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

Synthetic torpor protects rats from exposure to accelerated heavy ions

Hibernation 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

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

Fattori psicologici in pazienti affetti da epatite C in fase di pre-trattamento

Obiettivi: Nel presente studio controllato sono stati esplorati i costrutti psicologici di qualit\ue0 della vita (QoL), rabbia e sintomi depressivi in pazienti con epatite C (HCV) prima del trattamento antivirale confrontandoli con un campione della popolazione generale. Metodi: Lo studio comprende un campione sperimentale (56 pazienti HCV positivi) ed un campione di controllo (66 individui sani). Ad entrambi i gruppi sono stati somministrati i seguenti test psicometrici auto-valutativi: Beck Depression Inventory-II (BDI-II; Beck et al., 1996), State-trait Anger Expression Inventory-2 (STAXI-2; Spielberger, 1999), World Health Organization Quality of Life Instruments (WHOQOL-BREF; Whoqol Group, 1995). Risultati e Conclusioni: I pazienti HCV hanno mostrato punteggi significativamente inferiori nelle scale del WHOQOLBREF, superiori nella \u201crabbia di stato\u201d (S-Rab; STAXI-2) e nel BDI-II rispetto ai controlli. Nel gruppo sperimentale S-Rab e T-Rab (rabbia di tratto) correlano negativamente con le scale del WHOQOL-BREF e positivamente con il BDI-II. Inoltre le donne HVC mostravano qualit\ue0 di vita e umore peggiori rispetto ai pazienti maschi e maggiore rabbia di stato. Si pu\uf2 dunque concludere che i pazienti HCV presentano una minore soddisfazione nella propria vita, maggiore rabbia contingente e sintomi depressivi, rispetto agli individui sani

Residual eating disorder symptoms and clinical features in remitted and recovered eating disorder patients: A systematic review with meta-analysis

Objective: In psychiatry, the presence of residual symptoms after treatment is linked to the definitions of remission and recovery. To identify the presence of residual eating disorder (ED) symptoms and associated non-ED clinical features in remitted and recovered EDs, the current systematic review with meta-analysis was performed. Method: A systematic review was conducted on residual ED symptoms and non-ED clinical features including comorbid psychopathology, neurophysiological functioning, cognitive functioning, and quality of life in ED patients considered remitted or recovered. To examine residual ED symptoms, meta-analyses were performed while considering age, study quality, remission, and recovery criteria strictness as moderators. Sensitivity, publication bias, and heterogeneity analyses were also conducted. Results: The 64 studies selected for the systematic review underscored the presence of residual ED symptoms in anorexia nervosa (AN) and bulimia nervosa (BN), and impairments and deficits in the additional features examined. From the 64 studies, 31 were selected regarding residual ED symptoms in AN for meta-analysis. Large effect sizes indicated that remitted/recovered AN patients reported significantly lower body mass index (Hedges' g = 120.62[ 120.77, 120.46]) and significantly greater symptomatology in terms of ED examination-questionnaire (Hedges'g = 0.86 [0.48,1.23]) and ED inventory (Hedges' g = 0.94[0.64,1.24]) than healthy controls, independently of remission and recovery criteria strictness, age, and study quality. Discussion: The presence of residual ED symptoms in AN is quantitatively supported, whereas the presence of residual ED symptoms in BN should be further investigated. Data on binge-eating disorder are missing. Future research should use consistent, multicomponent, and standardized comparable indicators of recovery

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

EFFECTS OF SLEEP DEPRIVATION IN THE PROCESS OF TAU PROTEIN DEPHOSPHORYLATION FOLLOWING SYNTHETIC TORPOR IN THE RAT

Introduction:One of the main hallmarks of tauopathies is the hyperphosphorylation of neuronal Tau protein. Interestingly, the accumulation of hyperphosphorylated Tau (PPTau) also characterizes “synthetic torpor” (ST), a torpor-like condition that can be pharmacologically induced in rats (Cerri et al., 2013). However, after few hours of the recovery from ST, PPTau levels reverse to control (Luppi et al., 2019). Since during the first hours of the recovery from ST rats show a strong sleep-pressure, aim of the present study has been to investigate the role of sleep in the dephosphorylation of PPTau following ST. Materials and Methods:Twelve Sprague-Dawley male rats (250-350g), adapted to an ambient temperature (Ta) of 24±0.5 C and to a 12h:12h Light-Dark cycle, were implanted under general anesthesia with a microcannula in the Raphe Pallidus (RP). After one-week of recovery, ST was induced for 6 hours according to the protocol described by Cerri et al. (2013), by the repeated injection (one injection/h) in the RP of the GABA-A agonist muscimol (100 nL - 1 mM). Soon after their return to normothermia, animals were either sleep deprived by gentle handling for 3 (n1⁄43) or 6 (n1⁄43) hours (R3SD and R6SD, respectively) or allowed to sleep (normal sleep, NS) for 3 (n1⁄43) or 6 (n1⁄43) hours (R3NS and R6NS, respectively). Soon after animals’ euthanasia, fresh sample of parietal cortex (P-Cx) were collected in order to evaluate byWestern Blot the levels of the following proteins and enzymes: AT8 (p[Ser202/Thr205]-Tau, phosphorylated Tau form), Tau-1 (unphosphorylated Tau form), p[Thr205]-Tau (a neuroprotective form of phosphorylated Tau; Ittner et al., 2016); p[Ser9]-GSK3b (the inhibited form of the main kinase targeting Tau); PP2A (the main phosphatase targeting Tau) and p[Ser473]-Akt2 (active anti-apoptotic factor and GSK3b inhibitor). Moreover, the plasma levels of melatonin were determined by ELISA.Results:Overall, AT8 levels were reduced in the SD groups compared to the NS ones (p<0.05), while Tau-1 levels were not significantly affected. A clear trend towards higher p[Thr205]-Tau levels was also observed after SD. The decrease in PPTau induced by SDwas accompanied by an increase in both p [Ser9]-GSK3b and p[Ser473]-Akt2 levels, although statistical significance was reached only for the latter (p<0.05). Also, PP2A levels were lower in R3SD vs. R3NS (p< 0.05). Finally, melatonin levels were higher in R3SD vs. R3 (p <0.05). Conclusions:The present results indicate that SD soon after ST enhances PPTau dephosphorylation, coherently with the observed concomitant increase of p[Ser9]-GSK3b and p[Ser473]-Akt2. This molecular pattern is known as being neuroprotective, and may be mediated by melatonin that can activate Akt2 and, consequently, inhibit GSK3b by acting on the PI3K/ Akt2/mTOR antiapoptotic pathway (Risso et al., 2015). These findings open interestingly translational perspectives in the use of sleep deprivation in patients suffering from hypothermia-induced brain PPTau formation due to general anesthesia (Whittington et al., 2013). Acknowledgements: The authors wish to thank Fondazione Carisbo that supported this work

Hibernation and radioprotection: Gene expression in the liver and testicle of rats irradiated under synthetic torpor

Hibernation has been proposed as a tool for human space travel. In recent years, a procedure to induce a metabolic state known as “synthetic torpor” in non-hibernating mammals was successfully developed. Synthetic torpor may not only be an efficient method to spare resources and reduce psychological problems in long-term exploratory-class missions, but may also represent a countermeasure against cosmic rays. Here we show the preliminary results from an experiment in rats exposed to ionizing radiation in normothermic conditions or synthetic torpor. Animals were irradiated with 3 Gy X-rays and organs were collected 4 h after exposure. Histological analysis of liver and testicle showed a reduced toxicity in animals irradiated in torpor compared to controls irradiated at normal temperature and metabolic activity. The expression of ataxia telangiectasia mutated (ATM) in the liver was significantly downregulated in the group of animal in synthetic torpor. In the testicle, more genes involved in the DNA damage signaling were downregulated during synthetic torpor. These data show for the first time that synthetic torpor is a radioprotector in non-hibernators, similarly to natural torpor in hibernating animals. Synthetic torpor can be an effective strategy to protect humans during long term space exploration of the solar system