Modulation Of Body Temperature Research Articles

Rumen-protected methionine modulates body temperature and reduces the incidence of heat stress temperatures during the hottest hours of the day of grazing heat-stressed Bos indicus beef cows.

This study evaluated the effects of supplementation of rumen-protected methionine (RPM) on body thermoregulation and conception rate of Nelore cows exposed to high temperature-humidity index (THI). On -31 days before the artificial insemination protocol, 562 lactating, multiparous cows were assigned to receive (MG) or not (CG) RPM supplementation (3 g/cow mixed into 100 g of mineral supplement). Both groups remained in tropical pastures and received supplementation for 77 days. A subset of cows (n= 142) remained with an intravaginal thermometer collecting intravaginal temperature (IT). The respective minimum, average, and maximum environmental THI were 72.8, 78.0, and 83.3. Effects of treatment × hour of the day were detected (P< 0.0001) for IT. From 1330 to 1730 h and 1830 to 1900 h, IT was higher (P< 0.05) for CG versus MG cows when exposed to moderate and high THI. The supplementation with RPM did not affect conception rate (CG = 64.4% vs. MG = 58.2%; P> 0.05). In conclusion, 3g of RPM supplementation lowered internal body temperature and possibly altered critical THI threshold in Nelore cows with no impact on reproduction.

Cross-talk between immunity and behavior: insights from entomopathogenic fungi and their insect hosts.

Insects are one of the most successful animals in nature, and entomopathogenic fungi play a significant role in the natural epizootic control of insect populations in many ecosystems. The interaction between insects and entomopathogenic fungi has continuously coevolved over hundreds of millions of years. Many components of the insect innate immune responses against fungal infection are conserved across phyla. Additionally, behavioral responses, which include avoidance, grooming, and/or modulation of body temperature, have been recognized as important mechanisms for opposing fungal pathogens. In an effort to investigate possible cross-talk and mediating mechanisms between these fundamental biological processes, recent studies have integrated and/or explored immune and behavioral responses. Current information indicates that during discrete stages of fungal infection, several insect behavioral and immune responses are altered simultaneously, suggesting important connections between the two systems. This review synthesizes recent advances in our understanding of the physiological and molecular aspects influencing cross-talk between behavioral and innate immune antifungal reactions, including chemical perception and olfactory pathways.

Therapeutic hyperthermia for the treatment of infection-a narrative review.

Modulating body temperature, mostly through the use of antipyretics, is a commonly employed therapeutic intervention in medical practice. However, emerging evidence suggests that hyperthermia could serve as an adjuvant therapy for patients with infection. We performed a narrative review to explore the application of therapeutic hyperthermia in the treatment of infection. A number of studies have been performed in the pre-antibiotic era, enrolling patients with neurosyphilis and gonococcal infections, with reported cure rates at around 60%-80%. We have outlined the potential molecular and immunological mechanisms explaining the possible beneficial effects of therapeutic hyperthermia. For some pathogens increased temperature exerts a direct negative effect on virulence; however, it is presumed that temperature driven activation of the immune system is probably the most important factor affecting microbial viability. Lastly, we performed a review of modern-era studies where modulation of body temperature has been used as a treatment strategy. In trials of therapeutic hypothermia in patients with infection worse outcomes have been observed in the hypothermia group. Use of antipyretics has not been associated with any improvement in clinical outcomes. In modern-era therapeutic hyperthermia achieved by physical warming has been studied in one pilot trial, and better survival was observed in the hyperthermia group. To conclude, currently there is not enough data to support the use of therapeutic hyperthermia outside clinical trials; however, available studies are in favor of at least a temperature tolerance strategy for non-neurocritical patients.

The Gut Microbiome Modulates Body Temperature Both in Sepsis and Health.

Rationale: Among patients with sepsis, variation in temperature trajectories predicts clinical outcomes. In healthy individuals, normal body temperature is variable and has decreased consistently since the 1860s. The biologic underpinnings of this temperature variation in disease and health are unknown. Objectives: To establish and interrogate the role of the gut microbiome in calibrating body temperature. Methods: We performed a series of translational analyses and experiments to determine whether and how variation in gut microbiota explains variation in body temperature in sepsis and in health. We studied patient temperature trajectories using electronic medical record data. We characterized gut microbiota in hospitalized patients using 16S ribosomal RNA gene sequencing. We modeled sepsis using intraperitoneal LPS in mice and modulated the microbiome using antibiotics, germ-free, and gnotobiotic animals. Measurements and Main Results: Consistent with prior work, we identified four temperature trajectories in patients hospitalized with sepsis that predicted clinical outcomes. In a separate cohort of 116 hospitalized patients, we found that the composition of patients' gut microbiota at admission predicted their temperature trajectories. Compared with conventional mice, germ-free mice had reduced temperature loss during experimental sepsis. Among conventional mice, heterogeneity of temperature response in sepsis was strongly explained by variation in gut microbiota. Healthy germ-free and antibiotic-treated mice both had lower basal body temperatures compared with control animals. The Lachnospiraceae family was consistently associated with temperature trajectories in hospitalized patients, experimental sepsis, and antibiotic-treated mice. Conclusions: The gut microbiome is a key modulator of body temperature variation in both health and critical illness and is thus a major, understudied target for modulating physiologic heterogeneity in sepsis.

Patients with hypothermic sepsis have a unique gene expression profile compared to patients with fever and sepsis.

The pathophysiology of hypothermia during sepsis is unclear. Using genomic profiling of blood leukocytes, we aimed to determine if hypothermia is associated with a different gene expression profile compared to fever during sepsis. Patients with sepsis and either hypothermia or fever within 24 hours after ICU admission were included in the study (n = 168). Hypothermia was defined as body temperature below 36 °C. Fever was defined as body temperature equal to or above 38.3°C. We compared blood gene expression (whole‐genome transcriptome in leukocytes) in hypothermic septic compared to febrile septic patients in an unmatched analysis and matched for APACHE IV score and the presence of shock. In total, 67 septic patients were hypothermic and 101 patients were febrile. Hypothermia was associated with a distinct gene expression profile in both unmatched and matched analyses. There were significant differences related to the up‐ and downregulation of canonical signalling pathways. In the matched analysis, the top upregulated gene was cold‐inducible mRNA binding protein (CIRBP) which plays a role in cold‐induced suppression of cell proliferation. In addition, we found three signalling pathways significantly upregulated in hypothermic patients compared to febrile patients; tryptophan degradation X, phenylalanine degradation IV and putrescine degradation III. In conclusion, there are distinct signalling pathways and genes associated with hypothermia, including tryptophan degradation and CIRBP expression, providing a possible link to the modulation of body temperature and early immunosuppression. Future studies may focus on the canonical signalling pathways presented in this paper to further investigate spontaneous hypothermia in sepsis.

Thermoregulatory function and sexual dimorphism of the throat sack in Helmeted Guineafowl (Numida meleagris) across Africa

The responses of ground-dwelling birds to heat and cold stress encompass a variety of behavioural, physiological and even morphological mechanisms. However, the role of glabrous skin in this respect has been marginally addressed so far. The Helmeted Guineafowl (Numida meleagris) is a landfowl distributed across Sub-Saharan Africa with eight traditionally recognised extant subspecies. Among the most prominent morphological traits underlying intraspecific variability are size and pigmentation of the bare throat skin (or sack), which might be related to the different habitats and environmental conditions across its wide range. In order to explore the Helmeted Guineafowl range-wide sack variation and pigmentation in relation to thermoregulation and sexual signalling, we collected morphometric and environmental information for N. m. coronata integrating field data with the inspection of photographic material encompassing seven subspecies and environmental information from their habitats. Field data evidenced that sack size was significantly correlated with ambient temperature, thus pointing to a likely involvement of the throat sack in thermoregulation. When the pictorial data from all subspecies were pooled, sack size correlated negatively with biomass, rainfall and humidity, while a positive correlation was found with annual solar irradiation. Sack size correlated positively with monthly temperature variation among the blue-throated subspecies from southern Africa as opposed to the black-throated subspecies ranging north to Zambia and Mozambique. Still, in this latter group the sack was often larger during winter months, possibly to maximise solar radiation absorbance. Noteworthy, sack size was related to sex dimorphism in two subspecies. Sack morphology and colour in the Helmeted Guineafowl likely modulate body temperature by evaporative cooling or heating upon needs, but in some subspecies it is also seemingly related to sexual signalling. Additional studies are needed to fully understand the multifunctionality of this important morphological feature in this species.

Flight rapidly modulates body temperature in freely behaving bats

BackgroundBats are remarkable in their dynamic control over body temperature, showing both hypothermia with torpor and hyperthermia during flight. Despite considerable research in understanding bats’ thermoregulation mechanisms, knowledge on the relationship between flight and body temperature in bats remains limited, possibly due to technological restraints.ResultsWe used onboard dataloggers including a temperature sensor and an inertial sensor (accelerometers) and continuously recorded the flight behavior and skin temperature (Tsk) subcutaneously of a perch-hunting bat, Hipposideros armiger, both in the laboratory and in the field. We provide evidence that flight increases the body temperature of bats. The median of the maximum increase in the Tsk caused by flight bouts was 3.4 °C (between 1.9 and 5.3 °C for different individuals) in the laboratory. The maximum Tsk for the bats was narrowly centered around 40 °C (between 38.5 and 40.9 °C). Moreover, we found that the faster the Tsk rises, the greater the maximum increase in Tsk. Interestingly, bats can slow down the Tsk rises with intermittent fights, during which they perch after brief flight bouts to allow the body temperature to drop rapidly. Similar data were collected from field recordings in free-ranging bats.ConclusionsWe suggest that perch-hunting behavior observed in approximately 200 species of bats that results in intermittent flights may function as a thermoregulatory strategy, in addition to optimizing energy efficiency as demonstrated by previous studies.

Zona incerta neurons projecting to the ventral tegmental area promote action initiation towards feeding.

Key points The zona incerta (ZI) and ventral tegmental area (VTA) are brain areas that are both implicated in feeding behaviour. The ZI projects to the VTA, although it has not yet been investigated whether this projection regulates feeding.We experimentally (in)activated the ZI to VTA projection by using dual viral vector technology, and studied the effects on feeding microstructure, the willingness to work for food, general activity and body temperature.Activity of the ZI to VTA projection promotes feeding by facilitating action initiation towards food, as reflected in meal frequency and the willingness to work for food reward, without affecting general activity or directly modulating body temperature.We show for the first time that activity of the ZI to VTA projection promotes feeding, which improves the understanding of the neurobiology of feeding behaviour and body weight regulation. Both the zona incerta (ZI) and the ventral tegmental area (VTA) have been implicated in feeding behaviour. The ZI provides prominent input to the VTA, although it has not yet been investigated whether this projection regulates feeding. Therefore, we investigated the role of ZI to VTA projection neurons in the regulation of several aspects of feeding behaviour. We determined the effects of (in)activation of ZI to VTA projection neurons on feeding microstructure, food‐motivated behaviour under a progressive ratio schedule of reinforcement, locomotor activity and core body temperature. To activate or inactivate ZI neurons projecting to the VTA, we used a combination of canine adenovirus‐2 in the VTA, as well as Cre‐dependent designer receptors exclusively activated by designer drugs (DREADD) or tetanus toxin (TetTox) light chain in the ZI. TetTox‐mediated inactivation of ZI to VTA projection neurons reduced food‐motivated behaviour and feeding by reducing meal frequency. Conversely, DREADD‐mediated chemogenetic activation of ZI to VTA projection neurons promoted food‐motivated behaviour and feeding. (In)activation of ZI to VTA projection neurons did not affect locomotor activity or directly regulate core body temperature. Taken together, ZI neurons projecting to the VTA exert bidirectional control overfeeding behaviour. More specifically, activity of ZI to VTA projection neurons facilitate action initiation towards feeding, as reflected in both food‐motivated behaviour and meal initiation, without affecting general activity.

Hepatic c-Jun regulates glucose metabolism via FGF21 and modulates body temperature through the neural signals

Objectivec-Jun, a prominent member of the activator protein 1 (AP-1) family, is involved in various physiology processes such as cell death and survival. However, a role of hepatic c-Jun in the whole-body metabolism is poorly understood. MethodsWe generated liver-specific c-Jun knock-out (c-jun△li) mice to investigate the effect of hepatic c-Jun on the whole-body physiology, particularly in blood glucose and body temperature. Primary hepatocytes were also used to explore a direct regulation of c-Jun in gluconeogenesis. Resultsc-jun△li mice showed higher hepatic gluconeogenic capacity compared with control mice, and similar results were obtained in vitro. In addition, fibroblast growth factor 21 (FGF21) expression was directly inhibited by c-Jun knockdown and adenovirus-mediated hepatic FGF21 over-expression blocked the effect of c-Jun on gluconeogenesis in c-jun△li mice. Interestingly, c-jun△li mice also exhibited higher body temperature, with induced thermogenesis and uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT). Furthermore, the body temperature became comparable between c-jun△li and control mice at thermoneutral temperature (30 °C). Moreover, the activity of sympathetic nervous system (SNS) was increased in c-jun△li mice and the higher body temperature was inhibited by beta-adrenergic receptor blocker injection. Finally, the activated SNS and increased body temperature in c-jun△li mice was most likely caused by the signals from the brain and hepatic vagus nerve, as the expression of c-Fos (the molecular marker of neuronal activation) was changed in several brain areas controlling body temperature and body temperature was decreased by selective hepatic vagotomy. ConclusionsThese data demonstrate a novel function of hepatic c-Jun in the regulation of gluconeogenesis and body temperature via FGF21 and neural signals. Our results also provide novel insights into the organ crosstalk in the regulation of the whole-body physiology.

Central Mechanisms for Thermoregulation.

Maintenance of a homeostatic body core temperature is a critical brain function accomplished by a central neural network. This orchestrates a complex behavioral and autonomic repertoire in response to environmental temperature challenges or declining energy homeostasis and in support of immune responses and many behavioral states. This review summarizes the anatomical, neurotransmitter, and functional relationships within the central neural network that controls the principal thermoeffectors: cutaneous vasoconstriction regulating heat loss and shivering and brown adipose tissue for heat production. The core thermoregulatory network regulating these thermoeffectors consists of parallel but distinct central efferent pathways that share a common peripheral thermal sensory input. Delineating the neural circuit mechanism underlying central thermoregulation provides a useful platform for exploring its functional organization, elucidating the molecular underpinnings of its neuronal interactions, and discovering novel therapeutic approaches to modulating body temperature and energy homeostasis.

Elucidation of the neural circuits activated by a GABAB receptor positive modulator: Relevance to anxiety

Although there is much evidence for a role of GABAB receptors in the pathophysiology of anxiety, the underlying neuronal mechanisms are largely unclear. The GABAB receptor allosteric positive modulator, GS39783, exerts anxiolytic effects without interfering with GABAB-mediated modulation of body temperature, cognitive performance and locomotor activity thus offering advantages over GABAB receptor agonists. However, the precise neural circuits underlying the anxiolytic effects of GS39783 are unknown. The aim of the present study was to identify brain structures and associated neuronal circuits that are modulated by GS39783 under either basal or mild stress conditions. To this end, the expression pattern of c-Fos, a marker of neuronal activation, was examined in mice acutely treated with GS39783 under basal conditions or following a mild anxiogenic challenge induced by exposure to the Open Arm (OA) of an Elevated Plus Maze.OA exposure enhanced c-Fos expression in vehicle-treated animals in several brain regions, including the medial prefrontal cortex, lateral septum, amygdala, hippocampus, paraventricular nucleus of the hypothalamus and the periaqueductal gray (PAG). Under basal conditions, GS39783 increased c-Fos in a restricted panel of areas notably amygdala nuclei, cortical areas and PAG subregions, while it inhibited c-Fos expression in the dorsal raphe nucleus (DRN). Under stress conditions, GS39783 reversed OA-induced c-Fos expression in the granular cell layer of the dentate gyrus, no longer increased c-Fos expression in the amygdala nor reduced c-Fos expression in the DRN. These specific patterns of neural activation by GS39783 might explain the neurobiological correlates implicated in GABAB-mediated anti-anxiety effects.This article is part of the “Special Issue Dedicated to Norman G. Bowery”.

Imidazoline I2 receptors: An update.

Since first introduced more than two decades ago, the research in imidazoline I2 receptors has been steadily increasing. This review provides an update on the current status of I2 receptor pharmacology. Imidazoline I2 receptors or I2 binding sites refer to several (at least four) different proteins that bind to [3H]-idazoxan and [3H]-2-BFI with high affinity. The molecular identities of the proteins remain elusive. One of the proteins (45kD) seems to be consistent with the identity of brain creatine kinase. The biological functions of I2 receptors have been primarily unveiled by the studies of selective I2 receptor ligands. Accumulating evidence suggests that I2 receptor ligands are effective analgesics for persistent and chronic painful conditions such as inflammatory, neuropathic and postoperative pain. One selective I2 receptor ligand, CR4056, has been advanced to phase II clinical trial with the therapeutic indication of chronic inflammatory pain (osteoarthritis). The expansion to the treatment of other chronic pain conditions should be expected if CR4056 could eventually be approved as a new drug. I2 receptor ligands also demonstrate robust discriminative stimulus activity and induce a characteristic discriminative cue in animals. Biochemical and preclinical in vivo investigations also suggest that I2 receptor ligands have neuroprotective activity and modulate body temperature. The emerging discrepancies of a range of purported selective I2 receptor ligands suggest different pharmacological effects mediated by discrete I2 receptor components which likely attribute to the I2 receptor-related proteins. It is proposed that the I2 receptors represent an emerging drug target for the treatment of neurological disorders such as pain and stroke, and deserve more research attention to translate preclinical findings to pharmacotherapies.

Central control of body temperature.

Central neural circuits orchestrate the behavioral and autonomic repertoire that maintains body temperature during environmental temperature challenges and alters body temperature during the inflammatory response and behavioral states and in response to declining energy homeostasis. This review summarizes the central nervous system circuit mechanisms controlling the principal thermoeffectors for body temperature regulation: cutaneous vasoconstriction regulating heat loss and shivering and brown adipose tissue for thermogenesis. The activation of these thermoeffectors is regulated by parallel but distinct efferent pathways within the central nervous system that share a common peripheral thermal sensory input. The model for the neural circuit mechanism underlying central thermoregulatory control provides a useful platform for further understanding of the functional organization of central thermoregulation, for elucidating the hypothalamic circuitry and neurotransmitters involved in body temperature regulation, and for the discovery of novel therapeutic approaches to modulating body temperature and energy homeostasis.

Synergistic interaction between ketamine and magnesium in lowering body temperature in rats

A large body of evidence supports the existence of an endogenous glutamate system that tonically modulates body temperature via N-methyl-d-aspartate (NMDA) receptors. Ketamine and magnesium, both NMDA receptor antagonists, are known for their anesthetic, analgesic and anti-shivering properties. This study is aimed at evaluating the effects of ketamine and magnesium sulfate on body temperature in rats, and to determine the type of interaction between them. The body temperature was measured by insertion of a thermometer probe 5cm into the colon of unrestrained male Wistar rats (200–250g). Magnesium sulfate (5 and 60mg/kg, sc) showed influence neither on baseline, nor on morphine-evoked hyperthermic response. Subanesthetic doses of ketamine (5–30mg/kg, ip) given alone, produced significant dose-dependent reduction in both baseline colonic temperature and morphine-induced hyperthermia. Analysis of the log dose–response curves for the effects of ketamine and ketamine–magnesium sulfate combination on the baseline body temperature revealed synergistic interaction, and about 5.3 fold reduction in dosage of ketamine when the drugs were applied in fixed ratio (1:1) combinations. In addition, fixed low dose of magnesium sulfate (5mg/kg, sc) enhanced the temperature lowering effect of ketamine (1.25–10mg/kg, ip) on baseline body temperature and morphine-induced hyperthermia by factors of about 2.5 and 5.3, respectively. This study is the first to demonstrate the synergistic interaction between magnesium sulfate and ketamine in a whole animal study and its statistical confirmation. It is possible that the synergy between ketamine and magnesium may have clinical relevance.

Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: A novel hypothesis on the mechanism of hot flushes

Despite affecting millions of individuals, the etiology of hot flushes remains unknown. Here we review the physiology of hot flushes, CNS pathways regulating heat-dissipation effectors, and effects of estrogen on thermoregulation in animal models. Based on the marked changes in hypothalamic kisspeptin, neurokinin B and dynorphin (KNDy) neurons in postmenopausal women, we hypothesize that KNDy neurons play a role in the mechanism of flushes. In the rat, KNDy neurons project to preoptic thermoregulatory areas that express the neurokinin 3 receptor (NK3R), the primary receptor for NKB. Furthermore, activation of NK₃R in the median preoptic nucleus, part of the heat-defense pathway, reduces body temperature. Finally, ablation of KNDy neurons reduces cutaneous vasodilatation and partially blocks the effects of estrogen on thermoregulation. These data suggest that arcuate KNDy neurons relay estrogen signals to preoptic structures regulating heat-dissipation effectors, supporting the hypothesis that KNDy neurons participate in the generation of flushes.

The influence of different nanostructured scaffolds on fibroblast growth

Skin serves as a protective barrier, modulating body temperature and waste discharge. It is therefore desirable to be able to repair any damage that occurs to the skin as soon as possible. In this study, we demonstrate a relatively easy and cost-effective method for the fabrication of nanostructured scaffolds, to shorten the time taken for a wound to heal. Various scaffolds consisting of nanohemisphere arrays of poly(lactic-co-glycolic acid) (PLGA), polylactide and chitosan were fabricated by casting using a nickel (Ni) replica mold. The Ni replica mold is electroformed using the highly ordered nanohemisphere array of the barrier-layer surface of an anodic aluminum oxide membrane as the template. Mouse fibroblast cells (L929s) were cultured on the nanostructured polymer scaffolds to investigate the effect of these different nanohemisphere arrays on cell proliferation. The concentration of collagen type I on each scaffold was then measured through enzyme-linked immunosorbent assay to find the most effective scaffold for shortening the wound-healing process. The experimental data indicate that the proliferation of L929 is superior when a nanostructured PLGA scaffold with a feature size of 118 nm is utilized.

Arcuate NPY Controls Sympathetic Output and BAT Function via a Relay of Tyrosine Hydroxylase Neurons in the PVN

Neuropepetide Y (NPY) is best known for its powerful stimulation of food intake and its effects on reducing energy expenditure. However, the pathways involved and the regulatory mechanisms behind this are not well understood. Here we demonstrate that NPY derived from the arcuate nucleus (Arc) is critical forthe control of sympathetic outflow and brown adipose tissue (BAT) function. Mechanistically,a key change induced by Arc NPY signaling is a marked Y1 receptor-mediated reduction in tyrosine hydroxylase (TH) expression in the hypothalamic paraventricular nucleus (PVN), which is also associated with a reduction in TH expression in the locus coeruleus (LC) and other regions in the brainstem. Consistent with this, Arc NPY signaling decreased sympathetically innervated BAT thermogenesis, involving the downregulation of uncoupling protein 1 (UCP1) expression in BAT. Taken together, these data reveal a powerful Arc-NPY-regulated neuronal circuit that controls BAT thermogenesis and sympathetic output via TH neurons.

Persistent Histamine Excitation of Glutamatergic Preoptic Neurons

Thermoregulatory neurons of the median preoptic nucleus (MnPO) represent a target at which histamine modulates body temperature. The mechanism by which histamine excites a population of MnPO neurons is not known. In this study it was found that histamine activated a cationic inward current and increased the intracellular Ca2+ concentration, actions that had a transient component as well as a sustained one that lasted for tens of minutes after removal of the agonist. The sustained component was blocked by TRPC channel blockers. Single-cell reverse transcription-PCR analysis revealed expression of TRPC1, TRPC5 and TRPC7 subunits in neurons excited by histamine. These studies also established the presence of transcripts for the glutamatergic marker Vglut2 and for the H1 histamine receptor in neurons excited by histamine. Intracellular application of antibodies directed against cytoplasmic sites of the TRPC1 or TRPC5 channel subunits decreased the histamine-induced inward current. The persistent inward current and elevation in intracellular Ca2+ concentration could be reversed by activating the PKA pathway. This data reveal a novel mechanism by which histamine induces persistent excitation and sustained intracellular Ca2+ elevation in glutamatergic MnPO neurons.

Mechanism of H2 histamine receptor dependent modulation of body temperature and neuronal activity in the medial preoptic nucleus

Histamine is involved in the central control of arousal, circadian rhythms and metabolism. The preoptic area, a region that contains thermoregulatory neurons is the main locus of histamine modulation of body temperature. Here we report that in mice, histamine activates H2 subtype receptors in the medial preoptic nucleus (MPON) and induces hyperthermia. We also found that a population of glutamatergic MPON neurons express H2 receptors and are excited by histamine or H2 specific agonists. The agonists decreased the input resistance of the neuron and increased the depolarizing “sag” observed during hyperpolarizing current injections. Furthermore, at −60mV holding potential, activation of H2 receptors induced an inward current that was blocked by ZD7288, a specific blocker of the hyperpolarization activated cationic current (Ih). Indeed, activation of H2 receptors resulted in increased Ih amplitude in response to hyperpolarizing voltage steps and a depolarizing shift in its voltage-dependent activation. The neurons excited by H2 specific agonism expressed the HCN1 and HCN2 channel subunits. Our data indicate that at the level of the MPON histamine influences thermoregulation by increasing the firing rate of glutamatergic neurons that express H2 receptors.

Kv4.2 Mediates Histamine Modulation of Preoptic Neuron Activity and Body Temperature

Histamine regulates arousal, circadian rhythms, and thermoregulation. Activation of H3 histamine receptors expressed by preoptic GABAergic neurons results in a decrease of their firing rate and hyperthermia. Here we report that an increase in the A-type K+ current in preoptic GABAergic neurons in response to activation of H3 histamine receptors results in decreased firing rate and hyperthermia in mice. The Kv4.2 subunit is required for these actions in spite of the fact that Kv4.2−/− preoptic GABAergic neurons display A-type currents and firing characteristics similar to those of wild-type neurons. This electrical remodeling is achieved by robust upregulation of the expression of the Kv4.1 subunit and of a delayed rectifier current. Dynamic clamp experiments indicate that enhancement of the A-type current by a similar amount to that induced by histamine is sufficient to mimic its robust effect on firing rates. These data indicate a central role played by the Kv4.2 subunit in histamine regulation of body temperature and its interaction with pERK1/2 downstream of the H3 receptor. We also reveal that this pathway provides a mechanism for selective modulation of body temperature at the beginning of the active phase of the circadian cycle.