Matteo Cerri

The Inhibition of Neurons in the Central Nervous Pathways for Thermoregulatory Cold Defense Induces a Suspended Animation State in the Rat

The possibility of inducing a suspended animation state similar to natural torpor would be greatly beneficial in medical science, since it would avoid the adverse consequence of the powerful autonomic activation evoked by external cooling. Previous attempts to systemically inhibit metabolism were successful in mice, but practically ineffective in nonhibernators. Here we show that the selective pharmacological inhibition of key neurons in the central pathways for thermoregulatory cold defense is sufficient to induce a suspended animation state, resembling natural torpor, in a nonhibernator. In rats kept at an ambient temperature of 15°C and under continuous darkness, the prolonged inhibition (6 h) of the rostral ventromedial medulla, a key area of the central nervous pathways for thermoregulatory cold defense, by means of repeated microinjections (100 nl) of the GABAA agonist muscimol (1 mm), induced the following: (1) a massive cutaneous vasodilation; (2) drastic drops in deep brain temperature (reaching a nadir of 22.44 ± 0.74°C), heart rate (from 440 ± 13 to 207 ± 12 bpm), and electroencephalography (EEG) power; (3) a modest decrease in mean arterial pressure; and (4) a progressive shift of the EEG power spectrum toward slow frequencies. After the hypothermic bout, all animals showed a massive increase in NREM sleep Delta power, similarly to that occurring in natural torpor. No behavioral abnormalities were observed in the days following the treatment. Our results strengthen the potential role of the CNS in the induction of hibernation/torpor, since CNS-driven changes in organ physiology have been shown to be sufficient to induce and maintain a suspended animation state.

Physical exercise for late-life major depression.

BACKGROUNDnInterventions including physical exercise may help improve the outcomes of late-life major depression, but few studies are available.nnnAIMSnTo investigate whether augmenting sertraline therapy with physical exercise leads to better outcomes of late-life major depression.nnnMETHODnPrimary care patients (465 years) with major depression were randomised to 24 weeks of higher-intensity, progressive aerobic exercise plus sertraline (S+PAE), lower-intensity, non-progressive exercise plus sertraline (S+NPE) and sertraline alone. The primary outcome was remission (a score of ≤10 on the Hamilton Rating Scale for Depression).nnnRESULTSnA total of 121 patients were included. At study end, 45% of participants in the sertraline group, 73% of those in the S+NPE group and 81% of those in the S+PAE group achieved remission (P = 0.001). A shorter time to remission was observed in the S+PAE group than in the sertraline-only group.nnnCONCLUSIONSnPhysical exercise may be a safe and effective augmentation to antidepressant therapy in late-life major depression.

Provocative motion causes fall in brain temperature and affects sleep in rats.

AbstractnNeural substrate of nausea is poorly understood, contrasting the wealth of knowledge about the emetic reflex. One of the reasons for this knowledge deficit is limited number and face validity of animal models of nausea. Our aim was to search for new physiological correlates of nausea in rats. Specifically, we addressed the question whether provocative motion (40-min rotation at 0.5xa0Hz) affects sleep architecture, brain temperature, heart rate (HR) and arterial pressure. Six adult male Sprague–Dawley rats were instrumented for recordings of EEG, nuchal electromyographic, hypothalamic temperature and arterial pressure. Provocative motion had the following effects: (1) total abolition of REM sleep during rotation and its substantial reduction during the first hour post-rotation (from 20xa0±xa03 to 5xa0±xa01.5xa0%); (2) reduction in NREM sleep, both during rotation (from 57xa0±xa06 to 19xa0±xa05xa0%) and during the first hour post-rotation (from 56xa0±xa03 to 41xa0±xa09xa0%); (3) fall in the brain temperature (from 37.1xa0±xa00.1 to 36.0xa0±xa00.1xa0°C); and (4) reduction in HR (from 375xa0±xa06 to 327xa0±xa07xa0bpm); arterial pressure was not affected. Ondansetron, a 5-HT3 antagonist, had no major effect on all observed parameters during both baseline and provocative motion. We conclude that in rats, provocative motion causes prolonged arousing effects, however without evidence of sympathetic activation that usually accompanies heightened arousal. Motion-induced fall in the brain temperature complements and extends our previous observations in rats and suggests that similar to humans, provocative motion triggers coordinated thermoregulatory response, leading to hypothermia in this species.

The direct cooling of the preoptic-hypothalamic area elicits the release of thyroid stimulating hormone during wakefulness but not during REM sleep.

Thermoregulatory responses to temperature changes are not operant during REM sleep (REMS), but fully operant in non-REM sleep and wakefulness. The specificity of the relationship between REMS and the impairment of thermoregulation was tested by eliciting the reflex release of Thyrotropin Releasing Hormone (TRH), which is integrated at hypothalamic level. By inducing the sequential secretion of Thyroid Stimulating Hormone (TSH) and Thyroid Hormone, TRH intervenes in the regulation of obligatory and non-shivering thermogenesis. Experiments were performed on male albino rats implanted with epidural electrodes for EEG recording and 2 silver-copper wire thermodes, bilaterally placed in the preoptic-hypothalamic area (POA) and connected to small thermoelectric heat pumps driven by a low-voltage high current DC power supply. In preliminary experiments, a thermistor was added in order to measure hypothalamic temperature. The activation of TRH hypophysiotropic neurons by the thermode cooling of POA was indirectly assessed, in conditions in which thermoregulation was either fully operant (wakefulness) or not operant (REMS), by a radioimmunoassay determination of plasmatic levels of TSH. Different POA cooling were performed for 120 s or 40 s at current intensities of 80 mA and 125 mA, respectively. At both current intensities, POA cooling elicited, with respect to control values (no cooling current), a significant increase in plasmatic TSH levels in wakefulness, but not during REMS. These results confirm the inactivation of POA thermal sensitivity during REMS and show, for the first time, that this inactivation concerns also the fundamental endocrine control of non-shivering thermogenesis.

Enhanced slow-wave EEG activity and thermoregulatory impairment following the inhibition of the lateral hypothalamus in the rat.

Neurons within the lateral hypothalamus (LH) are thought to be able to evoke behavioural responses that are coordinated with an adequate level of autonomic activity. Recently, the acute pharmacological inhibition of LH has been shown to depress wakefulness and promote NREM sleep, while suppressing REM sleep. These effects have been suggested to be the consequence of the inhibition of specific neuronal populations within the LH, i.e. the orexin and the MCH neurons, respectively. However, the interpretation of these results is limited by the lack of quantitative analysis of the electroencephalographic (EEG) activity that is critical for the assessment of NREM sleep quality and the presence of aborted NREM-to-REM sleep transitions. Furthermore, the lack of evaluation of the autonomic and thermoregulatory effects of the treatment does not exclude the possibility that the wake-sleep changes are merely the consequence of the autonomic, in particular thermoregulatory, changes that may follow the inhibition of LH neurons. In the present study, the EEG and autonomic/thermoregulatory effects of a prolonged LH inhibition provoked by the repeated local delivery of the GABAA agonist muscimol were studied in rats kept at thermoneutral (24°C) and at a low (10°C) ambient temperature (Ta), a condition which is known to depress sleep occurrence. Here we show that: 1) at both Tas, LH inhibition promoted a peculiar and sustained bout of NREM sleep characterized by an enhancement of slow-wave activity with no NREM-to-REM sleep transitions; 2) LH inhibition caused a marked transitory decrease in brain temperature at Ta 10°C, but not at Ta 24°C, suggesting that sleep changes induced by LH inhibition at thermoneutrality are not caused by a thermoregulatory impairment. These changes are far different from those observed after the short-term selective inhibition of either orexin or MCH neurons, suggesting that other LH neurons are involved in sleep-wake modulation.

Waking and sleeping in the rat made obese through a high-fat hypercaloric diet

Sleep restriction leads to metabolism dysregulation and to weight gain, which is apparently the consequence of an excessive caloric intake. On the other hand, obesity is associated with excessive daytime sleepiness in humans and promotes sleep in different rodent models of obesity. Since no consistent data on the wake-sleep (WS) pattern in diet-induced obesity rats are available, in the present study the effects on the WS cycle of the prolonged delivery of a high-fat hypercaloric (HC) diet leading to obesity were studied in Sprague-Dawley rats. The main findings are that animals kept under a HC diet for either four or eight weeks showed an overall decrease of time spent in wakefulness (Wake) and a clear Wake fragmentation when compared to animals kept under a normocaloric diet. The development of obesity was also accompanied with the occurrence of a larger daily amount of REM sleep (REMS). However, the capacity of HC animals to respond to a Continuous darkness exposure condition (obtained by extending the Dark period of the Light-Dark cycle to the following Light period) with an increase of Sequential REMS was dampened. The results of the present study indicate that if, on one hand, sleep curtailment promotes an excess of energy accumulation; on the other hand an over-exceeding energy accumulation depresses Wake. Thus, processes underlying energy homeostasis possibly interact with those underlying WS behavior, in order to optimize energy storage.

Effects of chronic exposure to radiofrequency electromagnetic fields on energy balance in developing rats

The effects of radiofrequency electromagnetic fields (RF-EMF) on the control of body energy balance in developing organisms have not been studied, despite the involvement of energy status in vital physiological functions. We examined the effects of chronic RF-EMF exposure (900xa0MHz, 1xa0Vu2009m−1) on the main functions involved in body energy homeostasis (feeding behaviour, sleep and thermoregulatory processes). Thirteen juvenile male Wistar rats were exposed to continuous RF-EMF for 5xa0weeks at 24xa0°C of air temperature (Ta) and compared with 11 non-exposed animals. Hence, at the beginning of the 6th week of exposure, the functions were recorded at Ta of 24xa0°C and then at 31xa0°C. We showed that the frequency of rapid eye movement sleep episodes was greater in the RF-EMF-exposed group, independently of Ta (+42.1xa0% at 24xa0°C and +31.6xa0% at 31xa0°C). The other effects of RF-EMF exposure on several sleep parameters were dependent on Ta. At 31xa0°C, RF-EMF-exposed animals had a significantly lower subcutaneous tail temperature (−1.21xa0°C) than controls at all sleep stages; this suggested peripheral vasoconstriction, which was confirmed in an experiment with the vasodilatator prazosin. Exposure to RF-EMF also increased daytime food intake (+0.22xa0gu2009h−1). Most of the observed effects of RF-EMF exposure were dependent on Ta. Exposure to RF-EMF appears to modify the functioning of vasomotor tone by acting peripherally through α-adrenoceptors. The elicited vasoconstriction may restrict body cooling, whereas energy intake increases. Our results show that RF-EMF exposure can induce energy-saving processes without strongly disturbing the overall sleep pattern.

Waking and Sleeping following Water Deprivation in the Rat

Wake-sleep (W-S) states are affected by thermoregulation. In particular, REM sleep (REMS) is reduced in homeotherms under a thermal load, due to an impairment of hypothalamic regulation of body temperature. The aim of this work was to assess whether osmoregulation, which is regulated at a hypothalamic level, but, unlike thermoregulation, is maintained across the different W-S states, could influence W-S occurrence. Sprague-Dawley rats, kept at an ambient temperature of 24°C and under a 12 h∶12 h light-dark cycle, were exposed to a prolonged osmotic challenge of three days of water deprivation (WD) and two days of recovery in which free access to water was restored. Two sets of parameters were determined in order to assess: i) the maintenance of osmotic homeostasis (water and food consumption; changes in body weight and fluid composition); ii) the effects of the osmotic challenge on behavioral states (hypothalamic temperature (Thy), motor activity, and W-S states). The first set of parameters changed in WD as expected and control levels were restored on the second day of recovery, with the exception of urinary Ca++ that almost disappeared in WD, and increased to a high level in recovery. As far as the second set is concerned, WD was characterized by the maintenance of the daily oscillation of Thy and by a decrease in activity during the dark periods. Changes in W-S states were small and mainly confined to the dark period: i) REMS slightly decreased at the end of WD and increased in recovery; ii) non-REM sleep (NREMS) increased in both WD and recovery, but EEG delta power, a sign of NREMS intensity, decreased in WD and increased in recovery. Our data suggest that osmoregulation interferes with the regulation of W-S states to a much lesser extent than thermoregulation.

Overview of Physiological Processes During Sleep

Somatic and autonomic physiological regulation varies during the ultradian sleep cycle in mammals. The basic somatic features of nonrapid eye movement (NREM) sleep are thermoregulatory posture, a decrease in antigravity muscle activity, and slow eye movements. The basic somatic features of rapid eye movement (REM) sleep are skeletal muscle atonia, myoclonic twitches, and rapid eye movements. The autonomic phenomena of NREM sleep are indicative of an integrative neural regulation of the systemic physiological functions of respiration, circulation, and thermoregulation, maintaining the homeostasis of the organism at a lower level of energy expenditure compared with wakefulness. In contrast, the autonomic phenomena of REM sleep are indicative of a suspension of the integrative neural regulation (poikilostasis) of such physiological functions.

Provocative motion elicits hypothermia and tail vasodilation in rats and shrews: A new index of motion sickness in pre-clinical studies?

14.5 Provocative motion elicits hypothermia and tail vasodilation in rats and shrews: A new index of motion sickness in pre-clinical studies? Sukonthar Ngampramuan (Research Center for Neuroscience and Institute of Molecular Bioscience, Mahidol University, Bangkok, Thailand), Matteo Cerri, Flavia Del Vecchio (Department of Biomedical and Motor Sciences, University of Bologna, Bologna, Italy), Amornrat Kamphee (Research Center for Neuroscience and Institute of Molecular Bioscience, Mahidol University, Bangkok, Thailand), John Rudd (School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China), Eugene Nalivaiko (School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, Australia) Cardinal symptoms of motion sickness in humans include cold sweating, nausea and vomiting, and facial pallor; these indices cannot be employed in most laboratory animals. Few human studies also reported motion sickness-related hypothermia due to cutaneous vasodilation in the limbs. The aim of the present study was to investigate whether similar motion-induced hypothermic responses are present in rats and in musk shrews (an insectivore possessing vomiting reflex). Adult male Wistar rats were administered either antiemetic ondansetron (0.5 mg/kg s.c.) or vehicle, and 30 min later were subjected to provocative motion (rotation 0.5 Hz, 40 min) in their home cages; the experiment was repeated one week later using a crossover design (n= 7). Rotation provoked mild hypothermia (from 37.4 ± 0.1 to 35.6 ± 0.2 °C, p b 0.001) that was attenuated by ondansetron by 28% (p b 0.05). In another group of un-instrumented rats, we used infrared thermography and found that rotation induced a transient increase of tail temperature (from 22.9 ± 0.6 to 25.1 ±0.6 °C, p b 0.05) indicative of vasodilation; this rise preceded the fall in the core body temperature seen in the telemetered studies. Infrared thermography was also used to investigate skin temperature changes induced by motion (linear shaker, 1 Hz, 15 min) in shrews (n= 6). All animals exhibited episodes of retching and/or vomiting (latency 205 ± 38 s) that was preceded by a transient increase in tail temperature (from 24.0 ± 1.5 to 27.0 ± 2.2 °C, p b 0.05). A fall of interscapular temperature (from 38.4 ± 0.5 to 36.6 ± 0.4 °C, p b 0.001) was also seen during motion testing. Provocative motion induces hypothermia via mechanism involving dilatation of the vascular bed of the tail. The tail vasodilation that precedes retching/vomiting in Suncus murinus, and the tail vasodilation in rats could form the basis of a potential index of nausea in experimental animals. doi:10.1016/j.autneu.2013.08.024