arterial pressure (MAP), and heart rate. Inhibition of vLPO neurons with muscimol or AP5/CNQX elicited increases in BAT SNA, TBAT , tachycardia, and small elevations in MAP. The BAT thermogenesis evoked by AP5/CNQX in vLPO was inhibited by the activation of MPA neurons. The inhibition of BAT SNA by vLPO neurons does not require a GABAergic input to dorsomedial hypothalamus (DMH), but MPA provides a GABAergic input to DMH. The activation of vLPO neurons inhibits the BAT thermogenesis evoked by NMDA in the rostral raphe pallidus (rRPa), but not that after bicuculline in rRPa. The BAT thermogenesis elicited by vLPO inhibition is dependent on glutamatergic inputs to DMH and rRPa, but these excitatory inputs do not arise from MnPO neurons. The activation of neurons in the vLPO also inhibits cold- and prostaglandin-evoked muscle shivering, and vLPO inhibition is sufficient to evoke shivering. CONCLUSION: The vLPO contains neurons that are required for the warm ambient-evoked inhibition of muscle shivering and of BAT thermogenesis, mediated through a direct or indirect GABAergic input to rRPa from vLPO.

Central nervous system circuits that control body temperature.

Maintenance of mammalian core body temperature within a narrow range is a fundamental homeostatic process to optimize cellular and tissue function, and to improve survival in adverse thermal environments. Body temperature is maintained during a broad range of environmental and physiological challenges by central nervous system circuits that process thermal afferent inputs from the skin and the body core to control the activity of thermoeffectors. These include thermoregulatory behaviors, cutaneous vasomotion (vasoconstriction and, in humans, active vasodilation), thermogenesis (shivering and brown adipose tissue), evaporative heat loss (salivary spreading in rodents, and human sweating). This review provides an overview of the central nervous system circuits for thermoregulatory reflex regulation of thermoeffectors.

Efferent neural pathways for the control of brown adipose tissue thermogenesis and shivering.

The fundamental central neural circuits for thermoregulation orchestrate behavioral and autonomic repertoires that maintain body core temperature during thermal challenges that arise from either the ambient or the internal environment. This review summarizes our understanding of the neural pathways within the fundamental thermoregulatory reflex circuitry that comprise the efferent (i.e., beyond thermosensory) control of brown adipose tissue (BAT) and shivering thermogenesis: the motor neuron systems consisting of the BAT sympathetic preganglionic neurons and BAT sympathetic ganglion cells, and the alpha- and gamma-motoneurons; the premotor neurons in the region of the rostral raphe pallidus, and the thermogenesis-promoting neurons in the dorsomedial hypothalamus/dorsal hypothalamic area. Also included are inputs to, and neurochemical modulators of, these efferent neuronal populations that could influence their activity during thermoregulatory responses. Signals of metabolic status can be particularly significant for the energy-hungry thermoeffectors for heat production.

Preoptic area cooling increases the sympathetic outflow to brown adipose tissue and brown adipose tissue thermogenesis.

Modest cold exposures are likely to activate autonomic thermogenic mechanisms due to activation of cutaneous thermal afferents, whereas central thermosensitive neurons set the background tone on which this afferent input is effective. In addition, more prolonged or severe cold exposures that overwhelm cold defense mechanisms would directly activate thermosensitive neurons within the central nervous system. Here, we examined the involvement of the canonical brown adipose tissue (BAT) sympathoexcitatory efferent pathway in the response to direct local cooling of the preoptic area (POA) in urethane-chloralose-anesthetized rats. With skin temperature and core body temperature maintained between 36 and 39°C, cooling POA temperature by ~1-4°C evoked increases in BAT sympathetic nerve activity (SNA), BAT temperature, expired CO2, and heart rate. POA cooling-evoked responses were inhibited by nanoinjections of ionotropic glutamate receptor antagonists or the GABAA receptor agonist muscimol into the median POA or by nanoinjections of ionotropic glutamate receptor antagonists into the dorsomedial hypothalamic nucleus (bilaterally) or into the raphe pallidus nucleus. These results demonstrate that direct cooling of the POA can increase BAT SNA and thermogenesis via the canonical BAT sympathoexcitatory efferent pathway, even in the face of warm thermal input from the skin and body core.

Glucagon-like peptide-1 regulates brown adipose tissue thermogenesis via the gut-brain axis in rats.

Endogenous intestinal glucagon-like peptide-1 (GLP-1) controls satiation and glucose metabolism via vagal afferent neurons (VANs). Recently, VANs have received increasing attention for their role in brown adipose tissue (BAT) thermogenesis. It is, however, unclear whether VAN GLP-1 receptor (GLP-1R) signaling affects BAT thermogenesis and energy expenditure (EE) and whether this VAN mechanism contributes to energy balance. First, we tested the effect of the GLP-1R agonist exendin-4 (Ex4, 0.3 µg/kg ip) on EE and BAT thermogenesis and whether these effects require VAN GLP-1R signaling using a rat model with a selective Glp1r knockdown (kd) in VANs. Second, we examined the role of VAN GLP-1R in energy balance during chronic high-fat diet (HFD) feeding in VAN Glp1r kd rats. Finally, we used viral transsynaptic tracers to identify the possible neuronal substrates of such a gut-BAT interaction. VAN Glp1r kd attenuated the acute suppressive effects of Ex4 on EE and BAT thermogenesis. Consistent with this finding, the VAN Glp1r kd increased EE and BAT activity, diminished body weight gain, and improved insulin sensitivity compared with HFD-fed controls. Anterograde transsynaptic viral tracing of VANs infected major hypothalamic and hindbrain areas involved in BAT sympathetic regulation. Moreover, retrograde tracing from BAT combined with laser capture microdissection revealed that a population of VANs expressing Glp1r is synaptically connected to the BAT. Our findings reveal a novel role of VAN GLP-1R signaling in the regulation of EE and BAT thermogenesis and imply that through this gut-brain-BAT connection, intestinal GLP-1 plays a role in HFD-induced metabolic syndrome.

Activation of TRPV1 in nucleus tractus solitarius reduces brown adipose tissue thermogenesis, arterial pressure, and heart rate.

The sympathetic nerve activity (SNA) to brown adipose tissue (BAT) regulates BAT thermogenesis to defend body temperature in cold environments or to produce fever during immune responses. The vagus nerve contains afferents that inhibit the BAT SNA and BAT thermogenesis evoked by skin cooling. We sought to determine whether activation of transient receptor potential vanilloid 1 (TRPV1) channels in the nucleus tractus solitarius (NTS), which are prominently expressed in unmyelinated vagal afferents, would affect cold-evoked BAT thermogenesis, cardiovascular parameters, or their vagal afferent-evoked responses. In urethane-chloralose-anesthetized rats, during skin cooling, nanoinjection of the TRPV1-agonist resiniferatoxin in NTS decreased BAT SNA (from 695 ± 195% of baseline during cooling to 103 ± 8% of baseline after resiniferatoxin), BAT temperature (-0.8 ± 0.1°C), expired CO2 (-0.3 ± 0.04%), mean arterial pressure (MAP; -20 ± 5 mmHg), and heart rate (-44 ± 11 beats/min). Pretreatment of NTS with the TRPV1 antagonist capsazepine prevented these resiniferatoxin-mediated effects. Intravenous injection of the TRPV1 agonist dihydrocapsaicin also decreased all the measured variables (except MAP). Bilateral cervical or subdiaphragmatic vagotomy attenuated the decreases in BAT SNA and thermogenesis evoked by nanoinjection of resiniferatoxin in NTS but did not prevent the decreases in BAT SNA and BAT thermogenesis evoked by intravenous dihydrocapsaicin. We conclude that activation of TRPV1 channels in the NTS of vagus nerve intact rats inhibits BAT SNA and decreases BAT metabolism, blood pressure, and heart rate. In contrast, the inhibition of BAT thermogenesis following systemic administration of dihydrocapsaicin does not require vagal afferent activity, consistent with a nonvagal pathway through which systemic TRPV1 agonists can inhibit BAT thermogenesis.

Tonic inhibition of brown adipose tissue sympathetic nerve activity via muscarinic acetylcholine receptors in the rostral raphe pallidus.

KEY POINTS: A tonically active, muscarinic cholinergic inhibition of rostral raphe pallidus (rRPa) neurons influences thermogenesis of brown adipose tissue (BAT) independent of ambient temperature conditions. The tonically active cholinergic input to rRPa originates caudal to the hypothalamus. Muscarinic acetylcholine receptor (mAChR) activation in rRPa contributes to the inhibition of BAT sympathetic nerve activity (SNA) evoked by activation of neurons in the rostral ventrolateral medulla (RVLM). The RVLM is not the sole source of the muscarinic cholinergic input to rRPa. Activation of GABA receptors in rRPa does not mediate the cholinergic inhibition of BAT SNA. ABSTRACT: We sought to determine if body temperature and energy expenditure are influenced by a cholinergic input to neurons in the rostral raphe pallidus (rRPa), the site of sympathetic premotor neurons controlling thermogenesis of brown adipose tissue (BAT). Nanoinjections of the muscarinic acetylcholine receptor (mAChR) agonist, oxotremorine, or the cholinesterase inhibitor, neostigmine (NEOS), in the rRPa of anaesthetized rats decreased cold-evoked BAT sympathetic nerve activity (SNA, nadirs: -72 and -95%), BAT temperature (Tbat, -0.5 and -0.6°C), expired CO2 (Exp. CO2 , -0.3 and -0.5%) and heart rate (HR, -22 and -41 bpm). NEOS into rRPa reversed the increase in BAT SNA evoked by blockade of GABA receptors in rRPa. Nanoinjections of the mAChR antagonist, scopolamine (SCOP), in the rRPa of warm rats increased BAT SNA (peak: +1087%), Tbat (+1.8°C), Exp. CO2 (+0.7%), core temperature (Tcore, +0.5°C) and HR (+54 bpm). SCOP nanoinjections in rRPa produced similar activations of BAT during cold exposure, following a brain transection caudal to the hypothalamus, and during the blockade of glutamate receptors in rRPa. We conclude that a tonically active cholinergic input to the rRPa inhibits BAT SNA via activation of local mAChR. The inhibition of BAT SNA mediated by mAChR in rRPa does not depend on activation of GABA receptors in rRPa. The increase in BAT SNA following mAChR blockade in rRPa does not depend on the activity of neurons in the hypothalamus or on glutamate receptor activation in rRPa.

Reestablishment of Energy Balance in a Male Mouse Model With POMC Neuron Deletion of BMPR1A.

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.

Glycinergic inhibition of BAT sympathetic premotor neurons in rostral raphe pallidus.

The rostral raphe pallidus (rRPa) contains sympathetic premotor neurons controlling thermogenesis in brown adipose tissue (BAT). We sought to determine whether a tonic activation of glycineA receptors (GlyAR) in the rRPa contributes to the inhibitory regulation of BAT sympathetic nerve activity (SNA) and of cardiovascular parameters in anesthetized rats. Nanoinjection of the GlyAR antagonist, strychnine (STR), into the rRPa of intact rats increased BAT SNA (peak: +495%), BAT temperature (TBAT, +1.1°C), expired CO2, (+0.4%), core body temperature (TCORE, +0.2°C), mean arterial pressure (MAP, +4 mmHg), and heart rate (HR, +57 beats/min). STR into rRPa in rats with a postdorsomedial hypothalamus transection produced similar increases in BAT thermogenic and cardiovascular parameters. Glycine nanoinjection into the rRPa evoked a potent inhibition of the cooling-evoked increases in BAT SNA (nadir: -74%), TBAT (-0.2°C), TCORE (-0.2°C), expired CO2 (-0.2%), MAP (-8 mmHg), and HR (-22 beats/min) but had no effect on the increases in these variables evoked by STR nanoinjection into rRPa. Nanoinjection of GABA into the rRPa inhibited the STR-evoked BAT SNA (nadir: -86%) and reduced the expired CO2 (-0.4%). Blockade of glutamate receptors in rRPa reduced the STR-evoked increases in BAT SNA (nadir: -61%), TBAT (-0.5°C), expired CO2 (-0.3%), MAP (-9 mmHg), and HR (-33 beats/min). We conclude that a tonically active glycinergic input to the rRPa contributes to the inhibitory regulation of the discharge of BAT sympathetic premotor neurons and of BAT thermogenesis and energy expenditure.

Thermoregulatory inversion: a novel thermoregulatory paradigm.

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.

Vagal afferent activation decreases brown adipose tissue (BAT) sympathetic nerve activity and BAT thermogenesis.

In urethane/α-chloralose anesthetized rats, electrical stimulation of cervical vagal afferent fibers inhibited the increases in brown adipose tissue sympathetic nerve activity and brown adipose tissue thermogenesis evoked by cold exposure, by nanoinjection of the GABAA receptor antagonist, bicuculline, in the dorsomedial hypothalamus, and by nanoinjection of N-methyl-D-aspartate in the rostral raphe pallidus. Vagus nerve stimulation-evoked inhibition of brown adipose tissue sympathetic nerve activity was prevented by blockade of ionotropic glutamate receptors in the termination site of vagal afferents in the nucleus of the solitary tract, and by nanoinjection of GABAA receptor antagonists in the rostral raphe pallidus. In conclusion, the brown adipose tissue sympathoinhibitory effect of cervical afferent vagal nerve stimulation is mediated by glutamatergic activation of second-order sensory neurons in the nucleus of the solitary tract and by a GABAergic inhibition of brown adipose tissue sympathetic premotor neurons in the rostral raphe pallidus, but does not require GABAergic inhibition of the brown adipose tissue sympathoexcitatory neurons in the dorsomedial hypothalamus.

Medullary Reticular Neurons Mediate Neuropeptide Y-Induced Metabolic Inhibition and Mastication.

Hypothalamic neuropeptide Y (NPY) elicits hunger responses to increase the chances of surviving starvation: an inhibition of metabolism and an increase in feeding. Here we elucidate a key central circuit mechanism through which hypothalamic NPY signals drive these hunger responses. GABAergic neurons in the intermediate and parvicellular reticular nuclei (IRt/PCRt) of the medulla oblongata, which are activated by NPY-triggered neural signaling from the hypothalamus, potentially through the nucleus tractus solitarius, mediate the NPY-induced inhibition of metabolic thermogenesis in brown adipose tissue (BAT) via their innervation of BAT sympathetic premotor neurons. Intriguingly, the GABAergic IRt/PCRt neurons innervating the BAT sympathetic premotor region also innervate the masticatory motor region, and stimulation of the IRt/PCRt elicits mastication and increases feeding as well as inhibits BAT thermogenesis. These results indicate that GABAergic IRt/PCRt neurons mediate hypothalamus-derived hunger signaling by coordinating both autonomic and feeding motor systems to reduce energy expenditure and to promote feeding.

Hibernation, Hypothermia and a Possible Therapeutic "Shifted Homeostasis" Induced by Central Activation of A1 Adenosine Receptor (A1AR).

The positive outcome that hypothermia contributes to brain and cardiac protection following ischemia has stimulated research in the development of pharmacological approaches to induce a hypothermic/hypometabolic state. Pharmacological manipulation of central autonomic thermoregulatory circuits could represent a potential target for the induction of a hypothermic state. Here we present a brief description of the CNS thermoregulatory centers and how the manipulation of these circuits can be useful in the treatment of pathological conditions such as stroke or brain hemorrhage.