Central Thermoregulatory Mechanisms Research Articles

Tonic GABAergic signaling from prostaglandin EP3 receptor-expressing preoptic neurons bidirectionally controls body temperature

The principal controller neurons of the thermoregulatory center in the preoptic area (POA) have yet to be determined. In the present study using rats, we discovered that prostaglandin EP3 receptor-expressing POA neurons (POA EP3R neurons) are a pivotal bidirectional controller in the central thermoregulatory circuit mechanism. POA EP3R neurons were activated in response to elevated ambient temperature, but inhibited by prostaglandin E 2 , a pyrogenic mediator. In newly generated Ptger3 (EP3R)-tTA transgenic rats, chemogenetic stimulation of POA EP3R neurons at room temperature reduced body temperature by eliciting skin vasodilation (enhancing heat dissipation), whereas inhibition of them elicited hyperthermia involving brown adipose tissue thermogenesis and tachycardia, mimicking fever. Furthermore, we revealed that POA EP3R neurons innervate sympathoexcitatory neurons in the dorsomedial hypothalamus (DMH) via tonic inhibitory signaling. Although many POA EP3R neuronal cell bodies expressed a glutamatergic mRNA marker, paradoxically, most of their axons in the DMH contained GABAergic synaptic proteins. Interestingly, such GABAergic terminals of POA EP3R →DMH axons were increased by chronic heat exposure of rats, indicating a synaptic alteration to enhance heat tolerance. Consistent with the anatomical observation, slice patch-clamp recordings from DMH neurons combined with optogenetic stimulation of POA EP3R →DMH axon terminals showed that these terminals predominantly form GABAergic synapses onto DMH neurons. These findings demonstrate that tonic GABAergic inhibitory signaling from POA EP3R neurons is a fundamental determinant of body temperature for thermal homeostasis and fever. NEXT Program from JSPS (LS070 to K.N.); MEXT KAKENHI (JP21K06767, JP17K08568, JP26860159, JP23790271 to Y.N.; JP22K06844 to A.F.; JP22K06470, JP19K06954, JP16K19006 to N.K.; JP21H02592 to H.H.; JP20H03418, JP16H06276 (AdAMS), JP16H05128, JP15H05932, JP26118508, JP26713009, JP22689007 to K.N.); PRESTO (JPMJPR13M9 to K.N.), FOREST (JPMJFR204D to H.H.), Moonshot R&D (JPMJMS2024 to H.H.; JPMJMS2023 to K.N.) of JST; AMED (JP21wm0525002 to N.K.; JP21dm0207112 to H.H.; JP21gm5010002 to K.N.); Hori Sciences and Arts Foundation (to Y.N.); Kato Memorial Bioscience Foundation, Foundation of Kinoshita Memorial Enterprise (to N.K.); Takeda Science Foundation (to T.Y. and K.N.); Nakajima Foundation, Uehara Memorial Foundation, Ono Medical Research Foundation, Brain Science Foundation, Kowa Life Science Foundation (to K.N.). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Prostaglandin EP3 receptor–expressing preoptic neurons bidirectionally control body temperature via tonic GABAergic signaling

The bidirectional controller of the thermoregulatory center in the preoptic area (POA) is unknown. Using rats, here, we identify prostaglandin EP3 receptor-expressing POA neurons (POAEP3R neurons) as a pivotal bidirectional controller in the central thermoregulatory mechanism. POAEP3R neurons are activated in response to elevated ambient temperature but inhibited by prostaglandin E2, a pyrogenic mediator. Chemogenetic stimulation of POAEP3R neurons at room temperature reduces body temperature by enhancing heat dissipation, whereas inhibition of them elicits hyperthermia involving brown fat thermogenesis, mimicking fever. POAEP3R neurons innervate sympathoexcitatory neurons in the dorsomedial hypothalamus (DMH) via tonic (ceaseless) inhibitory signaling. Although many POAEP3R neuronal cell bodies express a glutamatergic messenger RNA marker, their axons in the DMH predominantly release γ-aminobutyric acid (GABA), and their GABAergic terminals are increased by chronic heat exposure. These findings demonstrate that tonic GABAergic inhibitory signaling from POAEP3R neurons is a fundamental determinant of body temperature for thermal homeostasis and fever.

Recent advances in thermoregulation.

Thermoregulation is the maintenance of a relatively constant core body temperature. Humans normally maintain a body temperature at 37°C, and maintenance of this relatively high temperature is critical to human survival. This concept is so important that control of thermoregulation is often the principal example cited when teaching physiological homeostasis. A basic understanding of the processes underpinning temperature regulation is necessary for all undergraduate students studying biology and biology-related disciplines, and a thorough understanding is necessary for those students in clinical training. Our aim in this review is to broadly present the thermoregulatory process taking into account current advances in this area. First, we summarize the basic concepts of thermoregulation and subsequently assess the physiological responses to heat and cold stress, including vasodilation and vasoconstriction, sweating, nonshivering thermogenesis, piloerection, shivering, and altered behavior. Current research is presented concerning the body's detection of thermal challenge, peripheral and central thermoregulatory control mechanisms, including brown adipose tissue in adult humans and temperature transduction by the relatively recently discovered transient receptor potential channels. Finally, we present an updated understanding of the neuroanatomic circuitry supporting thermoregulation.

Orexin neurons are indispensable for prostaglandin E2‐induced fever and defence against environmental cooling in mice

We recently showed using prepro-orexin knockout (ORX-KO) mice and orexin neuron-ablated (ORX-AB) mice that orexin neurons in the hypothalamus, but not orexin peptides per se, are indispensable for stress-induced thermogenesis. To examine whether orexin neurons are more generally involved in central thermoregulatory mechanisms, we applied other forms of thermogenic perturbations, including brain prostaglandin E2 (PGE2) injections which mimic inflammatory fever and environmental cold exposure, to ORX-KO mice, ORX-AB mice and their wild-type (WT) litter mates. ORX-AB mice, but not ORX-KO mice, exhibited a blunted PGE2-induced fever and intolerance to cold (5°C) exposure, and these findings were similar to the results previously obtained with stress-induced thermogenesis. PGE2-induced shivering was also attenuated in ORX-AB mice. Both mutants responded similarly to environmental heating (39°C). In WT and ORX-KO mice, the administration of PGE2 and cold exposure activated orexin neurons, as revealed by increased levels of expression of c-fos. Injection of retrograde tracer into the medullary raphe nucleus revealed direct and indirect projection from the orexin neurons, of which the latter seemed to be preserved in the ORX-AB mice. In addition, we found that glutamate receptor antagonists (D-(-)-2-amino-5-phosphonopentanoic acid and 6-cyano-7-nitroquinoxaline-2,3-dione) but not orexin receptor antagonists (SB334867 and OX2 29) successfully inhibited PGE2-induced fever in WT mice. These results suggest that orexin neurons are important in general thermogenic processes, and their importance is not restricted to stress-induced thermogenesis. In addition, these results indicate the possible involvement of glutamate in orexin neurons implicated in PGE2-induced fever.

Central circuitries for body temperature regulation and fever

Body temperature regulation is a fundamental homeostatic function that is governed by the central nervous system in homeothermic animals, including humans. The central thermoregulatory system also functions for host defense from invading pathogens by elevating body core temperature, a response known as fever. Thermoregulation and fever involve a variety of involuntary effector responses, and this review summarizes the current understandings of the central circuitry mechanisms that underlie nonshivering thermogenesis in brown adipose tissue, shivering thermogenesis in skeletal muscles, thermoregulatory cardiac regulation, heat-loss regulation through cutaneous vasomotion, and ACTH release. To defend thermal homeostasis from environmental thermal challenges, feedforward thermosensory information on environmental temperature sensed by skin thermoreceptors ascends through the spinal cord and lateral parabrachial nucleus to the preoptic area (POA). The POA also receives feedback signals from local thermosensitive neurons, as well as pyrogenic signals of prostaglandin E(2) produced in response to infection. These afferent signals are integrated and affect the activity of GABAergic inhibitory projection neurons descending from the POA to the dorsomedial hypothalamus (DMH) or to the rostral medullary raphe region (rMR). Attenuation of the descending inhibition by cooling or pyrogenic signals leads to disinhibition of thermogenic neurons in the DMH and sympathetic and somatic premotor neurons in the rMR, which then drive spinal motor output mechanisms to elicit thermogenesis, tachycardia, and cutaneous vasoconstriction. Warming signals enhance the descending inhibition from the POA to inhibit the motor outputs, resulting in cutaneous vasodilation and inhibited thermogenesis. This central thermoregulatory mechanism also functions for metabolic regulation and stress-induced hyperthermia.

Long-Lasting Effect of Changes in Incubation Temperature on Heat Stress Induced Neuronal Hypothalamic c-Fos Expression in Chickens

In birds, during prenatal 'critical periods' the thermoregulatory system can be life-long imprinted by the actual incubation temperature. The aim of the present study is to elucidate long-term effects of prenatal temperature experiences, applied at the end of incubation, on central thermoregulatory mechanisms by detection of neuronal hypothalamic c-Fos expression as a consequence of acute heat stress in growing and adult chickens using immunohistochemistry. From day 18 of incubation chicken embryos were incubated in three temperature groups: 37.5°C (regular incubated), 34.5°C (cold incubated) or 38.5°C (warm incubated). C-Fos expression was detected in 29 4-weeks old and 61 8-weeks old chickens after acute heat stress (42°C for 90 min). The results show, that prenatal temperature experiences can induce long-lasting changes in the heat induced neuronal hypothalamic c-Fos expression. But significant alterations could be only found in 8 weeks old chickens and these changes were in opposite as expected. It means that after acute heat stress cold incubated chickens have a significantly lower neuronal c-Fos expression compared with the warm incubated ones. This effect could be caused by cross adaptation to the actual ambient temperature during the growing period. Further, the developmental pattern of the hypothalamic neuronal network in different incubated birds, which is demonstrated by neuronal c-Fos expression in the actual study, is similar to the pattern, which we found after recordings of single neurons activity, to a higher extent. Correlations between both parameters, which are involved in neuronal plasticity, can be accepted.

Probable neurophysiological and neurochemical mechanisms of the pyrogenic reaction evoked by introduction of a bacterial toxin into rats

Intraperitoneal injection of 5 µg/kg lipopolysaccharide (LPS) of Escherichia coli in acute experiments on anesthetized rats under thermostabilized conditions (26°C) led to an increase in the frequency of multineuronal afferent impulsation in the n. vagus (recording at the cervical level); this increase began 10 min after injection and was preserved until the end of the observation period (160 min). Injection of apyrogenic physiological saline (APS) did not influence the above parameter. Rectal temperature (RT) increased 130 min after injection of LPS, as compared with the control (injection of APS), by 2.5°C, on average, and remained increased until the end of the recording period. Under these conditions, the activities of NADPh diaphorase, lactate dehydrogenase, succinate dehydrogenase, and acetylcholinesterase (cytochemical measurements) in neurons of the nucl. tractus solitarius (NTS) increased. A blocker of synthesis of nitric oxide, L-NAME (25 mg/kg), when injected i.p. 30 min before injection of 5 µg/kg LPS, prevented intensification of afferent impulsation in the n. vagus and a rise in RT. In this case, the activity of enzymes of energetic metabolism and intensity of synthesis of NO in neurons of the NTS decreased. The data obtained allow us to hypothesize that NO functions as a modulator in the central and peripheral thermoregulatory mechanisms.

Nitric oxide pathway is an important modulator of heat loss in rats during exercise

To assess the role of nitric oxide (NO) in central thermoregulatory mechanisms during exercise, 1.43 μmol (2 μL) of N ω-nitro- l-arginine methyl ester ( l-NAME, n = 6), a NO synthase inhibitor, or 2 μL of 0.15 M NaCl (SAL, n = 6) was injected into the lateral cerebral ventricle of male Wistar rats immediately before the animals started running (18 m min −1, 5% inclination). Core ( T b) and skin tail ( T tail) temperatures were measured. Body heating rate (BHR), threshold T b for tail vasodilation (TTbV), and workload ( W) were calculated. During the first 11 min of exercise, there was a greater increase in T b in the l-NAME group than in the SAL group (BRH = 0.17 ± 0.02 °C min −1, l-NAME, versus 0.09 ± 0.01 °C min −1, SAL, p < 0.05). Following the first 11 min until ∼40 min of exercise, T b levels remained stable in both groups, but levels remained higher in the l-NAME group than in the SAL group (39.16 ± 0.04 °C, l-NAME, versus 38.33 ± 0.02 °C, SAL, p < 0.01). However, exercise went on to induce an additional rise in T b in the SAL group prior to fatigue. These results suggest that the reduced W observed in l-NAME-treated rats (10.8 ± 2.0 kg m, l-NAME, versus 25.0 ± 2.1 kg m, SAL, p < 0.01) was related to the increased BHR in l-NAME-treated animals observed during the first 11 min of exercise ( r = 0.74, p < 0.01) due to the change in TTbV (39.12 ± 0.24 °C, l-NAME, versus 38.27 ± 0.10 °C, SAL, p < 0.05). Finally, our data suggest that the central nitric oxide pathway modulates mechanisms of heat dissipation during exercise through an inhibitory mechanism.

Cytokines and fever.

Cytokines are highly inducible, secreted proteins mediating intercellular communication in the nervous and immune system. Fever is the multiphasic response of elevation and decline of the body core temperature regulated by central thermoregulatory mechanisms localized in the preoptic area of the hypothalamus. The discovery that several proinflammatory cytokines act as endogenous pyrogens and that other cytokines can act as antipyretic agents provided a link between the immune and the central nervous systems and stimulated the study of the central actions of cytokines. The proinflammatory cytokines interleukin 1 (IL-1), interleukin 6 (IL-6) and the tumor necrosis factor alpha (TNF) as well as the antiinflammatory cytokines interleukin 1 receptor antagonist (IL-1ra) and interleukin 10 (IL-10) have been most investigated for their pyrogenic or antipyretic action. The experimental evidence demonstrating the role of these secreted proteins in modulating the fever response is as follows: 1) association between cytokine levels in serum and CSF and fever; 2) finding of the presence of cytokine receptors on various cell types in the brain and demonstration of the effects of pharmacological application of cytokines and of their neutralizing antibodies on the fever response; 3) fever studies on cytokine- and cytokine receptor- transgenic models. Studies on the peripheral and the central action of cytokines demonstrated that peripheral cytokines can communicate with the brain in several ways including stimulation of afferent neuronal pathways and induction of the synthesis of a non cytokine pyrogen, i.e. PGE2, in endothelial cells in the periphery and in the brain. Cytokines synthesized in the periphery may act by crossing the blood brain barrier and acting directly via neuronal cytokine receptors. The mechanisms that ultimately mediate the central action of cytokines and of LPS on the temperature-sensitive neurons in the preoptic hypothalamic region involved in thermoregulation, directly or via second mediators, remain to be fully elucidated.

Perioperative shivering: physiology and pharmacology.

IN homeothermic species, a thermoregulatory system coordinates defenses against cold and heat to maintain internal body temperature within a narrow range, thus optimizing normal physiologic and metabolic function. The combination of anesthetic-induced thermoregulatory impairment and exposure to a cool environment makes most unwarmed surgical patients hypothermic. Although shivering is but one consequence of perioperative hypothermia, and rarely the most serious, it occurs frequently (i.e., 40–60% after volatile anesthetics), and it remains poorly understood. While coldinduced thermoregulatory shivering remains an obvious etiology, the phenomenon has also been attributed to numerous other causes. Our first goal is to review the organization of the thermoregulatory system, and particularly the physiology of postanesthetic shivering. We then discuss the pharmacology of thermoregulation and review the putative mechanisms and sites of action of various antishivering drugs.

Role of adenosine in the hypoxia-induced hypothermia of toads.

The concept that hypoxia elicits a drop in body temperature (T(b)) in a wide variety of animals is not new, but the mechanisms remain unclear. We tested the hypothesis that adenosine mediates hypoxia-induced hypothermia in toads. Measurements of selected T(b) were performed using a thermal gradient. Animals were injected (into the lymph sac or intracerebroventricularly) with aminophylline (an adenosine receptor antagonist) followed by an 11-h period of hypoxia (7% O(2)) or normoxia exposure. Control animals received saline injections. Hypoxia elicited a drop in T(b) from 24.8 +/- 0.3 to 19. 5 +/- 1.1 degrees C (P < 0.05). Systemically applied aminophylline (25 mg/kg) did not change T(b) during normoxia, indicating that adenosine does not alter normal thermoregulatory function. However, aminophylline (25 mg/kg) significantly blunted hypoxia-induced hypothermia (P < 0.05). To assess the role of central thermoregulatory mechanisms, a smaller dose of aminophylline (0.25 mg/kg), which did not alter hypoxia-induced hypothermia systemically, was injected into the fourth cerebral ventricle. Intracerebroventricular injection of aminophylline (0.25 mg/kg) caused no significant change in T(b) under normoxia, but it abolished hypoxia-induced hypothermia. The present data indicate that adenosine is a central and possibly peripheral mediator of hypoxia-induced hypothermia.

Fetal alcohol exposure attenuates interleukin-1β-induced fever: neuroimmune mechanisms

Central mechanisms for the attenuating effects of fetal alcohol exposure (FAE) on interleukin-1β (IL-1)-induced fever were studied in adult male offspring of dams fed a liquid diet supplemented with ethanol (E), in pair-fed (P) control and in normal (N) offspring. Hypothalamic levels of IL-1 were significantly lower in E than in N rats at 2 h, but not at 4 and 6 h, after intraperitoneal administration of lipopolysaccharide. Fever induced by intracerebroventricular (icv) IL-1 was significantly lower in E than in N and P rats. In contrast, E rats showed a normal febrile response to icv prostaglandin-E 2. Thus, whereas FAE does not affect central thermoregulatory mechanisms, per se, FAE alters the kinetics of hypothalamic IL-1 production/appearance and decreases the responsiveness of central mechanisms which mediate the febrile response to IL-1.

Central thermoregulatory effects of lactate in the toad Bufo paracnemis

Hypoxia induces a regulated decrease in body temperature (Tb; anapyrexia) in organisms ranging from protozoans to mammals, but very little is known about the mechanisms involved. Several candidates have been suggested to mediate hypoxia-induced anapyrexia, among them lactate, which is a classical companion of hypoxic stress in vertebrates. The present study was designed to assess the central thermoregulatory effects of lactate in Bujo paracnemis. Toads equipped with a temperature probe were tested over a thermal gradient (10–40°C). Lactate injected systemically (4.0 mmol kg −1) caused a significant reduction of Tb from 24.6±2.1 to 17.4±3.9°C. To assess the role of central thermoregulatory mechanisms, a lower dose (0.4 mmol kg −1) of lactate was injected into the fourth cerebral ventricle or systemically. Intracerebroventricular injection of lactate caused a similar decrease in Tb, whereas systemic injection caused no change. The data indicate that lactate may play a role in hypoxia-induced anapyrexia in central rather than peripheral sites.

Role of nitric oxide in systemic vasopressin-induced hypothermia.

It has been reported that arginine vasopressin (AVP) plays a thermoregulatory action, but very little is known about the mechanisms involved. In the present study, we tested the hypothesis that nitric oxide (NO) plays a role in systemic AVP-induced hypothermia. Rectal temperature was measured before and after AVP, AVP blocker, or NG-nitro-L-arginine methyl ester (L-NAME; NO synthase inhibitor) injection. Control animals received saline injections of the same volume. The basal body temperature (Tb) measured in control animals was 36.53 +/- 0.08 degreesC. We observed a significant (P < 0.05) reduction in Tb to 35.44 +/- 0.19 degreesC after intravenous injection of AVP (2 micrograms/kg) and to 35.74 +/- 0. 10 degreesC after intravenous injection of L-NAME (30 mg/kg). The systemic injection of the AVP blocker [beta-mercapto-beta, beta-cyclopentamethylenepropionyl1,O-Et-Tyr2,Val4,Arg8]vasopressin (10 micrograms/kg) caused a significant increase in Tb to 37.33 +/- 0.23 degreesC, indicating that AVP plays a tonic role by reducing Tb. When the treatments with AVP and L-NAME were combined, systemically injected L-NAME blunted AVP-induced hypothermia. To assess the role of central thermoregulatory mechanisms, a smaller dose of L-NAME (1 mg/kg) was injected into the third cerebral ventricle. Intracerebroventricular injection of L-NAME caused an increase in Tb, but when intracerebroventricular L-NAME was combined with systemic AVP injection (2 micrograms/kg), no change in Tb was observed. The data indicate that central NO plays a major role mediating systemic AVP-induced hypothermia.

Role of the nitric oxide pathway in hypoxia-induced hypothermia of rats.

Hypothermia is a response to hypoxia that occurs in organisms ranging from protozoans to mammals, but very little is known about the mechanisms involved. Recently, the NO pathway has been suggested to be involved in thermoregulation. In the present study, we assessed the participation of nitric oxide in hypoxia-induced hypothermia by means of NO synthase inhibition using NG-nitro-L-arginine methyl ester (L-NAME). The rectal temperature of awake, unrestrained rats was measured before and after hypoxia or L-NAME injection or both treatments together. Control animals received saline injections of the same volume. We observed a significant (P < 0.05) reduction in body temperature of 1.32 +/- 0.36 degrees C after hypoxia (7% inspired O2) and of 0.96 +/- 0.42 degree C after L-NAME (30 mg/kg body wt) injected intravenously. When the two treatments were combined, no significant difference in body temperature was observed. To assess the role of central thermo-regulatory mechanisms, a smaller dose of L-NAME (1 mg/kg) was injected into the third cerebral ventricle or intravenously. Intracerebroventricular injection of L-NAME caused an increase in body temperature, but when L-NAME was combined with hypoxia (7% inspired O2) no change in body temperature was observed. Intravenous injection of 1 mg/kg L-NAME had no effect. The data indicate that NO plays a major role in hypoxia-induced hypothermia at central rather than peripheral sites.

Involvement of Central Neurotensin in Thermoregulatory and Neuroimmune Function in Pregnant Rats Exposed to Heat

To examine a functional relationship among pregnancy and central neurotensin and thermoregulatory and neuroimmune systems during heat stress, we monitored colonic temperature in six virgin female rats and six pregnant rats (9 to 11 days gestation) exposed to a microwave source. We also assayed splenic natural killer cell activity (NKCA), blood corticosterone (CS), and ACTH as indicators of the hypothalamic-pituitary-adrenal axis, β-endorphin (β-EP), and neurotensin (NT) in discrete brain regions. Additionally, we clarified the effects of intracerebroventricular (icv) administration of NT antiserum on these same responses in pregnant rats exposed to heat stress. Repeated-measures analysis of variance showed significant main effects of heat and pregnancy and a significant interactive effect on colonic temperature. Significant elevation in blood CS, ACTH, β-EP, and NT in the hypothalamus and significant reductions in splenic NKCA and NT in the nucleus accumbens were produced by heat. In the experiment examining the effect of icv administration of NT antiserum, significant main effects of heat and administration and a significant interactive effect on colonic temperature were observed. Icv administration of NT antiserum increased splenic NKCA and decreased blood β-EP. These results show that pregnancy enhances thermal homeostasis, suggesting central thermoregulatory mechanisms through NT in nucleus accumbens and hypothalamus in which placental or pituitary β-EP may be involved. NT and β-EP seem to play central roles simultaneously in heat-induced immunosuppression during pregnancy. Clarification for the effects of NT antiserum on β-EP in virgin rats or manipulation of agents related to opioid system should be the focus of future work.

Effects of 2-deoxy-D-glucose and insulin on plasma glucose levels and behavioral thermoregulation of toads.

The present study was designed to test the hypothesis that hypoglycemia induces hypothermia in ectotherms and to elucidate the mechanisms responsible for behavioral hypothermia. Behavioral hypothermia is a stress response that occurs in organisms ranging from protozoans to mammals, but very little is known about the cellular mechanisms involved. Toads equipped with a temperature probe were tested in a thermal gradient (10-40 degrees C). Insulin was used to reduce plasma glucose levels, and an inhibitor of glucose utilization, 2-deoxy-D-glucose (2-DG), was used to cause intracellular glucopenia. Insulin injections into the dorsal lymph sac caused significant reductions of both plasma glucose levels and body temperature. To determine if the response was mediated by extracellular glucose receptors or an intracellular mechanism. 2-DG was also injected into the lymph sac. 2-DG caused a similar drop in body temperature and a marked increase in plasma glucose. To assess the role of central thermoregulatory mechanisms, a smaller dose of 2-DG was injected into the fourth cerebral ventricle or the lymph sac. Intracerebroventricular injection of 2-DG caused a decrease in body temperature despite elevated circulating glucose levels, whereas injection into the lymph sac caused no significant change. The data indicate that exclusion of glucose from central rather than peripheral sites plays a major role in the hypoglycemia-induced behavioral hypothermia and that intracellular mechanisms rather than extracellular glucose receptors are involved in this response. Hypothermia may be a beneficial response to hypoglycemia in toads because it dampens cellular oxidative demands during glucose deprivation.

Altered Shivering Threshold in Postmenopausal Women with Hot Flashes

Abstract Although the etiology of menopausal hot flashes is not known, it has been hypothesized that they are triggered by a downward resetting of the central thermoregulatory mechanism. Previous studies suggest that the sweating threshold may be reduced in postmenopausal women with hot flashes. In this study, we sought to determine whether their shivering threshold is reduced as well. Nine postmenopausal women reporting frequent hot flashes and seven asymptomatic postmenopausal women were recorded under basal conditions and during shivering at 4°C ambient temperature. The threshold of mean body temperature for shivering (defined by electromyographic activity) was significantly higher in the symptomatic versus the asymptomatic women. Mean body temperature declined significantly during shivering in the symptomatic women, due to significantly higher levels of mean skin temperature. These data suggest that the thermoneutral zone between the threshold for shivering and that for heat loss is narrowed in postmenopausal women with hot flashes.

The Thermoregulatory Effects of Menopausal Hot Flashes on Sleep

Menopausal hot flashes are thought to be a disorder of thermoregulation initiated centrally within the medial preoptic area of the hypothalamus. These heat-loss mechanisms appear to be activated in the presence of normal core body temperature. Previous studies have demonstrated that thermal stimuli have the potential to alter sleep stages. We performed 24-hour ambulatory recordings of hot flashes and all-night sleep parameters on 12 postmenopausal women with hot flashes and seven postmenopausal women without flashes to determine whether the presence of hot flashes prior to sleep or during sleep itself would result in alterations in sleep pattern. The results show that hot flashes are associated with increased Stage 4 sleep and a shortened first rapid eye movement period. Hot flashes occurring in the 2 hours prior to sleep onset were positively correlated with the amount of slow-wave sleep. The central thermoregulatory mechanism underlying hot flashes may affect hypnogenic pathways inducing sleep and heat loss in the absence of a thermal load.

Acute heat exposure causes cellular alteration in cerebral cortex of young rats

The possibility that prolonged heat exposure resulting in a failure of central thermoregulatory mechanism may induce cellular damage in brain was examined in young rats. Children exposed to Indian summer heat can develop sudden pathophysiological symptoms. Subjection of young animals to similar acute systemic heat exposure at 38 degrees C (relative humidity, 46%) for 4 h resulted in a profound hyperthermia, and behavioral stress symptoms e.g. salivation and prostration. Subsequent morphological examination of the brain tissue revealed profound cellular changes. In the cerebral cortex, dark neurons, swollen astrocytes, and expanded white and gray matter were quite frequent. At the ultrastructural level, collapse of microvessels, perivascular edema, vacuolation and damage to postsynaptic membrane was very common. Thus, profound hyperthermia can induce cellular changes by some direct or indirect (e.g. neurochemical) mechanism.