Central Control Of Body Temperature Research Articles

Bone, Growth Plate and Mineral Metabolism

It has been an outstanding year of publications in the field of pediatric endocrinology. We have made a subjective selection of 19 papers and divided the chapter into ’bone’, ’growth plate’ and ’mineral metabolism’ where each paper is discussed from a pediatric endocrine point of view. A clear breakthrough and mechanism of the year is the discovery of RANKL/RANK as key thermoregulators creating a link between bone physiology and central control of body temperature and fever. A new paradigm is represented by two papers discovering that serotonin regulates bone mass accrual in opposite directions depending on site of synthesis. A paper describing a new mechanism of IGF-1 to modulate thyroid hormone effects in the growth plate is also highligted. We selected a few papers identifying new genes linked to to important clinical conditions if mutated. These include cyclophilin B – linked to severe osteogenesis imperfecta, and ENPP1 – linked to hypophosphatemic rickets. As food for thought, we included a paper disclosing how hibernating bears prevent bone loss.

Central Norepinephrine‐Kisspeptin Pathway as Part of the Vaso‐motor Effects of Estrogen in an Animal Model of Menopausal Hot Flashes

Menopausal transition includes the vasomotor disturbance hot flash as a significant symptom. Thus, the lack of estrogen has pronounced effects on thermoregulation, but how estrogen modulates thermoregulation remains poorly understood. Both norepinephrine (NE) and kisspeptin (Kp) have been shown to be involved in the central control of body temperature. In this work, we investigated the role of NE in the activation of hypothalamic Kp neurons and vasomotor effects caused by the lack of 17β‐estradiol (E2) in ovariectomized (OVX) rats. The first experiment was designed to determine the effects of E2 on tail skin temperature (TST) and correlate neuronal activation. Adult female rats were OVX and implanted with subcutaneous Silastic capsules containing oil (OVX) or E2 (6 ug/capsule/rat; OVX+E2). The TST was recorded for 2 hours on days 3, 7 and 14 after surgery. Rats were perfused on the morning of day 14 and the brains were processed for immunohistochemistry. OVX+E2 rats displayed greater uterine weight than OVX rats. The TST was higher in OVX compared to OVX+E2 rats at 7 and 14 days after ovariectomy. On day 14, OVX rats displayed an increased percentage of tyrosine hydroxylase (TH)‐immunoreactive (ir) neurons expressing Fos in the A1, A2 and locus coeruleus (LC), which was positively correlated with TST. The number of Fos‐ir neurons was also higher in the anteroventral periventricular (AVPV), median preoptic (MnPO), medial preoptic (MPO), and paraventricular (PVN) nuclei of OVX rats compared with OVX+E2. In the arcuate nucleus (ARC), the numbers of Kp single‐labeled and Fos/Kp double‐labeled neurons were markedly higher in OVX rats. In a second experiment, we investigated whether NE projections to the hypothalamus would drive the activity of Kp neurons in OVX rats. The α2‐adrenergic agonist clonidine (CLO) was used to reduce central norepinephrine release and TST and Kiss1 gene expression were measured. OVX and OVX+E2 rats received daily intracerebroventricular injections of CLO (10 ug/3 μL/rat; OVX+CLO) or vehicle (OVX+V and OVX+E2+V) on days 12, 13 and 14 after ovariectomy. OVX+V rats displayed higher TST than OVX+E2+V, and this response was completely restored in OVX+CLO rats, whose TST was similar to that of OVX+E2+V rats. The same response was found for Kiss1 mRNA in the ARC, with higher expression in OVX than in OVX+E 2, and levels fully restored in OVX+CLO rats. On the other hand, CLO significantly increased Kiss1 expression in the AVPV of OVX+CLO rats compared to OVX+V and OVX+E2+V rats, and this response was associated with an increased secretion of luteinizing hormone (LH) in OVX + CLO rats. Thus, the increase in TST caused by the absence of E2 in OVX rats is associated with an increased activity of noradrenergic and hypothalamic nuclei and seems to depend on the NE activation of Kp neurons in the ARC. These findings provide evidence of the involvement of a central NE‐Kp pathway as part of the vasomotor effects of estrogen, with possible implication in origin of postmenopausal hot flash.Support or Funding InformationCNPq; FAPEMIGThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

3-Iodothyronamine Induces Tail Vasodilation Through Central Action in Male Mice.

3-Iodothyronamine (3-T1AM) is an endogenous thyroid hormone (TH)-derived metabolite that induces severe hypothermia in mice after systemic administration; however, the underlying mechanisms have remained enigmatic. We show here that the rapid 3-T1AM-induced loss in body temperature is a consequence of peripheral vasodilation and subsequent heat loss (e.g., over the tail surface). The condition is subsequently intensified by hypomotility and a lack of brown adipose tissue activation. Although the possible 3-T1AM targets trace amine-associated receptor 1 or α2a-adrenergic receptor were detected in tail artery and aorta respectively, myograph studies did not show any direct effect of 3-T1AM on vasodilation, suggesting that its actions are likely indirect. Intracerebroventricular application of 3-T1AM, however, replicated the phenotype of tail vasodilation and body temperature decline and led to neuronal activation in the hypothalamus, suggesting that the metabolite causes tail vasodilation through a hypothalamic signaling pathway. Consequently, the 3-T1AM response constitutes anapyrexia rather than hypothermia and closely resembles the heat-stress response mediated by hypothalamic temperature-sensitive neurons. Our results thus underline the well-known role of the hypothalamus as the body's thermostat and suggest an additional molecular link between TH signaling and the central control of body temperature.

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.

On the Horizon From the ORS

On the Horizon From the ORS

Cold exposure impairs dark‐pulse capacity to induce REM sleep in the albino rat

In the albino rat, a REM sleep (REMS) onset can be induced with a high probability and a short latency when the light is suddenly turned off (dark pulse, DP) during non-REM sleep (NREMS). The aim of this study was to investigate to what extent DP delivery could overcome the integrative thermoregulatory mechanisms that depress REMS occurrence during exposure to low ambient temperature (Ta). To this aim, the efficiency of a non-rhythmical repetitive DP (3 min each) delivery during the first 6-h light period of a 12 h:12 h light-dark cycle in inducing REMS was studied in the rat, through the analysis of electroencephalogram, electrocardiogram, hypothalamic temperature and motor activity at different Tas. The results showed that DP delivery triggers a transition from NREMS to REMS comparable to that which occurs spontaneously. However, the efficiency of DP delivery in inducing REMS was reduced during cold exposure to an extent comparable with that observed in spontaneous REMS occurrence. Such impairment was associated with low Delta activity and high sympathetic tone when DPs were delivered. Repetitive DP administration increased REMS amount during the delivery period and a subsequent negative REMS rebound was observed. In conclusion, DP delivery did not overcome the integrative thermoregulatory mechanisms that depress REMS in the cold. These results underline the crucial physiological meaning of the mutual exclusion of thermoregulatory activation and REMS occurrence, and support the hypothesis that the suspension of the central control of body temperature is a prerequisite for REMS occurrence.

Autonomic and Behavioral Thermoregulation in Golden Hamsters Exposed Perinatally to Dioxin

Perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a permanent change in thermoregulatory control of male offspring of the rat, characterized by a reduced core temperature (Tc) over a wide range of ambient temperatures (Ta). To examine the similarities in this effect across species, the thermoregulatory effects of perinatal TCDD were evaluated in the golden hamster, a species which is very resistant to the lethal effects of TCDD. Adult male hamsters exposed on Gestational Day 11.5–11.75 to 2.0 μg TCDD/kg by gavage were subjected to a variety of behavioral and autonomic thermoregulatory measurements. NocturnalTcof TCDD-treated animals was 0.4 to 1.0°C below that of controls over aTarange of 14 to 34°C. Hypothermia persisted in spite of normal metabolic responses to cold exposure. The hypothermic effect of perinatal TCDD exposure was found to persist over a 24-hr period in unrestrained hamsters monitored by radiotelemetry. The TCDD-treated hamster offspring placed in a temperature gradient exhibited a preference for warmTa’s for 2 to 3 hr; however, when maintained over a 22-hr period in the gradient there was no effect of TCDD on behavioral thermoregulation. TCDD had no effect on motor activity measured over a 24-hr period. TCDD resulted in a ∼30% reduction in body weight compared to controls; however, this weight loss appeared to have no bearing on the thermoregulatory deficiencies of the TCDD-treated animals. TCDD-treated hamsters displayed a normal metabolic response to cold exposure; thus, it would appear that perinatal exposure to TCDD leads to a dysfunction in the central control of body temperature. The perinatal effects of TCDD on thermoregulation in the rat and hamster appear to be similar.

Cold- and ethanol-induced hypothermia reduces cellular levels of mRNA-encoding Thyrotropin-Releasing Hormone (TRH) in neurons of the preoptic area

Thyrotropin-releasing hormone (TRH)-containing neurons have been implicated in the central control of body temperature. TRH-containing neurons are located in brain areas known to influence body temperature, and TRH injected into these areas can produce changes in body temperature. While these lines of evidence support the view that central TRH is involved in thermoregulation, it has been difficult to confirm that TRH-containing neurons of the preoptic area are involved in this process. We used a different approach to test this hypothesis, based on recent evidence that changes in cellular levels of neuropeptide mRNA are linked to changes in neurosecretory processes. Hence, we predicted that if TRH neurons of the preoptic area are involved in body temperature regulation, cellular levels of TRH mRNA would be altered in animals in which body temperature had been experimentally altered. TRH mRNA levels were measured by in situ hybridization histochemistry in neurons of the preoptic area (POA) of animals that had been exposed to cold (5°C) or that had been given a hypothermic dose of ethanol. Cellular levels of TRH mRNA were reduced by both treatments. However, cellular levels of the mRNA-encoding gastrin-releasing peptide were not affected by these treatments in neurons of the POA, indicating that hypothermia exerted selective effects on TRH neurons in this brain region. Considering that both cold exposure and ethanol administration increase blood pressure, that the POA contains neurons which are both thermosensitive and barosensitive, and that TRH has been implicated in the control of blood pressure, we manipulated arterial blood pressure pharmacologically without changing body temperature to determine whether TRH neurons were also responsive to cardiovascular changes. Infusions with either nitroprusside, a vasodilator, or phenylephrine, a vasoconstrictor, produced significant changes in arterial blood pressure and heart rate, but did not affect TRH mRNA in the POA. These findings demonstrate that TRH neurons of the POA are thermoresponsive, supporting the view that they play a role in the central control of body temperature.

Hypothermic effect of d-Ala-deltorphin II, a selective δ opioid receptor agonist

The natural heptapeptide d-Ala-deltorphin II, the most selective agonist for δ-receptors currently available, was used to study the role of brain δ opioid receptors in the control of body temperature. In rats placed in a cold ambient temperature (4°C), intracerebroventricular injections of d-Ala-deltorphin II produced a significant hypothermia. In animals at an ambient temperature of 22°C, only the highest dose employed induced a slight fall in body temperature. At a warm temperature (34°C), d-Ala-deltorphin II induced no significant changes in body temperature. d-Ala-deltorphin II-induced hypothermia, unaffected by naloxone, was significantly reduced by the selective δ receptor antagonist naltrindole. These findings indicate that d-Ala-deltorphin II produces its hypothermic effects at a supraspinal δ receptor, and support the involvement of δ receptors in central control of body temperature.

Properties of central control of body temperature in the rabbit.

The structure of the central temperature controller in rabbits has been analysed. On the one hand, experiments were carried out to obtain the necessary data for system analysis; on the other hand, a mathematical model of the passive system was developed which describes the thermal characteristics of the body in accordance with the experimental results. In applying the model, different controller equations for the effector mechanisms involved were tested to fit the experimental data best. They are compared with already existing models of metabolic control. In addition, mechanisms of the effector coordination are discussed. It is shown that the three effectors make use of a similar controller structure that feeds core temperature as well as skin temperature back into the controller. The system is insensitive to variations of the controller gains, whereas a slight change in the controller reference temperature causes significant changes of the controlled core temperature. Furthermore it is shown that any mutual effector blockings are dispensible.

The central role of a cholinergic synapse in thermoregulation in the sheep

1. 1.|A study has been done to reinvestigate the evidence for the involvement of a cholinergic synapse in the central control of body temperature in the sheep. 2. 2.|Intracerebroventricular (ICV) injections of atropine sulphate attenuated the thermoregulatory reactions to a low ambient temperature as well as those caused by ICV administration of carbachol and prostaglandin E 1, and by TAB vaccine given intravenously. 3. 3.|We conclude that a cholinergic synapse (or synapses) exists on the hypothalamic pathway from cold-sensors to thermoregulatory effectors.

Role of brain Ca2+ in central control of body temperature during exercise in the monkey

Role of brain Ca2+ in central control of body temperature during exercise in the monkey

Thermoregulatory deficits in the monkey produced by 5,6-dihydroxytryptamine injected into the hypothalamus

In 7 male rhesus monkeys ( Macaco mulatta), an array of 4–8 guide cannulae was implanted stereotaxically so that the tips rested just above the intended sites of microinjection in the rostral and other regions of the hypothalamus. To examine the thermoregulatory capacity of each monkey, the air in their chair chamber was elevated to 40°C or cooled to 4°C by a stream of warm or cold air, respectively, for an interval of 3 hr. After a baseline temperature was recorded colonically, serotonin was microinjected in 1.0–1.5 μl volumes in doses of 3.5 to 7.5 μg at a total of 96 sites in order to determine the sensitive loci at which the indoleamine evoked hyperthermia. 5,6-Dihydroxytryptamine (5,6-DHT), an agent which destroys serotonergic nerve endings, was injected on a different day, in doses of 2–7 to 12. μg in a similar volume at the serotonin-sensitive sites. The initial effect of 5,6-DHT was dose-dependent hyperthermia similar to that evoked earlier by serotonin. Severe thermoregulatory deficits in response to the cold challenge were observed on subsequent days after low doses of 5,6-DHT were injected primarily in the region of the anterior hypothalamus. Impairment in thermoregulation to the warm temperature also occurred after higher doses of the neurotoxin were given. However, serotonin still evoked a temperature response nearly identical to that seen before 5,6-DHT treatment. These results support the theory that serotonergic neurones in the hypothalamus are involved in the central control of body temperature in the primate.

Temperature responses of lambs after centrally injected prostaglandins and pyrogens.

It has been proposed that pyrogens may produce their febrile response by the release of prostaglandins in the hypothalamus. To test this theory, prostaglandin E1 (PGE1) was injected into a lateral ventricle in dosages of 2-200 ug into conscious newborn lambs, ages 4-168 h. Fiifteen of 40 injections were followed by rises in rectal temperature but the remainder were followed either by no change or by falls. Temperature responses did not appear to be related to age and a variation in responses to the same dosage of PGE was often observed. Some lambs were able to develop fevers in response to intravenous bacterial pyrogen yet did not develop fever after intraventricular PGE 1. Intraventricular bacterial pyrogen (3 ng) produced no change in body temperature, whereas three of four injections of 300 ng pyrogen caused fever. The results suggest that the newborn lamb may be able to develop a fever independently of the central involvement of PGE1. Alternatively, the intraventricular approach may not be useful for the study of the central control of body temperature in the newborn lamb.

A study of potential cholinergic mechanisms involved in the central control of body temperature in golden hamsters

The intrahypothalamic injection of 0·003 and 0·006 μmol of carbamylcholine chloride (CCh) was found to elicit a dose-dependent increase in rectal temperature in unanaesthetized, normothermic golden hamsters. In agreement with a proposed depolarization block in heat gain pathways, the similar administration of 0·01 μmol of this cholinergic agonist produced a significant hypothermic response. In the case of hyperthermia, thermogenesis appeared to be initiated mainly by shivering with a possible lesser contribution from an increase in cardiac rate. Heat conservation in this instance was indicated by the occurrence of peripheral vasoconstriction. Heat loss and the resultant hypothermia elicited by the highest CCh dose was primarily achieved by peripheral vasodilation. In addition, a possible decrease in thermogenesis was indicated by a reduction in cardiac rate. However, this dose of agonist also produced marked behavioural agitation and struggling which led to a substantial increase in electromyographic activity. The effects of both 0·006 and 0·01 μmol of CCh were abolished by the prior central administration of atropine, whereas similar pretreatment with phentolamine and methysergide failed to alter either CCh response.

Noradrenergic mechanism in the central control of body temperature.

Noradrenergic mechanism in the central control of body temperature.

The effects of centrally administered chlorpromazine on temperature regulation in the hamster

THE demonstrated importance of hypothalamic centers in the control of body temperature (1) has stimulated considerable interest in the central component of action of several chemical agents observed to have a disruptive effect on temperature regulation. Chlorpromazine (CPZ), based on its general central depressant activity, has been assumed to produce this disruptive effect by a deppression of hypothalamic neuromechanisms involved in temperature control. However, CPZ has a broad spectrum of peripheral as well as central activity (2) and few attempts have been made to achieve a definitive indication of the relative importance of these components in eliciting alterations in body temperature. The present study was undertaken to investigate the central component of CPZ induced hypothermia in hamsters by means of the direct injection of this agent into the anterior hypothalamus at a low ambient temperature. Because of our interest in the influence of genetic predisposition on the effects of psychotropic drugs (3,4,5) and since the hamster is the most readily available animal whose innate thermoregulatory control mechanisms permit a state of hibernation, it was decided to compare the central effects of CPZ in this species with those reported to occur in a non-hibernator such as the rat. Rewerski and co-workers (6,7) have observed a hyperthermic effect following the intrahypothalamic injection of CPZ in rats subjected to ether anesthesia and stereotaxic restraint at 20°C. However, since it is well known that ambient temperature and degree of stress both influence the effect of CPZ on body temperature (2,8), it was decided to perform the experiments described below in unanesthetized, partially restrained animals at an ambient temperature of 10°C. Finally, on the basis of the demonstrated hypothermia mediated by the central activity of several cholinergic agents (9,10,11) and cholinesterase inhibitors (12), the ability of atropine to prevent this effect and to elicit hyperthermia following central administration (13), and the anticholinesterase activity of CPZ by pretreatment with centrally administered atropine. The injection of 12.5 – 37.5 ug of CPZ into the anterior hypothalamus of hamsters has been shown to elicit an immediate, dose-dependent hypothermia when the experiments are conducted at a low environmental temperature. A 50 ug dose of CPZ sulfoxide produced only a slight fall in rectal temperature comparable to that obtained following the lowest dose of CPZ. The CPZ response was not antagonized by an equimolar dose of atropine and was not accompanied by changes in EMG or skin temperature indicative of interference with the thermoregulatory mechanisms of shivering and peripheral vascular tone. However, undetected vascular changes may have occured. These results are consistent with the possibility that the effect of CPZ on the central control of body temperature in the hamster may be mediated through its influence on non-shivering thermogenesis.

Central effects of 6-hydroxydopamine on the body temperature of the rat.

1. Rats which had been pretreated with intraventricular injections of 6-hydroxydopamine (6-OHDA) to cause a selective depletion of brain noradrenaline (NA) to 20.7% of control brain NA and brain dopamine (DA) to 34.6% of control brain DA retained an unimpaired ability to regulate their body temperatures on exposure to heat or cold. This is discussed in relation to the possible role of brain NA in the central control of body temperature.2. Intraventricular injections of 6-OHDA in normal rats at room temperature caused an acute, dose dependent hypothermia of up to 4.5 degrees C which lasted for 4-5 hours. Depletion of brain NA and DA by prior treatment with 6-OHDA markedly reduced the hypothermic response to a subsequent dose of 6-OHDA. Selective depletion of brain NA without affecting brain DA did not reduce the response to 6-OHDA. The acute hypothermic response to 6-OHDA, may therefore, be related to a release of DA in the brain.

Temperature changes following iontophoretic injection of acetylcholine into the rostral hypothalamus of the rat

A method is described for iontophoretic injection of acetylcholine into the central nervous system of experimental animals. A fall in body temperature occurred when acetylcholine was delivered into the rostral hypothalamic thermoregulatory centers of the rat, but not when the drug was introduced at other sites in the hypothalamus. Systemic injection of atropine prevented the hypothermic response to subsequently injected acetylcholine. These results support the concept that central control of body temperature involves cholinergic receptors in the thermoregulatory centers.