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PS06.2 REM sleep deprivation induced increased brain excitability is mediated by modulation of Na-K ATPase activity in the rat brain
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2nd WASM World Congress, Bangkok, 4–8 February 2007 / Sleep Medicine 8 Suppl. 1 (2007) S5–S9
PS05.2 Neural circuit of orexin neurons: a mechanism that maintains proper sleep/wakefulness states according to inner and outer environments of animals T. Sakurai. Department of Pharmacology, Institute of Basic Medical Science, University of Tsukuba, Tsukuba, Ibaraki 305−8575, Japan A series of studies over the past decade has identified the brain circuitry and neurotransmitters that regulate our daily cycles of sleep and wakefulness. Recent studies have shown that hypothalamic neurons that produce recently identified neuropeptides, orexin A and orexin B (also known as hypocretin 1 and hypocretin 2) are included in these mechanisms as critical regulators of sleep/wakefulness states. These peptides activate wakingactive monoaminergic neurons in the hypothalamus/brain stem regions to maintain long, consolidated waking period, and it is this role in particular that will form the focus of my talk. We initially identified orexins as endogenous ligands for two orphan G-protein-coupled receptors. Orexins were initially recognized as regulators of feeding behavior due to their exclusive production in the lateral hypothalamic area (LHA), a region known as the feeding center, and their pharmacological activity; they induce feeding in rats or mice when injected centrally during light period. Subsequently, the finding that orexin deficiency causes narcolepsy in humans and animals suggested that these hypothalamic neuropeptides play a critical role in regulating sleep/wakefulness states. Recent studies on efferent and afferent systems of orexin neurons, and phenotypic characterizations of genetically-modified mice on orexin systems have suggested further roles of orexin in the coordination of emotion, energy homeostasis, reward system, drug addiction, and arousal. Orexin neurons have shown to receive abundant input from the limbic system. The link between the limbic system and orexin neurons might be important for increasing arousal during emotional stimuli. Orexin neurons are also regulated by peripheral metabolic cues, including ghrelin, leptin and glucose, suggesting that they might have important roles as a link between energy homeostasis and vigilance states. Together, these observations suggest that in a broad sense, orexin neurons are involved in sensing the outer and inner environments of the body, and are involved in maintaining proper wakefulness of animals for survival. In this review, I will discuss the mechanisms by which orexins maintain sleep/wakefulness states, and how this mechanism relates to other systems that regulate emotion, reward, and energy homeostasis. Reference(s) [1] Sakurai, T. et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573−85 (1998). [2] Chemelli, R. M. et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437−51 (1999). [3] Hara, J. et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30, 345−54 (2001). [4] Yamanaka, A. et al. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38, 701−13 (2003). [5] Sakurai, T. et al. Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron 46, 297–308 (2005). PS05.3 Neuroanatomical and genetic dissection of brain circuitry regulating REM sleep behavior disorder (RBD) and cataplexy J. Lu. Neurology Department, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA REM sleep behavior disorder (RBD) is associated with synucleinopathies such as Parkinson’s disease and dementia with Lewy bodies. The underlying circuitry responsible for REM atonia has not been identified. We hypothesize that a set of glutamatergic neurons in the sublaterdorsal tegmental nucleus (SLD, the homologue of the sub-locus coeruleus in human) projecting to glycine interneurons in the ventral horn are responsible for atonia during REM sleep. This model predicts that loss of either neurons or glutamate in the SLD causes REM sleep without atonia (animal version of the RBD). We made cell specific lesions in the SLD by injecting ibotenic acid in rats, indeed these rats showed REM
without atonia. To eliminate glutamate, we injected adeno-associated virusCre recombinase (AAV-Cre) into the SLD in mice with lox P sites flanking exon 2 of vesicular glutamate transporter 2 (VGLUT2) gene, these mice showed REM without atonia. Although degeneration of orexin (also hypocretin) containing neurons in the lateral hypothalamus is recognized as the cause of human narcolepsy and cataplexy, it is not known where orexin modulates motor behavior. We propose that a set of spinal-projecting glutamatergic neurons in the lateral pontine tegmentum (LPT) that receives orexin inputs and contains orexin 2 receptors is the putative site. If this hypothesis is correct, lesions in the LPT or removal of glutamate in the LPT should produce cataplexy. We found that ibotenic acid lesions of the LPT in rats and elimination of glutamate by AAV-cre injection into the LPT in flox-VGLUT2 mice produce cataplexy.
PS06. REM functions
PS06.1 Functions of REM-sleep A.J. Hobson. Harvard University Medical School, Boston, MA, USA Recent research concerning the function of REM sleep in memory and learning will be reviewed. I will also present new data concerning the subjective experience of dreaming and speculate about its functional significance. With respect to learning, it is clear that REM sleep favors the consolidation and even improvement of procedural task mastery. The emotional salience of dreams despite their cognitive disorganization suggests that emotional equilibrium may also be enhanced by this state. The psychological evidence is surprising in supporting a generic theory of dream content determination rather than the exclusively individualistic model embraced by dynamic psychology.
PS06.2 REM sleep deprivation induced increased brain excitability is mediated by modulation of Na-K ATPase activity in the rat brain B.N. Mallick. School of Life Science, Jawaharlal Nehru University, New Delhi 110067, India Most mammals spend a significant amount of sleeping time in Rapid Eye Movement (REM) sleep. It was proposed that REM sleep deprivation (REMSD) induced effects are mediated by alteration in neuronal excitability, however, the reason and mechanism thereof were unknown. Since Na-K ATPase is a key player in maintaining transmembrane potential and neuronal excitability, it was hypothesized that REMSD affects neuronal and brain excitability by modulating its activity. Rats were REM sleep deprived by two methods; one, by classical flower-pot method and two, by injecting picrotoxin into locus coeruleus which did not allow the REM-OFF neurons to cease firing and suitable control studies were conducted. Na-K ATPase activity was estimated in synaptosome prepared from REMSD and control rat whole brain or after separation of neuron and glia. REMSD increased Na-K ATPase activity and decreased calcium-ions in the synaptosome prepared from the neurons, however, glia Na-K ATPase activity was inhibited. This was mediated by enhanced norepinephrine (NE) level which was due to non-cessation of REM-OFF neurons in the locus coeruleus. The elevated NE acted on alpha1 adrenoceptor, which through phospholipase C pathway activated calcium dependent-calmodulin and dephosphorylated the enzyme, while it reduced the membrane lipid peroxidation and calcium influx; both these mechanisms increased the Na-K ATPase activity. Additionally, circumstantial evidence suggests that some calcium ions required for the dephosphorylation of the enzyme were released from the neuronal membrane. Further, REMSD also increased the synthesis of Na-K ATPase molecules and this was also mediated by NE, both in vivo and in vitro. Thus, the findings support my hypothesis that “One of the functions of REM sleep is to maintain brain excitability” and it is mediated by modulating Na-K ATPase activity. Funding from CSIR, DBT, ICMR, UGC and UPOE are acknowledged.
2nd WASM World Congress, Bangkok, 4–8 February 2007 / Sleep Medicine 8 Suppl. 1 (2007) S5–S9
PS05.2 Neural circuit of orexin neurons: a mechanism that maintains proper sleep/wakefulness states according to inner and outer environments of animals T. Sakurai. Department of Pharmacology, Institute of Basic Medical Science, University of Tsukuba, Tsukuba, Ibaraki 305−8575, Japan A series of studies over the past decade has identified the brain circuitry and neurotransmitters that regulate our daily cycles of sleep and wakefulness. Recent studies have shown that hypothalamic neurons that produce recently identified neuropeptides, orexin A and orexin B (also known as hypocretin 1 and hypocretin 2) are included in these mechanisms as critical regulators of sleep/wakefulness states. These peptides activate wakingactive monoaminergic neurons in the hypothalamus/brain stem regions to maintain long, consolidated waking period, and it is this role in particular that will form the focus of my talk. We initially identified orexins as endogenous ligands for two orphan G-protein-coupled receptors. Orexins were initially recognized as regulators of feeding behavior due to their exclusive production in the lateral hypothalamic area (LHA), a region known as the feeding center, and their pharmacological activity; they induce feeding in rats or mice when injected centrally during light period. Subsequently, the finding that orexin deficiency causes narcolepsy in humans and animals suggested that these hypothalamic neuropeptides play a critical role in regulating sleep/wakefulness states. Recent studies on efferent and afferent systems of orexin neurons, and phenotypic characterizations of genetically-modified mice on orexin systems have suggested further roles of orexin in the coordination of emotion, energy homeostasis, reward system, drug addiction, and arousal. Orexin neurons have shown to receive abundant input from the limbic system. The link between the limbic system and orexin neurons might be important for increasing arousal during emotional stimuli. Orexin neurons are also regulated by peripheral metabolic cues, including ghrelin, leptin and glucose, suggesting that they might have important roles as a link between energy homeostasis and vigilance states. Together, these observations suggest that in a broad sense, orexin neurons are involved in sensing the outer and inner environments of the body, and are involved in maintaining proper wakefulness of animals for survival. In this review, I will discuss the mechanisms by which orexins maintain sleep/wakefulness states, and how this mechanism relates to other systems that regulate emotion, reward, and energy homeostasis. Reference(s) [1] Sakurai, T. et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573−85 (1998). [2] Chemelli, R. M. et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437−51 (1999). [3] Hara, J. et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30, 345−54 (2001). [4] Yamanaka, A. et al. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38, 701−13 (2003). [5] Sakurai, T. et al. Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron 46, 297–308 (2005). PS05.3 Neuroanatomical and genetic dissection of brain circuitry regulating REM sleep behavior disorder (RBD) and cataplexy J. Lu. Neurology Department, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA REM sleep behavior disorder (RBD) is associated with synucleinopathies such as Parkinson’s disease and dementia with Lewy bodies. The underlying circuitry responsible for REM atonia has not been identified. We hypothesize that a set of glutamatergic neurons in the sublaterdorsal tegmental nucleus (SLD, the homologue of the sub-locus coeruleus in human) projecting to glycine interneurons in the ventral horn are responsible for atonia during REM sleep. This model predicts that loss of either neurons or glutamate in the SLD causes REM sleep without atonia (animal version of the RBD). We made cell specific lesions in the SLD by injecting ibotenic acid in rats, indeed these rats showed REM
without atonia. To eliminate glutamate, we injected adeno-associated virusCre recombinase (AAV-Cre) into the SLD in mice with lox P sites flanking exon 2 of vesicular glutamate transporter 2 (VGLUT2) gene, these mice showed REM without atonia. Although degeneration of orexin (also hypocretin) containing neurons in the lateral hypothalamus is recognized as the cause of human narcolepsy and cataplexy, it is not known where orexin modulates motor behavior. We propose that a set of spinal-projecting glutamatergic neurons in the lateral pontine tegmentum (LPT) that receives orexin inputs and contains orexin 2 receptors is the putative site. If this hypothesis is correct, lesions in the LPT or removal of glutamate in the LPT should produce cataplexy. We found that ibotenic acid lesions of the LPT in rats and elimination of glutamate by AAV-cre injection into the LPT in flox-VGLUT2 mice produce cataplexy.
PS06. REM functions
PS06.1 Functions of REM-sleep A.J. Hobson. Harvard University Medical School, Boston, MA, USA Recent research concerning the function of REM sleep in memory and learning will be reviewed. I will also present new data concerning the subjective experience of dreaming and speculate about its functional significance. With respect to learning, it is clear that REM sleep favors the consolidation and even improvement of procedural task mastery. The emotional salience of dreams despite their cognitive disorganization suggests that emotional equilibrium may also be enhanced by this state. The psychological evidence is surprising in supporting a generic theory of dream content determination rather than the exclusively individualistic model embraced by dynamic psychology.
PS06.2 REM sleep deprivation induced increased brain excitability is mediated by modulation of Na-K ATPase activity in the rat brain B.N. Mallick. School of Life Science, Jawaharlal Nehru University, New Delhi 110067, India Most mammals spend a significant amount of sleeping time in Rapid Eye Movement (REM) sleep. It was proposed that REM sleep deprivation (REMSD) induced effects are mediated by alteration in neuronal excitability, however, the reason and mechanism thereof were unknown. Since Na-K ATPase is a key player in maintaining transmembrane potential and neuronal excitability, it was hypothesized that REMSD affects neuronal and brain excitability by modulating its activity. Rats were REM sleep deprived by two methods; one, by classical flower-pot method and two, by injecting picrotoxin into locus coeruleus which did not allow the REM-OFF neurons to cease firing and suitable control studies were conducted. Na-K ATPase activity was estimated in synaptosome prepared from REMSD and control rat whole brain or after separation of neuron and glia. REMSD increased Na-K ATPase activity and decreased calcium-ions in the synaptosome prepared from the neurons, however, glia Na-K ATPase activity was inhibited. This was mediated by enhanced norepinephrine (NE) level which was due to non-cessation of REM-OFF neurons in the locus coeruleus. The elevated NE acted on alpha1 adrenoceptor, which through phospholipase C pathway activated calcium dependent-calmodulin and dephosphorylated the enzyme, while it reduced the membrane lipid peroxidation and calcium influx; both these mechanisms increased the Na-K ATPase activity. Additionally, circumstantial evidence suggests that some calcium ions required for the dephosphorylation of the enzyme were released from the neuronal membrane. Further, REMSD also increased the synthesis of Na-K ATPase molecules and this was also mediated by NE, both in vivo and in vitro. Thus, the findings support my hypothesis that “One of the functions of REM sleep is to maintain brain excitability” and it is mediated by modulating Na-K ATPase activity. Funding from CSIR, DBT, ICMR, UGC and UPOE are acknowledged.