1,720,984 research outputs found
Turn it off and on again:Characteristics and control of torpor
Full text linkTorpor is a hypothermic, hypoactive, hypometabolic state entered into by a wide range of animals in response to environmental challenge. This review summarises the current understanding of torpor. We start by describing the characteristics of the wide-ranging physiological adaptations associated with torpor. Next follows a discussion of thermoregulation, control of food intake and energy expenditure, and the interactions of sleep and thermoregulation, with particular emphasis on how those processes pertain to torpor. We move on to take a critical view of the evidence for the systems that control torpor entry, including both the efferent circulating factors that signal the need for torpor, and the central processes that orchestrate it. Finally, we consider how the putative circuits responsible for torpor induction integrate with the established understanding of thermoregulation under non-torpid conditions and highlight important areas of uncertainty for future studies.</p
Wake-sleep, thermoregulatory, and autonomic effects of cholinergic activation of the lateral hypothalamus in the rat: a pilot study
No full textA major role in the wake-promoting effects of the activation of the lateral hypothalamus (LH) has been ascribed to a population of orexin (ORX)-containing neurons that send projections to central areas which regulate Wake-Sleep and autonomic function. Since, in the rat, a substantial amount of ORX neurons receive cholinergic projections from cells involved in Wake-Sleep regulation, the aim of this study was to assess the role played by LH cholinoceptive cells in Wake-Sleep and autonomic regulations. To this end, the effects of a microinjection of the cholinergic agonist Carbachol (CBL) into the LH were compared to those obtained through the activation of a wider cell population by the microinjection of the GABAA antagonist GABAzine (GBZ). The results of this pilot study showed that both drugs elicited the same behavioral and autonomic effects, those caused by GBZ being larger and longer-lasting than those following administration of CBL. Briefly, wakefulness was enhanced and sleep was depressed, and brain temperature and heart rate consistently increased, while mean arterial pressure showed only a mild increment. Surprisingly, the administration of the drug vehicle (SAL) elicited a similar pattern of Wake-Sleep effects which, although much smaller, were sufficient to mask any statistical significance between treatment and control data. In conclusion, the results of this work show that the arousal elicited by LH disinhibition by GABAzine is concomitant with autonomic responses set by the intervention of cold-defense mechanisms. Since the same response is elicited at a lower level by CBL administration, the hypothesis of an involvement of cholinoceptive ORX neurons in its generation is discussed
Reversible Tau Phosphorylation Induced by Synthetic Torpor in the Spinal Cord of the Rat
No full textTau is a key protein in neurons, where it affects the dynamicsof the microtubulesystem. The hyperphosphorylation of Tau (PP-Tau) commonlyleads to the formationof neurofibrillary tangles, as it occurs in tauopathies, a group of neurodegenerativediseases, including Alzheimer’s. Hypothermia-related accumulation of PP-Tau has beendescribed in hibernators and during synthetic torpor (ST),a torpor-like condition that hasbeen induced in rats, a non-hibernating species. Remarkably, in ST PP-Tau is reversibleand Tau de-phosphorylates within a few hours following the torpor bout, apparentlynot evolving into pathology. These observations have been limited to the brain, but inanimal models of tauopathies, PP-Tau accumulation also appears to occur in the spinalcord (SpCo). The aim of the present work was to assess whetherST leads to PP-Tauaccumulation in the SpCo and whether this process is reversible. Immunofluorescence(IF) for AT8 (to assess PP-Tau) and Tau-1 (non-phosphorylated Tau) was carried out onSpCo coronal sections. AT8-IF was clearly expressed in the dorsal horns (DH) duringST, while in the ventral horns (VH) no staining was observed.The AT8-IF completelydisappeared after 6h from the return to euthermia. Tau-1-IFdisappeared in both DH andVH during ST, returning to normal levels during recovery. Toshed light on the cellularprocess underlying the PP-Tau pattern observed, the inhibited form of the glycogen-synthase kinase 3β(the main kinase acting on Tau) was assessed using IF: VH (i.e., inmotor neurons) were highly stained mainly during ST, while in DH there was no staining.Since tauopathies are also related to neuroinflammation, microglia activation was alsoassessed through morphometric analyses, but no ST-inducedmicroglia activation wasfound in the SpCo. Taken together, the present results show that, in the DH of SpCo, STinduces a reversible accumulation of PP-Tau. Since during ST there is no motor activity,the lack of AT8-IF in VH may result from an activity-related process at a cellular level. Thus,ST demonstrates a newly-described physiological mechanism that is able to resolve theaccumulation of PP-Tau and apparently avoid the neurodegenerative outcome.Keywords: hypothermia, hibernation, microglia, tauopathies, GSK3β, motor neurons, adaptive respons
Activation of orexin-A (hypocretin-1) receptors in the Raphe Pallidus at different ambient temperatures in the rat: effects on thermoregulation, cardiovascular control, sleep, and feeding behavior
Full text linkThe Raphe Pallidus (RPa) is a brainstem nucleus containing sympathetic premotor neurons that control thermogenesis and modulate cardiovascular function. It receives inputs from various hypothalamic areas, including the Lateral Hypothalamus (LH), a heterogeneous region intricately involved in several autonomic and behavioral functions. A key subpopulation of neurons in the LH expresses orexin/hypocretin, a neuropeptide which is crucially involved in the regulation of the wake-sleep states and feeding behavior. The RPa receives orexinergic projections from the LH and orexinergic signalling in the RPa has been shown to enhance thermogenesis in the anaesthetized rat, but only in the presence of an already existing thermogenic drive, without significantly affecting cardiovascular function. The present work was aimed at exploring the effects on thermoregulation and autonomic function and the possible role in the modulation of the wake-sleep states and feeding behavior of orexin injection in the RPa in the free-behaving rat. In order to assess the influence of an already present thermogenic drive on orexinergic signalling in the RPa, animals were studied at three different ambient temperatures (Ta, 10 degrees C, 24 degrees C, and 32 degrees C). We found that orexin injection into the RPa variably affected the wake-sleep states, autonomic functions, motor activity, and feeding behavior, at the different Tas. In particular, in the first post-injection hour, we observed an increase in wakefulness, which was large at Ta 24 degrees C and Ta 10 degrees C and rather mild at Ta 32 degrees C. Deep brain temperature was increased by orexin injection at Ta 10 degrees C, but not at either Ta 24 degrees C or Ta 32 degrees C. Moreover, an increase in mean arterial blood pressure occurred at Ta 24 degrees C, which was probably masked by the high baseline levels at Ta 10 degrees C and was completely absent at Ta 32 degrees C. Finally, an enhancement in feeding behavior was observed at Ta 24 degrees C and 10 degrees C only. In accordance with what observed in anaesthetized rats, orexinergic signalling in the RPa seems to be ineffective in the absence of any thermogenic drive. Moreover, the effects observed on the wake-sleep states and feeding behavior introduce the RPa as a novel player in the central neural network promoting wakefulness and feeding
Ultrasonic vocalisations during rapid eye movement sleep in the rat
Full text linkRats are known to use a 22-kHz ultrasonic vocalisation as a distress call to warn of danger to other members of their group. We monitored 22-kHz ultrasonic vocalisation emissions in rats (lean and obese) as part of a sleep deprivation study to detect the eventual presence of stress during the procedure. Unexpectedly, we detected ultrasonic vocalisation emission during rapid eye movement (REM) sleep, but not during non-REM (NREM) sleep, in all the rats. The event occurs during the expiratory phase and can take place singularly or as a train. No difference was detected in the number or duration of these events in lean versus obese rats, during the light versus the dark period, and after sleep deprivation. As far as we know, this is the first report showing that rats can vocalise during REM sleep
Wake-sleep and cardiovascular regulatory changes in rats made obese by a high-fat diet
No full textObesity is known to be associated with alterations in wake-sleep (WS) architecture and cardiovascular parameters. This study was aimed at assessing the possible influence of diet-induced obesity (DIO) on sleep homeostasis and on the WS state‐dependent levels of arterial pressure (AP) and heart rate in the rat. Two groups of age-matched Sprague-Dawley rats were fed either a high-fat hypercaloric diet, leading to DIO, or a normocaloric standard diet (lean controls) for 8 weeks. While under general anesthesia, animals were implanted with instrumentation for the recording of electroencephalogram, electromyogram, arterial pressure, and deep brain temperature. The experimental protocol consisted of 48 h of baseline, 12 h of gentle handling, enhancing wake and depressing sleep, and 36-h post-handling recovery. Compared to lean controls, DIO rats showed: i) the same amount of rapid-eye movement (REM) and non-REM (NREM) sleep in the rest period, although the latter was characterized by more fragmented episodes; ii) an increase in both REM sleep and NREM sleep in the activity period; iii) a comparable post-handling sleep homeostatic response, in terms of either the degree of Delta power increase during NREM sleep or the quantitative compensation of the REM sleep loss at the end of the 36-h recovery period; iv) significantly higher levels of AP, irrespectively of the different WS states and of the changes in their intensity throughout the experimental protocol. Overall, these changes may be the reflection of a modification in the activity of the hypothalamic areas where WS, autonomic, and metabolic regulations are known to interact
c-Fos expression in the limbic thalamus following thermoregulatory and wake-sleep changes in the rat
No full textA cellular degeneration of two thalamic nuclei belonging to the "limbic thalamus", i.e., the anteroventral (AV) and mediodorsal (MD) nuclei, has been shown in patients suffering from Fatal Familial Insomnia (FFI), a lethal prion disease characterized by autonomic activation and severe insomnia. To better assess the physiological role of these nuclei in autonomic and sleep regulation, c-Fos expression was measured in rats during a prolonged exposure to low ambient temperature (Ta, - 10 °C) and in the first hours of the subsequent recovery period at normal laboratory Ta (25 °C). Under this protocol, the thermoregulatory and autonomic activation led to a tonic increase in waking and to a reciprocal depression in sleep occurrence, which was more evident for REM sleep. These effects were followed by a clear REM sleep rebound and by a rebound of Delta power during non-REM sleep in the following recovery period. In the anterior thalamic nuclei, c-Fos expression was (1) larger during the activity rather than the rest period in the baseline; (2) clamped at a level in-between the normal daily variation during cold exposure; (3) not significantly affected during the recovery period in comparison to the time-matched baseline. No significant changes were observed in either the MD or the paraventricular thalamic nucleus, which is also part of the limbic thalamus. The observed changes in the activity of the anterior thalamic nuclei appear, therefore, to be more specifically related to behavioral activation than to autonomic or sleep regulation
Synthetic torpor protects rats from exposure to accelerated heavy ions
No full textHibernation or torpor is considered a possible tool to protect astronauts from the deleterious effects of space radiation that contains high-energy heavy ions. We induced synthetic torpor in rats by injecting adenosine 5′-monophosphate monohydrate (5′-AMP) i.p. and maintaining in low ambient temperature room (+ 16 °C) for 6 h immediately after total body irradiation (TBI) with accelerated carbon ions (C-ions). The 5′-AMP treatment in combination with low ambient temperature reduced skin temperature and increased survival following 8 Gy C-ion irradiation compared to saline-injected animals. Analysis of the histology of the brain, liver and lungs showed that 5′-AMP treatment following 2 Gy TBI reduced activated microglia, Iba1 positive cells in the brain, apoptotic cells in the liver, and damage to the lungs, suggesting that synthetic torpor spares tissues from energetic ion radiation. The application of 5′-AMP in combination with either hypoxia or low temperature environment for six hours following irradiation of rat retinal pigment epithelial cells delays DNA repair and suppresses the radiation-induced mitotic catastrophe compared to control cells. We conclude that synthetic torpor protects animals from cosmic ray-simulated radiation and the mechanism involves both hypothermia and hypoxia
Mitochondrial respiration in rats during hypothermia resulting from central drug administration
Full text link: The ability to induce a hypothermia resembling that of natural torpor would be greatly beneficial in medical and non-medical fields. At present, two procedures based on central nervous pharmacological manipulation have been shown to be effective in bringing core body temperature well below 30 °C in the rat, a non-hibernator: the first, based on the inhibition of a key relay in the central thermoregulatory pathway, the other, based on the activation of central adenosine A1 receptors. Although the role of mitochondria in the activation and maintenance of torpor has been extensively studied, no data are available for centrally induced hypothermia in non-hibernators. Thus, in the present work the respiration rate of mitochondria in the liver and in the kidney of rats following the aforementioned hypothermia-inducing treatments was studied. Moreover, to have an internal control, the same parameters were assessed in a well-consolidated model, i.e., mice during fasting-induced torpor. Our results show that state 3 respiration rate, which significantly decreased in the liver of mice, was unchanged in rats. An increase of state 4 respiration rate was observed in both species, although it was not statistically significant in rats under central adenosine stimulation. Also, a significant decrease of the respiratory control ratio was detected in both species. Finally, no effects were detected in kidney mitochondria in both species. Overall, in these hypothermic conditions liver mitochondria of rats remained active and apparently ready to be re-activated to produce energy and warm up the cells. These findings can be interpreted as encouraging in view of the finalization of a translational approach to humans
Neurophysiological and metabolic regulation of spontaneous and synthetic torpor: a translational perspective
Full text linkTorpor is an energy-saving physiological state characterized by a transient and reversible decrease in metabolic rate and core temperature, which occurs in different species in conditions of scarce food availability. At present, the mechanism underlying torpor occurrence is unknown. The attempt to imitate natural torpor is pursued in clinical practice, in order to overcome the severe side effects that follow the induction of therapeutic hypothermia. Several attempts to induce a torpor-like state (synthetic torpor) by manipulating central nervous activity have been made in rodents. Most promising are the activation of central adenosine type-1 receptors and the pharmacological inhibition of the Raphe Pallidus (RPa).
Aims of the present project were: i) to unravel the neural pathway of spontaneous torpor in mice, a species that enters daily torpor spontaneously; ii) to understand the possible mechanism of metabolic rate reduction in spontaneous and synthetic torpor, in mice and rats, respectively, by evaluating mitochondrial activity during deep hypothermia; iii) to explore the possibility to induce synthetic torpor in a large mammal, the swine, by the central manipulation of the RPa.
In summary, the results showed that: i) Paraventricular and Dorsomedial Hypothalamic nuclei showed a specific neural activation at the entrance in torpor; ii) liver mitochondria showed a reduction in maximum respiration rate in spontaneous, but not in synthetic torpor, while no major changes occurred in kidney and brain; iii) central manipulation of the RPa in swine induced physiological modifications similar to those observed in rats
- …
