Step-wise changes in thermoregulatory responses to slowly changing thermal stimuli

Summary We report experiments on two species (sheep and squirrel monkeys) in which one local body temperature was slowly raised, while temperatures in the rest of the body were maintained as closely as possible to a steady state. The appropriate physiological or behavioral thermoregulatory response to the thermal stimulus often changed to new levels in discrete steps. When the stimulus changed at higher rates, the phenomenon was not observed. A step-change in the responses of both animal species occurred after a 0.8–1.0°C increase in the thermal stimulus. Our results indicate that the occurrence of the step response phenomenon depends upon a slow rate of change in one neural input to the central nervous system. Thus the basic step function response could be masked in more typical (normal) stimulusresponse relationships because several neural inputs vary concomitantly.This work was supported by National Institutes of Health Grant HE-12038 from the National Heart Institute and by United States Public Health Service Grant ES-00354. We acknowledge the technical assistance of K. P. Quick and B. A. Wright.     

Interaction of central and superficial peripheral thermosensors in control of thermoregulatory behaviors of the rat

The interaction of localized central and superficial peripheral thermal stimulation was studied in rats using diathermic warming of different brain areas controlling postural extension, locomotion, and grooming and a thermal floor warmed from thermally neutral 26.5 to 33.5 or 40.5°C, which induced locomotion and grooming. When behaviors were elicited by both central and superficial stimuli, combined stimuli were additive (activity) or partially additive subject to a ceiling (grooming). When behaviors were elicited by only one (or predominantly one) of two stimuli, combinations of the stimuli evidenced inhibition (grooming), multiplicative summation (activity), or mixtures of facilitation at low intensities and inhibition at high intensities (extension). Behaviors not elicited in significant amounts by either stimulus did not increase when both were combined (extension). It was concluded that the varied influences on thermoregulatory behaviors exerted by superficial and central thermosensors acting separately and in combination can largely explain the differences in behavioral response patterns induced by various thermal stress conditions that distribute heat differently between the surface and core of the body.     

Central actions of arginine vasopressin and a V1a receptor antagonist on maternal aggression, maternal behavior, and grooming in lactating rats

Maternal aggression is a robust type of aggression displayed by lactating female rats. Although arginine vasopressin (AVP) has been implicated in the control of male aggression, its involvement in maternal aggression has not been thoroughly investigated. Previous neuroanatomical studies suggest that AVP may mediate the display of aggression during lactation. In the current study, AVP and an AVP V1a receptor antagonist were centrally administered to primiparous rats on days 5 and 15 of lactation, and aggression, maternal behavior, and grooming were recorded. Although AVP did not affect the number of attacks or duration of aggression, it increased the latency to initiate aggression on day 5, in addition to decreasing maternal behavior and increasing grooming. Conversely, V1a antagonist treatment increased maternal aggression on both days of lactation, decreased maternal behavior on day 15, and decreased grooming on day 5. Thus, it appears that central AVP activity modulates maternal aggression, as well as maternal behavior and grooming behavior during lactation.     

Translational aspects of pharmacological research into anxiety disorders: the stress-induced hyperthermia (SIH) paradigm

In anxiety research, the search for models with sufficient clinical predictive validity to support the translation of animal studies on anxiolytic drugs to clinical research is often challenging. This review describes the stress-induced hyperthermia (SIH) paradigm, a model that studies the activation of the autonomic nervous system in response to stress by measuring body temperature. The reproducible and robust SIH response, combined with ease of testing, make the SIH paradigm very suitable for drug screening. We will review the current knowledge on the neurobiology of the SIH response, discuss the role of GABA_A and serotonin (5-HT) pharmacology, as well as how the SIH response relates to infectious fever. Furthermore, we will present novel data on the SIH response variance across different mice and their sensitivity to anxiolytic drugs. The SIH response is an autonomic stress response that can be successfully studied at the level of its physiology, pharmacology, neurobiology and genetics and possesses excellent animal-to-human translational properties.     

Repeat exposure to ciguatoxin leads to enhanced and sustained thermoregulatory, pain threshold and motor activity responses in mice: relationship to blood ciguatoxin concentrations

Ciguatera is a common illness in tropical and subtropical regions that manifests in complex and long-lived symptoms which are more severe in subsequent exposures. This study measures central and peripheral neurologic signs, in parallel with blood toxin levels, in mice exposed once or twice (at 3 days interval) to a sublethal dose of ciguatoxin P-CTX-1 (0.26ng/g via i.p.). Mice were implanted with radiotransmitters to monitor motor activity and core temperature. A single exposure to ciguatoxin elicited an immediate and transient decrease in motor activity and temperature, and subsequent long-lasting thermoregulatory dysfunction resulting in stabilized body temperature around 36.0 degrees C with no observable circadian rhythm. The hypothermic response and the reduced activity were enhanced with a second exposure with 30% of the mice dying within 7h. Measurement of the peripheral nervous system by the tail flick assay revealed increased latency with a single ciguatoxin exposure, and a greater effect following the second exposure. Toxin was measurable in blood up to 3 days following the first exposure; at the 1h time point the concentrations were significantly elevated after a second exposure. These findings indicate an early response to ciguatoxin manifest in a central response to lower body temperature and reduce motor activity and a more persistent effect on the peripheral system leading to spinal heat antinociception and delayed fever-like response. The greater neurological response to a second ciguatoxin exposure was associated with elevated concentrations of ciguatoxin in the blood solely over the first hour of exposure. In conclusion, a single exposure to toxin exerts a significant neurological response which may be enhanced with subsequent exposure.     

Comparison of different wheelchair seating on thermoregulation and perceptual responses in thermoneutral and hot conditions in children

We examined the effects of 4 different wheelchair seatings on physiological and perceptual measures in 21 healthy, pre-pubertal children (9 ± 2 years). Participants were able-bodied and did not regularly use a wheelchair. Participants sat for 2 h in Neutral (∼22.5 °C, ∼40%RH) and Hot (∼35 °C, ∼37%RH) conditions. Four seating technologies were: standard incontinent cover and cushion (SEAT1); standard incontinent cover with new cushion (SEAT2) were tested in Neutral and Hot; new non-incontinent cover with new cushion (SEAT3); new incontinent cover and new cushion (SEAT4) were tested in Neutral only. Measurements included skin blood flow (SkBF), sweating rate (SR) and leg skin temperature (T_legB) on the bottom of the leg (i.e. skin-seat interface), heart rate (HR), mean skin temperature, tympanic temperature, thermal comfort, and thermal sensation. During Neutral, SkBF and T_legB were lower (∼50% and ∼1 °C, respectively) and SR higher (∼0.5 mg cm⁻²·min⁻¹) (p < 0.05) with SEAT3 compared to all other seats. SkBF was ∼30% lower (p < 0.05) for SEAT2 and SEAT4 compared to SEAT1. No other differences were observed between SEATs (all p > 0.05). During Hot, HR and temperatures were higher than in Neutral but there were no differences (p > 0.05) between SEATs. New cover and cushion improved thermoregulatory responses during Neutral but not Hot. An impermeable incontinent cover negated improvements from cushion design. Seat cover appears more important than seat cushion during typical room conditions.     

Altered ventilatory and thermoregulatory control in male and female adult Pet-1 null mice

The integrity of the serotonin (5-HT) system is essential to normal respiratory and thermoregulatory control. Male and female transgenic mice lacking central 5-HT neurons (Lmx1b(f/f/p) mice) show a 50% reduction in the hypercapnic ventilatory response and insufficient heat generation when cooled (Hodges and Richerson, 2008a; Hodges et al., 2008b). Lmx1b(f/f/p) mice also show reduced body temperatures (T(body)) and O(2) consumption [Formula: see text] , and breathe less at rest and during hypoxia and hypercapnia when measured below thermoneutrality (24 °C), suggesting a role for 5-HT neurons in integrating ventilatory, thermal and metabolic control. Here, the hypothesis that Pet-1 null mice, which retain 30% of central 5-HT neurons, will demonstrate similar deficits in temperature and ventilatory control was tested. Pet-1 null mice had fewer medullary tryptophan hydroxylase-immunoreactive (TPH(+)) neurons compared to wild type (WT) mice, particularly in the midline raphé. Female (but not male) Pet-1 null mice had lower baseline ventilation (V(E)), breathing frequency (f), [Formula: see text] and T(body) relative to female WT mice (P < 0.05). In addition, V(E) and [Formula: see text] were decreased in male and female Pet-1 null mice during hypoxia and hypercapnia (P < 0.05), but only male Pet-1 null mice showed a significant deficit in the hypercapnic ventilatory response when expressed as % of control (P < 0.05). Finally, male and female Pet-1 null mice showed significant decreases in T(body) when externally cooled to 4 °C. These data demonstrate that a moderate loss of 5-HT neurons leads to a modest attenuation of mechanisms defending body temperature, and that there are gender differences in the contributions of 5-HT neurons to ventilatory and thermoregulatory control.     

Why do we yawn? Primitive versus derived features

Guggisberg et al. (2010) reviewed the evidence for the origin and function of yawning, and conclude that theories describing a physiological role lack support. Instead, they argue research supports the notion that yawning has a communicative function. Contrary to the authors’ claim that the social/communication hypothesis has the “best experimental evidence”, there is in fact no definitive experimental support for the predictions of this model. Furthermore, the authors claim to take an evolutionary perspective, but sufficient examples across the comparative (non-primate) literature are missing, and they fail to acknowledge phylogenic history. Due to the ubiquity of this behavior across vertebrates, and the regularity of its occurrence in a number of different physiological states and social contexts, it is likely that instead of serving one purpose, yawning is multifunctional across a number of species. The most parsimonious explanation for the origin of yawning suggests that any social value is a derived feature, while the primitive feature or function is physiological. The current paper addresses these concerns, and identifies a number of other weaknesses in the social/communication hypothesis as a global explanation for the origin and function of yawning.     

Serotonin release in the preoptic area and anterior hypothalamus is not involved in thermoregulation during low-intensity exercise in a warm environment

The aim of the present study was to assess the response of serotonin (5-hydroxytryptamine; 5-HT) in the preoptic area and anterior hypothalamus (PO/AH) to thermoregulation during exercise in a warm environment. In addition, it was investigated whether a rapid increase in extracellular 5-HT levels in the PO/AH modifies the thermoregulatory response under the same exercise conditions. Rats were made to run for 120 min at 10 m min⁻¹ on a treadmill at the ambient temperature of 30 °C. Body core temperature (T_core) was monitored using a biotelemetry system, and tail skin temperature (T_tail) was simultaneously measured as an index of heat loss response. Microdialysis in combination with HPLC was used to measure concentrations of monoamines in the PO/AH. Both T_core and T_tail increased during the first 20 min of exercise and remained stable until the end of the exercise period. Low-intensity exercise did not induce any changes in 5-HT release in the PO/AH, although the levels of norepinephrine and dopamine were increased. Moreover, increased extracellular 5-HT by local perfusion of 1 μM citalopram (selective 5-HT reuptake inhibitor; SSRI) in the PO/AH had no effect on the thermoregulatory response during acute low-intensity exercise in a warm environment. These results suggest that enhanced release of only 5-HT in the PO/AH may not intervene thermoregulation during exercise in a warm environment.     

Rostral ventromedial periaqueductal gray: a source of inhibition of the sympathetic outflow to brown adipose tissue

Central inhibitory pathways play a significant role in determining the level of sympathetic outflow to the cold defense efferents in mammals. We tested the hypothesis that neurons in the rostral ventromedial periaqueductal gray (rvmPAG) are a source of inhibitory regulation of the sympathetic nerve activity (SNA) to brown adipose tissue (BAT). In urethane/chloralose-anesthetized, paralyzed, artificially ventilated rats, microinjection of PGE2 (200 pmol in 70 nl) into the medial preoptic area (POA) or microinjection of the GABAA antagonists, bicuculline or SR95531 (60 pmol in 60 nl), into the dorsomedial hypothalamic area (DMH) increased BAT SNA by +853 +/- 176 and +898 +/- 249% of control, respectively. These evoked increases in BAT SNA were reversed by microinjection of bicuculline (60 pmol in 60 nl) into the rvmPAG at the level of the posterior commissure. Microinjection of muscimol (160 pmol in 80 nl) into the rvmPAG increased BAT SNA by an amount (+191 +/- 92% of control) that was significantly (P < 0.05) smaller than the peak increase observed after bicuculline microinjection into the rostral raphe pallidus (+1340 +/- 547% of control), but not different from that observed after transaction of the midbrain posterior to the rvmPAG (+423 +/- 123% of control). We conclude that the rvmPAG contains neurons that exert an inhibitory influence on the sympathetic outflow to BAT. These BAT sympathoinhibitory neurons are, themselves, under a tonic GABAergic inhibition. Blockade of this tonic inhibition reveals an inhibitory influence of rvmPAG neurons that is capable of reversing BAT SNA activations from POA or from DMH. Augmenting the tonic inhibition of rvmPAG neurons elicits a modest increase in BAT SNA. Neurons in rvmPAG provide some, but not all, of the tonic inhibition regulating the discharge of BAT sympathetic premotor neurons in RPa and ultimately the level of thermogenesis in BAT.