Jean-Marie Petit

Sleep deprivation modulates brain mRNAs encoding genes of glycogen metabolism

Replenishment of brain glycogen stores depleted during waking has been suggested to constitute one of the functions of sleep [Benington, J. H. & Heller H. C. (1995) Prog. Neurobiol., 45, 347]. We have tested the hypothesis that the level of expression of enzymes involved in glycogen metabolism could undergo variations throughout the sleep‐waking or rest‐activity cycle, and after 6 h of ‘gentle’ total sleep deprivation in mice. Specifically, we determined the variations in mRNAs coding for protein targeting to glycogen (PTG), glycogen synthase and glycogen phosphorylase, all considered as key regulators of glycogen metabolism. Glycogen synthase and glycogen phosphorylase mRNAs exhibited significant variations throughout the light‐dark cycle with a maximum at the middle of the light period and a minimum at the middle of the dark period. Following sleep deprivation, a two‐fold increase in PTG mRNA and a decrease of mRNAs encoding glycogen synthase and glycogen phosphorylase were observed. These transcriptional events have functional consequences as the activity of glycogen synthase was increased 2.5‐fold indicating a stimulating effect of sleep deprivation on glycogen synthesis. These results indicate that (i) expression of genes related to brain glycogen metabolism exhibit variations throughout the sleep‐waking or rest‐activity cycle and (ii) given the almost selective localization of glycogen to astrocytes, these cells might participate in the regulation of sleep.

Sustained sleep fragmentation affects brain temperature, food intake and glucose tolerance in mice

Sleep fragmentation is present in numerous sleep pathologies and constitutes a major feature of patients with obstructive sleep apnea. A prevalence of metabolic syndrome, diabetes and obesity has been shown to be associated to obstructive sleep apnea. While sleep fragmentation has been shown to impact sleep homeostasis, its specific effects on metabolic variables are only beginning to emerge. In this context, it is important to develop realistic animal models that would account for chronic metabolic effects of sleep fragmentation. We developed a 14‐day model of instrumental sleep fragmentation in mice, and show an impact on both brain‐specific and general metabolism. We first report that sleep fragmentation increases food intake without affecting body weight. This imbalance was accompanied by the inability to adequately decrease brain temperature during fragmented sleep. In addition, we report that sleep‐fragmented mice develop glucose intolerance. We also observe that sleep fragmentation slightly increases the circadian peak level of glucocorticoids, a factor that may be involved in the observed metabolic effects. Our results confirm that poor‐quality sleep with sustained sleep fragmentation has similar effects on general metabolism as actual sleep loss. Altogether, these results strongly suggest that sleep fragmentation is an aggravating factor for the development of metabolic dysfunctions that may be relevant for sleep disorders such as obstructive sleep apnea.

Comparison of the effects of modafinil and sleep deprivation on sleep and cortical EEG spectra in mice.

Modafinil is a wakefulness-promoting substance whose profile differs from that of the classical psychostimulants. It is still unknown whether waking induced by modafinil and wakefulness induced by sleep deprivation differ in terms of their effect on subsequent sleep. To investigate this problem sleep was recorded in two groups of OF1 mice. One group received modafinil (200 mg/kg, i.p.) at light onset which induced a period of wakefulness of approx. 5 h, while animals of the subsequent control group were injected with vehicle and kept awake for an equivalent duration. The effect of the two treatments on sleep was similar. REM sleep was initially reduced and slow-wave activity (SWA; EEG power in the 0.75-4.0 Hz range) in nonREM sleep was enhanced for several hours. The SWA increase was more prominent over the frontal cortex than over the occipital cortex after both treatments. A minor difference was seen at the occipital site where the initial rise of power in the low-frequency range was larger after vehicle combined with enforced waking than after modafinil. The study shows that the homeostatic sleep response following the modafinil-induced wakefulness corresponds largely to the response following a non-pharmacologically induced extended waking episode.

Altered Glycogen Metabolism in Cultured Astrocytes from Mice with Chronic Glutathione Deficit; Relevance for Neuroenergetics in Schizophrenia

Neurodegenerative and psychiatric disorders including Alzheimers, Parkinsons or Huntingtons diseases and schizophrenia have been associated with a deficit in glutathione (GSH). In particular, a polymorphism in the gene of glutamate cysteine ligase modulatory subunit (GCLM) is associated with schizophrenia. GSH is the most important intracellular antioxidant and is necessary for the removal of reactive by-products generated by the utilization of glucose for energy supply. Furthermore, glucose metabolism through the pentose phosphate pathway is a major source of NADPH, the cofactor necessary for the regeneration of reduced glutathione. This study aims at investigating glucose metabolism in cultured astrocytes from GCLM knockout mice, which show decreased GSH levels. No difference in the basal metabolism of glucose was observed between wild-type and knockout cells. In contrast, glycogen levels were lower and its turnover was higher in knockout astrocytes. These changes were accompanied by a decrease in the expression of the genes involved in its synthesis and degradation, including the protein targeting to glycogen. During an oxidative challenge induced by tert-Butylhydroperoxide, wild-type cells increased their glycogen mobilization and glucose uptake. However, knockout astrocytes were unable to mobilize glycogen following the same stress and they could increase their glucose utilization only following a major oxidative insult. Altogether, these results show that glucose metabolism and glycogen utilization are dysregulated in astrocytes showing a chronic deficit in GSH, suggesting that alterations of a fundamental aspect of brain energy metabolism is caused by GSH deficit and may therefore be relevant to metabolic dysfunctions observed in schizophrenia.

Glycogen metabolism and the homeostatic regulation of sleep

In 1995 Benington and Heller formulated an energy hypothesis of sleep centered on a key role of glycogen. It was postulated that a major function of sleep is to replenish glycogen stores in the brain that have been depleted during wakefulness which is associated to an increased energy demand. Astrocytic glycogen depletion participates to an increase of extracellular adenosine release which influences sleep homeostasis. Here, we will review some evidence obtained by studies addressing the question of a key role played by glycogen metabolism in sleep regulation as proposed by this hypothesis or by an alternative hypothesis named “glycogenetic” hypothesis as well as the importance of the confounding effect of glucocorticoïds. Even though actual collected data argue in favor of a role of sleep in brain energy balance-homeostasis, they do not support a critical and direct involvement of glycogen metabolism on sleep regulation. For instance, glycogen levels during the sleep-wake cycle are driven by different physiological signals and therefore appear more as a marker-integrator of brain energy status than a direct regulator of sleep homeostasis. In support of this we provide evidence that blockade of glycogen mobilization does not induce more sleep episodes during the active period while locomotor activity is reduced. These observations do not invalidate the energy hypothesis of sleep but indicate that underlying cellular mechanisms are more complex than postulated by Benington and Heller.

Inadequate Brain Glycogen or Sleep Increases Spreading Depression Susceptibility

Glycogen in astrocyte processes contributes to maintenance of low extracellular glutamate and K+ concentrations around excitatory synapses. Sleep deprivation (SD), a common migraine trigger, induces transcriptional changes in astrocytes, reducing glycogen breakdown. We hypothesize that when glycogen utilization cannot match synaptic energy demand, extracellular K+ can rise to levels that activate neuronal pannexin‐1 channels and downstream inflammatory pathway, which might be one of the mechanisms initiating migraine headaches.

Sleep fragmentation alters brain energy metabolism without modifying hippocampal electrophysiological response to novelty exposure

Sleep is viewed as a fundamental restorative function of the brain, but its specific role in neural energy budget remains poorly understood. Sleep deprivation dampens brain energy metabolism and impairs cognitive functions. Intriguingly, sleep fragmentation, despite normal total sleep duration, has a similar cognitive impact, and in this paper we ask the question of whether it may also impair brain energy metabolism. To this end, we used a recently developed mouse model of 2 weeks of sleep fragmentation and measured 2‐deoxy‐glucose uptake and glycogen, glucose and lactate concentration in different brain regions. In order to homogenize mice behaviour during metabolic measurements, we exposed them to a novel environment for 1 h. Using an intra‐hippocampal electrode, we first showed that hippocampal electroencephalograph (EEG) response to exploration was unaltered by 1 or 14 days of sleep fragmentation. However, after 14 days, sleep fragmented mice exhibited a lower uptake of 2‐deoxy‐glucose in cortex and hippocampus and lower cortical lactate levels than control mice. Our results suggest that long‐term sleep fragmentation impaired brain metabolism to a similar extent as total sleep deprivation without affecting the neuronal responsiveness of hippocampus to a novel environment.

Gender-specific alteration of energy balance and circadian locomotor activity in the Crtc1 knockout mouse model of depression

Obesity and depression are major public health concerns, and there is increasing evidence that they share etiological mechanisms. CREB-regulated transcription coactivator 1 (CRTC1) participates in neurobiological pathways involved in both mood and energy balance regulation. Crtc1−/− mice rapidly develop a depressive-like and obese phenotype in early adulthood, and are therefore a relevant animal model to explore possible common mechanisms underlying mood disorders and obesity. Here, the obese phenotype of male and female Crtc1−/− mice was further characterized by investigating CRTC1’s role in the homeostatic and hedonic regulation of food intake, as well as its influence on daily locomotor activity. Crtc1−/− mice showed a strong gender difference in the homeostatic regulation of energy balance. Mutant males were hyperphagic and rapidly developed obesity on normal chow diet, whereas Crtc1−/− females exhibited mild late-onset obesity without hyperphagia. Overeating of mutant males was accompanied by alterations in the expression of several orexigenic and anorexigenic hypothalamic genes, thus confirming a key role of CRTC1 in the central regulation of food intake. No alteration in preference and conditioned response for saccharine was observed in Crtc1−/− mice, suggesting that mutant males’ hyperphagia was not due to an altered hedonic regulation of food intake. Intriguingly, mutant males exhibited a hyperphagic behavior only during the resting (diurnal) phase of the light cycle. This abnormal feeding behavior was associated with a higher diurnal locomotor activity indicating that the lack of CRTC1 may affect circadian rhythmicity. Collectively, these findings highlight the male-specific involvement of CRTC1 in the central control of energy balance and circadian locomotor activity.

Noradrenergic System and Memory: The Role of Astrocytes

There is ample evidence indicating that noradrenaline plays an important role in memory mechanisms. Noradrenaline is thought to modulate these processes through activation of adrenergic receptors in neurons. Astrocytes that form essential partners for synaptic function, also express alpha- and beta-adrenergic receptors. In astrocytes, noradrenaline triggers metabolic actions such as the glycogenolysis leading to an increase in l-lactate formation and release. l-Lactate can be used by neurons as a source of energy during memory tasks and can also induce transcription of plasticity genes in neurons. Activation of α-adrenergic receptors can also trigger gliotransmitter release resulting of intracellular calcium waves. These gliotransmitters modulate the synaptic activity and thereby can modulate long-term potentiation mechanisms. In summary, recent evidences indicate that noradrenaline exerts its memory-promoting effects through different modes of action both on neurons and astrocytes.Abstract There is ample evidence indicating that noradrenaline plays an important role in memory mechanisms. Noradrenaline is thought to modulate these processes through activation of adrenergic receptors in neurons. Astrocytes that form essential partners for synaptic function, also express alpha- and beta-adrenergic receptors. In astrocytes, noradrenaline triggers metabolic actions such as the glycogenolysis leading to an increase in l -lactate formation and release. l -Lactate can be used by neurons as a source of energy during memory tasks and can also induce transcription of plasticity genes in neurons. Activation of α-adrenergic receptors can also trigger gliotransmitter release resulting of intracellular calcium waves. These gliotransmitters modulate the synaptic activity and thereby can modulate long-term potentiation mechanisms. In summary, recent evidences indicate that noradrenaline exerts its memory-promoting effects through different modes of action both on neurons and astrocytes.