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The 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°C, 24°C, and 32°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°C and Ta 10°C and rather mild at Ta 32°C. Deep brain temperature was increased by orexin injection at Ta 10°C, but not at either Ta 24°C or Ta 32°C. Moreover, an increase in mean arterial blood pressure occurred at Ta 24°C, which was probably masked by the high baseline levels at Ta 10°C and was completely absent at Ta 32°C. Finally, an enhancement in feeding behavior was observed at Ta 24°C and 10°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. [ABSTRACT FROM AUTHOR]

Summary: Rats 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. [ABSTRACT FROM AUTHOR]

Background: The hyperphosphorylation of tau protein (PPtau) in the brain is the main pathophysiological marker of tauopathies. Recently was found that when induced by a "synthetic torpor" (ST)1 condition (induced on rats), PPtau accumulations is reversible, as observed in hibernators2. Thus, ST uncover a latent physiological mechanism able to cope with PPtau and not specifically evolved with hibernation. Aim of the present work was to describe it. Methods: We induced ST as already reported2 on 12 Sprague‐Dawley rats. Hippocampal and plasma samples were collected at the following experimental conditions: nadir of hypothermia (N); early recovery (ER), as soon as animals reached normothermia following N; 6h following ER (R6). Control (C) animals were also included. Levels of AT8 (p[S020/T205]‐tau), p[S9]‐GSK3β (inhibited form of the main kinase targeting tau) and plasma melatonin were determined. To better understand in vivo experimental results, we performed in silico simulations of melatonin‐tubulin interactions3. Results: Figure 1 shows, at N, a huge amount of AT8 and high levels of p[S9]‐GSK3β and melatonin in respect to C. All factors returned to normal at R6. These paradoxical results (i.e. the coexistence of high levels of PPtau and p[S9]‐GSK3β) could be interpreted considering the destabilization of microtubules (MTs) induced by hypothermia as the main trigger of the whole process, then eliciting a neuroprotective physiological response mediated by melatonin, also interacting with MTs. To sustain this hypothesis, we also provide computational analysis of the microtubule stability as a function of temperature and other factors, such as melatonin binding. The molecular docking simulation shows that melatonin did not bind to 1sa0 structure, but it binds to one site of 1jff structure on the α‐tubulin monomer (Figure 2). This is further elucidated using a molecular fingerprint representation (Figure 3), showing the binding site of melatonin with respect to those well‐known binding locations. Conclusions: Our results could pave the way for an effective new strategy to contrast tauopathies, with next‐step studies aimed to pharmacologically interacting with this process at physiological temperature. References: (1) Luppi et al. Front Neuroanat 2019, 13:57; (2) Stieler et al. PLoS One 2011, 6: e14530. 3Craddock, et al. Sci Reports 2017, 7:1. [ABSTRACT FROM AUTHOR]

The Raphe Pallidus (RPa) is a region of the brainstem that was shown to modulate the sympathetic outflow to many tissues and organs involved in thermoregulation and energy expenditure. In rodents, the pharmacological activation of RPa neurons was shown to increase the activity of the brown adipose tissue, heart rate, and expired CO2, whereas their inhibition was shown to induce cutaneous vasodilation and a state of hypothermia that, when prolonged, leads to a state resembling torpor referred to as synthetic torpor. If translatable to humans, this synthetic torpor‐inducing procedure would be advantageous in many clinical settings. A first step to explore such translatability, has been to verify whether the neurons within the RPa play the same role described for rodents in a larger mammal such as the pig. In the present study, we show that the physiological responses inducible by the pharmacological stimulation of RPa neurons are very similar to those observed in rodents. Injection of the GABAA agonist GABAzine in the RPa induced an increase in heart rate (from 99 to 174 bpm), systolic (from 87 to 170 mm Hg) and diastolic (from 51 to 98 mm Hg) arterial pressure, and end‐tidal CO2 (from 49 to 62 mm Hg). All these changes were reversed by the injection in the same area of the GABAA agonist muscimol. These results support the possibility for RPa neurons to be a key target in the research for a safe and effective procedure for the induction of synthetic torpor in humans. [ABSTRACT FROM AUTHOR]

A 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.