In a model of SAH-induced neurogenic fever, BAT thermogenesis is mediated by erythrocytes and blocked by agonism of adenosine A1 receptors

Neurogenic fever (NF) after subarachnoid hemorrhage (SAH) is a major cause of morbidity that is associated with poor outcomes and prolonged stay in the neurointensive care unit (NICU). Though SAH is a much more common cause of fever than sepsis in the NICU, it is often a diagnosis of exclusion, requiring significant effort to rule out an infectious source. NF does not respond to standard anti-pyretic medications such as COX inhibitors, and lack of good medical therapy has led to the introduction of external cooling systems that have their own associated problems. In a rodent model of SAH, we measured the effects of injecting whole blood, blood plasma, or erythrocytes on the sympathetic nerve activity to brown adipose tissue and on febrile thermogenesis. We demonstrate that following SAH the acute activation of brown adipose tissue leading to NF, is not dependent on PGE , that subarachnoid space injection of whole blood or erythrocytes, but not plasma alone, is sufficient to trigger brown adipose tissue thermogenesis, and that activation of adenosine A1 receptors in the CNS can block the brown adipose tissue thermogenic component contributing to NF after SAH. These findings point to a distinct thermogenic mechanism for generating NF, compared to those due to infectious causes, and will hopefully lead to new therapies

Thermoregulation in mice: The road to understanding torpor hypothermia and the shortcomings of a circuit for generating fever

N

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 \ub0C 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

Neural control of fasting-induced torpor in mice

Torpor is a peculiar mammalian behaviour, characterized by the active reduction of metabolic rate, followed by a drop in body temperature. To enter torpor, the activation of all thermogenic organs that could potentially defend body temperature must be prevented. Most of these organs, such as the brown adipose tissue, are controlled by the key thermoregulatory region of the Raphe Pallidus (RPa). Currently, it is not known which brain areas mediate the entrance into torpor. To identify these areas, the expression of the early gene c-Fos at torpor onset was assessed in different brain regions in mice injected with a retrograde tracer (Cholera Toxin subunit b, CTb) into the RPa region. The results show a network of hypothalamic neurons that are specifically activated at torpor onset and a direct torpor-specific projection from the Dorsomedial Hypothalamus to the RPa that could putatively mediate the suppression of thermogenesis during torpor

Phosphorylation and dephosphorylation of tau protein during synthetic torpor

Tau protein is of primary importance for many physiological processes in neurons, where it affects the dynamics of the microtubule system. When hyperphosphorylated (PP-Tau), Tau monomers detach from microtubules and tend to aggregate firstly in oligomers, and then in neurofibrillary tangles, as it occurs in a group of neurodegenerative disorders named thauopathies. A hypothermia-related accumulation of PP-Tau, which is quickly reversed after the return to normothermia, has been shown to occur in the brain of hibernators during torpor. Since, recently, in our lab, a hypothermic torpor-like condition (synthetic torpor, ST) was pharmacologically induced in the rat, a non-hibernator, the aim of the present work was to assess whether ST can lead to a reversible PP-Tau accumulation in the rat brain. PP-Tau was immunohistochemically assessed by staining for AT8 (phosphorylated Tau) and Tau-1 (non-phosphorylated Tau) in 19 brain structures, which were chosen mostly due to their involvement in the regulation of autonomic and cognitive functions in relation to behavioral states. During ST, AT8 staining was strongly expressed throughout the brain, while Tau-1 staining was reduced compared to control conditions. During the following recovery period, AT8 staining progressively reduced close to zero after 6 h from ST. However, Tau-1 staining remained low even after 38 h from ST. Thus, overall, these results show that ST induced an accumulation of PP-Tau that was, apparently, only partially reversed to normal during the recovery period. While the accumulation of PP-Tau may only depend on the physicochemical characteristics of the enzymes regulating Tau phosphorylation, the reverse process of dephosphorylation should be actively regulated, also in non-hibernators. In conclusion, in this work a reversible and widespread PP-Tau accumulation has been induced through a procedure that leads a non-hibernator to a degree of reversible hypothermia, which is comparable to that observed in hibernators. Therefore, the physiological mechanism involved in this process can sustain an adaptive neuronal response to extreme conditions, which may however lead to neurodegeneration when particular intensities and durations are exceeded

Central Control of Neurogenic Fever Following Subarachnoid Hemorrhage

Subarachnoid hemorrhage (SAH) is a devastating form of stroke that is associated with autonomic dysfunction including neurogenic fever (NF) that contributes to an increase in mortality and worse outcomes. Drugs that inhibit cyclooxygenase (COX) are generally ineffective in treating NF which suggesting a different central mediator for the generation of NF than prostaglandins. The aim of this work was to determine in a rat model of SAH if (1) the generation of NF requires the same central thermogenic control and (2) the same thermogenic organs, as that required for the generation of PGE2 mediated fever. In urethane chloralose-anesthetized Wistar rats direct injection of blood into the subarachnoid space evoked an increase of brown adipose tissue sympathetic nerve activity (BAT SNA) and thermogenesis leading to a rapid increase in core temperature. Inhibition of central regions important for cold-evoked and PGE2-mediated thermogenesis, such as the dorsal medial hypothalamus and medullary raphe pallidus, promptly blocked the NF response. However the use of a COX inhibitor to prevent the production of PGE2, failed to completely inhibit NF. We demonstrate for the first time that NF following SAH requires the same central neuronal thermoregulatory circuit and thermogenic organs involved in the generation of PGE2 mediated fever. A significant component of NF appears to be dependent on a different trigger than PGE2. Merit Award Department of Veterans Affair

Atropine Reduces Cardiac Arrhythmias That Occur During the Hypothermic State Induced by Central Activation of Adenosine A1 Receptors

The positive outcome that hypothermia contributes to neuroprotection following brain ischemia has stimulated recent clinical interest in the development of techniques to induce a hypothermic and hypometabolic state. As demonstrated in hibernating animals, we recently showed that hypothermia and a torpor-like state can be induced in rat by central activation of A1AR. Both the reduction in metabolism and the reduced cortical function (i.e., lower EEG amplitude) are of interest in the application of a pharmacological approach to induce hypothermia to ameliorate the outcomes of ischemic stroke. The central activation of A1AR in rat is, however, accompanied by cardiovascular events, such as skipped beats and transient deep bradycardia associated with strong neck muscle activation. Similar events have been reported during naturally occurring torpor. Here we tested the hypothesis that these events arise from vagal input to the heart, by determining the effect of the muscarinic antagonist, atropine. Wistar male rats were implanted with a telemetric probe for the recording of the arterial pressure, with a thermistor located in the mediastinic cavity for the recording of core temperature and electrodes for the recording of the EEG and nuchal EMG. Following a day of baseline recording, rats were placed in an ambient temperature of 15 °C and treated with N6-Cyclohexyladenosine (CHA, 1 mM, 10 μL, ICV) to induce hypothermia. One hour after the injection, animals were treated with intraperitoneal injection of atropine or saline. Our preliminary result showed that atropine prevented the occurrence of the transient bradycardic events and skipped beats, but not the muscular contraction. This result suggests a role of cardiac vagal transmission in driving these cardiovascular events. Our conclusion that treatment with a cholinergic blocker could eliminate this cardiovascular side effect during a deep hypothermic state will support the translational potential of this approach for induction of hypothermia for human use following ischemic stroke