There is mounting evidence that the neuropeptide oxytocin is a possible candidate for the treatment of drug addiction. Oxytocin was shown to reduce methamphetamine self-administration, conditioned place-preference, hyperactivity and reinstatement in rodents, highlighting its potential for the management of methamphetamine addiction. Thus, we hypothesised that the central endogenous oxytocinergic system is dysregulated following chronic methamphetamine administration. We tested this hypothesis by examining the effect of chronic methamphetamine administration on oxytocin receptor density in mice brains with the use of quantitative receptor autoradiographic binding. Saline (4 ml/kg/day, i.p.) or methamphetamine (1 mg/kg/day, i.p.) was administered daily for 10 days to male, CD1 mice. Quantitative autoradiographic mapping of oxytocin receptors was carried out with the use of [125I]-vasotocin in brain sections of these animals. Chronic methamphetamine administration induced a region specific upregulation of oxytocin receptor density in the amygdala and hypothalamus, but not in the nucleus accumbens and caudate putamen. As there is evidence suggesting an involvement of central adenosine A2A receptors on central endogenous oxytocinergic function, we investigated whether these methamphetamine-induced oxytocinergic neuroadaptations are mediated via an A2A receptor-dependent mechanism. To test this hypothesis, autoradiographic oxytocin receptor binding was carried out in brain sections of male CD1 mice lacking A2A receptors which were chronically treated with methamphetamine (1 mg/kg/day, i.p. for 10 days) or saline. Similar to wild-type animals, chronic methamphetamine administration induced a region-specific upregulation of oxytocin receptor binding in the amygdala and hypothalamus of A2A receptor knockout mice and no genotype effect was observed. These results indicate that chronic methamphetamine use can induce profound neuroadaptations of the oxytocinergic receptor system in brain regions associated with stress, emotionality and social bonding and that these neuroadaptations are independent on the presence of A2A receptors. These results may at least partly explain some of the behavioural consequences of chronic methamphetamine use. © 2013 Elsevier Inc. All rights reserved.
Hasan S, Winsky-Sommerer R, Dijk D-J, Archer SN (2012) Sleep in transgenic mouse models for a polymorphism in the human PER3 gene, JOURNAL OF SLEEP RESEARCH 21 pp. 79-79 WILEY-BLACKWELL
Zanos P, Wright SR, Georgiou P, Yoo JH, Hourani SM, Kitchen I, Winsky-Sommerer R, Bailey A, Ledent C (2013) Chronic methamphetamine treatment induces oxytocin receptor up-regulation in the amygdala and hypothalamus via an adenosine A receptor-independent mechanism, Pharmacology Biochemistry and Behavior
There is mounting evidence that the neuropeptide oxytocin is a possible candidate for the treatment of drug addiction. Oxytocin was shown to reduce methamphetamine self-administration, conditioned place-preference, hyperactivity and reinstatement in rodents, highlighting its potential for the management of methamphetamine addiction. Thus, we hypothesised that the central endogenous oxytocinergic system is dysregulated following chronic methamphetamine administration. We tested this hypothesis by examining the effect of chronic methamphetamine administration on oxytocin receptor density in mice brains with the use of quantitative receptor autoradiographic binding. Saline (4 ml/kg/day, i.p.) or methamphetamine (1 mg/kg/day, i.p.) was administered daily for 10 days to male, CD1 mice. Quantitative autoradiographic mapping of oxytocin receptors was carried out with the use of [I]-vasotocin in brain sections of these animals. Chronic methamphetamine administration induced a region specific upregulation of oxytocin receptor density in the amygdala and hypothalamus, but not in the nucleus accumbens and caudate putamen. As there is evidence suggesting an involvement of central adenosine A receptors on central endogenous oxytocinergic function, we investigated whether these methamphetamine-induced oxytocinergic neuroadaptations are mediated via an A receptor-dependent mechanism. To test this hypothesis, autoradiographic oxytocin receptor binding was carried out in brain sections of male CD1 mice lacking A receptors which were chronically treated with methamphetamine (1 mg/kg/day, i.p. for 10 days) or saline. Similar to wild-type animals, chronic methamphetamine administration induced a region-specific upregulation of oxytocin receptor binding in the amygdala and hypothalamus of A receptor knockout mice and no genotype effect was observed. These results indicate that chronic methamphetamine use can induce profound neuroadaptations of the oxytocinergic receptor system in brain regions associated with stress, emotionality and social bonding and that these neuroadaptations are independent on the presence of A receptors. These results may at least partly explain some of the behavioural consequences of chronic methamphetamine use. © 2013 Elsevier Inc. All rights reserved.
Zanos P, Alshehri M, Sahabandu T, Winsky-Sommerer R, Kitchen I, Bailey A (2011) Persistent brain region-specific upregulation of vasopressin (V1ar) and oxytocin receptors in chronic intermittent escalating dose morphine administration in mice, PHARMACOL REP 63 (1) pp. 252-252 POLISH ACAD SCIENCES INST PHARMACOLOGY
Winsky-Sommerer R (2008) New insights from basic animal research on GABAA receptor mediated inhibition to understand selective pharmacological profiles of hypnotics, JOURNAL OF SLEEP RESEARCH 17 pp. 58-58 WILEY-BLACKWELL PUBLISHING, INC
Nollet M, Stenson G, Martynhak B, Wafford K, Dijk D-J, Winsky-Sommerer R (2014) Characterisation of the development of sleep disturbances in the unpredictable chronic mild stress murine model of major depression, JOURNAL OF SLEEP RESEARCH 23 pp. 78-78 WILEY-BLACKWELL
Wright SR, Zanos P, Georgiou P, Yoo JH, Ledent C, Hourani SM, Kitchen I, Winsky-Sommerer R, Bailey A (2015) A critical role of striatal A2A R-mGlu5 R interactions in modulating the psychomotor and drug-seeking effects of methamphetamine., Addict Biol 21 (4) pp. 811-825
Addiction to psychostimulants is a major public health problem with no available treatment. Adenosine A2A receptors (A2A R) co-localize with metabotropic glutamate 5 receptors (mGlu5 R) in the striatum and functionally interact to modulate behaviours induced by addictive substances, such as alcohol. Using genetic and pharmacological antagonism of A2A R in mice, we investigated whether A2A R-mGlu5 R interaction can regulate the locomotor, stereotypic and drug-seeking effect of methamphetamine and cocaine, two drugs that exhibit distinct mechanism of action. Genetic deletion of A2A R, as well as combined administration of sub-threshold doses of the selective A2A R antagonist (SCH 58261, 0.01 mg/kg, i.p.) with the mGlu5 R antagonist, 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (0.01 mg/kg, i.p.), prevented methamphetamine- but not cocaine-induced hyperactivity and stereotypic rearing behaviour. This drug combination also prevented methamphetamine-rewarding effects in a conditioned-place preference paradigm. Moreover, mGlu5 R binding was reduced in the nucleus accumbens core of A2A R knockout (KO) mice supporting an interaction between these receptors in a brain region crucial in mediating addiction processes. Chronic methamphetamine, but not cocaine administration, resulted in a significant increase in striatal mGlu5 R binding in wild-type mice, which was absent in the A2A R KO mice. These data are in support of a critical role of striatal A2A R-mGlu5 R functional interaction in mediating the ambulatory, stereotypic and reinforcing effects of methamphetamine but not cocaine-induced hyperlocomotion or stereotypy. The present study highlights a distinct and selective mechanistic role for this receptor interaction in regulating methamphetamine-induced behaviours and suggests that combined antagonism of A2A R and mGlu5 R may represent a novel therapy for methamphetamine addiction.
Winsky-Sommerer R, Boutrel B, de Lecea L (2005) Stress and arousal - The corticotrophin-releasing factor/hypocretin circuitry, MOL NEUROBIOL 32 (3) pp. 285-294 HUMANA PRESS INC
The hypocretins (also know as orexins) are two neuropeptides now commonly described as critical components for maintaining and regulating the stability of arousal. Several lines of evidence have raised the hypothesis that hypocretin-producing neurons are part of the circuitries that mediate the hypothalamic response to acute stress. New data indicate that the corticotrophin-releasing factor (CRF) peptidergic system directly innervates hypocretin-expressing neurons. CRF depolarizes hypocretin neurons, and this effect is blocked by a CRF-R1 antagonist. Furthermore, activation of hypocretinergic neurons by stress is impaired in CRF-R1 knockout mice. These data suggest that CRF-R1 receptor mediates the stress-induced activation of the hypocretinergic system. A significant amount of evidence also indicates that hypocretin cells connect reciprocally to the CRF system. We propose that upon stressor stimuli, CRF activates the hypocretin system, which relays these signals to brain stem nuclei involved in the modulation of arousal as well as to the extended amygdala, a structure involved in the negative motivational state that drives addiction.
Stenson GM, Nollet M, Winsky-Sommerer R (2014) Characterisation of the role of extrasynaptic GABA(A) receptors in sleep and mood regulation in a rodent model, JOURNAL OF SLEEP RESEARCH 23 pp. 256-256 WILEY-BLACKWELL
Since the 1950s, sleep science has revealed much about its structure and patterns. Even so, its origins and functions remain largely mysterious. © 2012 Reed Business Information Ltd, England.
In humans, a primate-specific variable-number tandem-repeat (VNTR) polymorphism (4 or 5 repeats 54 nt in length) in the circadian gene PER3 is associated with differences in sleep timing and homeostatic responses to sleep loss. We investigated the effects of this polymorphism on circadian rhythmicity and sleep homeostasis by introducing the polymorphism into mice and assessing circadian and sleep parameters at baseline and during and after 12 h of sleep deprivation (SD). Microarray analysis was used to measure hypothalamic and cortical gene expression. Circadian behavior and sleep were normal at baseline. The response to SD of 2 electrophysiological markers of sleep homeostasis, electroencephalography (EEG) ¸ power during wakefulness and ´ power during sleep, were greater in the Per3(5/5) mice. During recovery, the Per3(5/5) mice fully compensated for the SD-induced deficit in ´ power, but the Per3(4/4) and wild-type mice did not. Sleep homeostasis-related transcripts (e.g., Homer1, Ptgs2, and Kcna2) were differentially expressed between the humanized mice, but circadian clock genes were not. These data are in accordance with the hypothesis derived from human data that the PER3 VNTR polymorphism modifies the sleep homeostatic response without significantly influencing circadian parameters.
Zanos P, Georgiou P, Metaxas A, Kitchen I, Winsky-Sommerer R, Bailey A (2015) Region-specific up-regulation of oxytocin receptor binding in the brain of mice following chronic nicotine administration., Neurosci Lett 600 pp. 33-37
Nicotine addiction is considered to be the main preventable cause of death worldwide. While growing evidence indicates that the neurohypophysial peptide oxytocin can modulate the addictive properties of several abused drugs, the regulation of the oxytocinergic system following nicotine administration has so far received little attention. Here, we examined the effects of long-term nicotine or saline administration on the central oxytocinergic system using [(125)I]OVTA autoradiographic binding in mouse brain. Male, 7-week old C57BL6J mice were treated with either nicotine (7.8 mg/kg daily; rate of 0.5 ¼l per hour) or saline for a period of 14-days via osmotic minipumps. Chronic nicotine administration induced a marked region-specific upregulation of the oxytocin receptor binding in the amygdala, a brain region involved in stress and emotional regulation. These results provide direct evidence for nicotine-induced neuroadaptations in the oxytocinergic system, which may be involved in the modulation of nicotine-seeking as well as emotional consequence of chronic drug use.
In this pilot study, a symbolic sequence decomposition method was used in conjunction with Shannon?s entropy to investigate the changes in electroencephalogram signals of 11 patients with Alzheimer?s disease and 11 age-matched control subjects. Results were statistically analysed by student t-test and later classified with receiver operating curves. Statistically significant differences between both groups were found at electrodes Fp1, O2, P3, T4 and T5. Sensitivity (defined as percentages of correctly classified patients) and
specificity (defined as correctly classified controls) were evaluated using the receiver operating curves method. Accuracy of the methods was calculated according to sensitivity and specificity measures of electrodes showing statistically significant differences between the control group and Alzheimer's disease patients and ranged between 72.73-77.27%. These accuracy values were in agreement with previously published entropy studies on this data set. Although combining these methods did not provide any greater accuracy over previous findings, using a symbolic sequence decomposition method enhanced the data processing.
Grouselle D, Winsky-Sommerer R, David JP, Delacourte A, Dournaud P, Epelbaum J (1998) Loss of somatostatin-like immunoreactivity in the frontal cortex of Alzheimer patients carrying the apolipoprotein epsilon 4 allele, NEUROSCIENCE LETTERS 255 (1) pp. 21-24 ELSEVIER SCI IRELAND LTD
Winsky-Sommerer R, Grouselle D, Rougeot C, Laurent V, David JP, Delacourte A, Dournaud P, Seidah NG, Lindberg I, Trottier S, Epelbaum J (2003) The proprotein convertase PC2 is involved in the maturation of prosomatostatin to somatostatin-14 but not in the somatostatin deficit in Alzheimer's disease, NEUROSCIENCE 122 (2) pp. 437-447 PERGAMON-ELSEVIER SCIENCE LTD
Winsky-Sommerer R, Spier AD, Fabre V, de Lecea L, Criado JR (2004) Overexpression of the human beta-amyloid precursor protein downregulates cortistatin mRNA in PDAPP mice, BRAIN RESEARCH 1023 (1) pp. 157-162 ELSEVIER SCIENCE BV
Dissel S, Angadi V, Kirszenblat L, Suzuki Y, Donlea J, Klose M, Koch Z, English D, Winsky-Sommerer R, van Swinderen B, Shaw PJ (2015) Sleep restores behavioral plasticity to Drosophila mutants., Curr Biol 25 (10) pp. 1270-1281
Given the role that sleep plays in modulating plasticity, we hypothesized that increasing sleep would restore memory to canonical memory mutants without specifically rescuing the causal molecular lesion. Sleep was increased using three independent strategies: activating the dorsal fan-shaped body, increasing the expression of Fatty acid binding protein (dFabp), or by administering the GABA-A agonist 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol (THIP). Short-term memory (STM) or long-term memory (LTM) was evaluated in rutabaga (rut) and dunce (dnc) mutants using aversive phototaxic suppression and courtship conditioning. Each of the three independent strategies increased sleep and restored memory to rut and dnc mutants. Importantly, inducing sleep also reverses memory defects in a Drosophila model of Alzheimer's disease. Together, these data demonstrate that sleep plays a more fundamental role in modulating behavioral plasticity than previously appreciated and suggest that increasing sleep may benefit patients with certain neurological disorders.
Winsky-Sommerer R, Boutrel B, de Lecea L (2003) The role of the hypcretinergic system in the integration of networks that dictate the states of arousal, DRUG NEWS PERSPECT 16 (8) pp. 504-512 PROUS SCIENCE, SA
Recent studies have led to the discovery of a neuropeptide system that regulates arousal states, The hypocretins (hcrt1 and hcrt2, also called the orexins) are neuropeptides of related sequence derived from the same precursor whose expression is restricted to a few thousand neurons of the lateral hypothalamus. Two G-protein-coupled receptors for the hypocretins have been identified, and these have different distributions within the central nervous system and differential affinities for the two hypocretins. Hypocretin fibers project throughout the brain, including several areas implicated in cardiovascular function and regulation of the sleep-wake cycle. Central administration of synthetic hypocretin-1 affects blood pressure, hormone secretion and locomotor activity, and increases wakefulness while suppressing rapid eye movement sleep. Most human patients with narcolepsy have greatly reduced levels of hypocretin peptides in their cerebral spinal fluid and no or barely detectable hypocretin neurons in their hypothalami, suggestive of autoimmune attack. Development of nonpeptidergic hypocretin antagonists may prove useful in sleep disorders, whereas hypocretin agonists may be used to treat narcolepsy and excessive daytime sleepiness. The hypocretins are also an excellent target for the pharmacological treatment of the deregulated arousal state that characterizes depression or addictive behavior. (C) 2003 Prous Science. All rights reserved.
Boutrel B, Kenny PJ, Specio SS, Winsky-Sommerer R, Halfon O, Magistretti PJ, Markou A, Koob GF, de Lecea L (2005) A key role for hypocretin in regulating brain reward function and reinstatement for drug-seeking behavior in rats, BEHAVIOURAL PHARMACOLOGY 16 pp. S60-S60 LIPPINCOTT WILLIAMS & WILKINS
Kovacs Z, Tobler I, Winsky-Sommerer R (2009) Role of the GABAA Alpha4-Subtype in Sleep and Sleep Regulation, Neuropsychobiology: international journal of experimental and clinical research in biological psychiatry, pharmacopsychiatry, biological psychology, pharmacopsychology and pharmacoelectroencephalography 4 (59) pp. 267-267
Kovacs Z, Tobler I, Winsky-Sommerer R (2009) DECIPHERING THE ROLE OF THE GABA-A ALPHA4-SUBTYPE IN SLEEP, SLEEP 32 pp. A14-A15 AMER ACAD SLEEP MEDICINE
Palchykova S, Gerling A, Winsky-Sommerer R, Tobler I (2009) Sleep Regulation in Mice with Adenosine Metabolism Deficiency, NEUROPSYCHOBIOLOGY 59 (4) pp. 261-262 KARGER
Kovacs Z, Tobler I, Winsky-Sommerer R (2008) A role for GABAA alpha 4-subunit-containing receptors in sleep regulation?, JOURNAL OF SLEEP RESEARCH 17 pp. 203-204 WILEY-BLACKWELL PUBLISHING, INC
Epelbaum J, Winsky-Sommerer R (2006) Brain Somatostatin-Related Peptides, Handbook of Biologically Active Peptides pp. 645-654
This chapter focuses on brain somatostatin-related peptides. Somatostatin-14 was originally characterized as a hypothalamic neurohormone responsible for the inhibition of pituitary growth hormone secretion. In the mammalian brain, two genes encode for the prosomatostatin-derived peptides, somatostatin-14 and -28, and procortistatin-related ones, respectively. Somatotropin release inhibiting factor (SRIF) immunoreactivity is largely distributed in many neurons in mammalian brain, including the human brain. The highest levels are found in the mediobasal hypothalamus and median eminence, amygdala, preoptic area, accumbens nucleus, cerebral cortex, striatum olfactory regions, and brain stem. SRIF mediates its biological functions via at least six receptor subtypes, termed sstl, sst2A, sst2B, sst3, sst4, and sst5, which all belong to the family of seven transmembrane domain G-protein-coupled receptors. With the noticeable exception of sst4, all subtypes do internalize in various cellular models following agonist treatment. In the brain, this has only been shown in vivo for the sst2 receptor. Although the sst2 receptor is the candidate likely to mediate the anticonvulsant effects of SRIF in the rat hippocampus, in the mouse hippocampus recent observations support a central role of sst4 and/or sst1 receptors in mediating SRIF inhibition of epileptiform activity. © 2006 Elsevier Inc. All rights reserved.
The main challenge in treating opioid addicts is to maintain abstinence due to the affective consequences associated with withdrawal which may trigger relapse. Emerging evidence suggests a role of the neurohypophysial peptide oxytocin (OT) in the modulation of mood disorders as well as drug addiction. However, its involvement in the emotional consequences of drug abstinence remains unclear. We investigated the effect of 7-day opioid abstinence on the oxytocinergic system and assessed the effect of the OT analogue carbetocin (CBT) on the emotional consequences of opioid abstinence, as well as relapse. Male C57BL/6J mice were treated with a chronic escalating-dose morphine regimen (20-100 mg/kg/day, i.p.). Seven days withdrawal from this administration paradigm induced a decrease of hypothalamic OT levels and a concomitant increase of oxytocin receptor (OTR) binding in the lateral septum and amygdala. Although no physical withdrawal symptoms or alterations in the plasma corticosterone levels were observed after 7 days of abstinence, mice exhibited increased anxiety-like and depressive-like behaviors and impaired sociability. CBT (6.4 mg/kg, i.p.) attenuated the observed negative emotional consequences of opioid withdrawal. Furthermore, in the conditioned place preference paradigm with 10 mg/kg morphine conditioning, CBT (6.4 mg/kg, i.p.) was able to prevent the stress-induced reinstatement to morphine-seeking following extinction. Overall, our results suggest that alterations of the oxytocinergic system contribute to the mechanisms underlying anxiety, depression, and social deficits observed during opioid abstinence. This study also highlights the oxytocinergic system as a target for developing pharmacotherapy for the treatment of emotional impairment associated with abstinence and thereby prevention of relapse.
Winsky-Sommerer R, Yamanaka A, Diano S, Borok E, Roberts AJ, Sakurai T, Kilduff TS, Horvath TL, de Lecea L (2004) Interaction between the corticotropin-releasing factor system and hypocretins (Orexins): A novel circuit mediating stress response, JOURNAL OF NEUROSCIENCE 24 (50) pp. 11439-11448 SOC NEUROSCIENCE
de Lecea L, Winsky-Sommerer R, Suzuki C, Xu Y, Reinscheid R (2005) Neuropeptide S projects to arousal nuclei, SLEEP 28 pp. A10-A10 AMER ACADEMY SLEEP MEDICINE
Cervera P, Videau C, Viollet C, Petrucci C, Lacombe J, Winsky-Sommerer R, Csaba Z, Helboe L, Daumas-Duport C, Reubi JC, Epelbaum J (2002) Comparison of somatostatin receptor expression in human gliomas and medulloblastomas, JOURNAL OF NEUROENDOCRINOLOGY 14 (6) pp. 458-471 BLACKWELL PUBLISHING LTD
Conti B, Sanchez-Alavez M, Winsky-Sommerer R, Morale MC, Lucero J, Brownell S, Fabre V, Huitron-Resendiz S, Henriksen S, Zorrilla EP, de Lecea L, Bartfai T (2006) Transgenic mice with a reduced core body temperature have an increased life span, SCIENCE 314 (5800) pp. 825-828 AMER ASSOC ADVANCEMENT SCIENCE
Huitron-Resendiz S, Clark SD, Sanchez-Alavez M, Winsky-Sommerer R, Civelli O, Nothacker HP, Henriksen SJ, Criado JR, de Lecea L (2003) Effects of urotensin-II in the regulation of REM sleep, SLEEP 26 pp. A47-A48 AMER ACADEMY SLEEP MEDICINE
Winsky-Sommerer R, Knapman A, Tobler I (2008) Sleep and sleep regulation in mice lacking the GABA-A receptor A3-subunit, SLEEP 31 pp. A17-A18 AMER ACAD SLEEP MEDICINE
Dijk DJ, Winsky-Sommerer R (2012) Sleep: Moving to a 24/7 society, New Scientist 213 (2850)
The growing scientific interest in sleep, its organisation and recognition of its importance to health will transform how we approach it in the future. © 2012 Reed Business Information Ltd, England.
Winsky-Sommerer R (2009) Mechanisms Underlying the Effects of GABAA Sedative-Hypnotic Drugs, NEUROPSYCHOBIOLOGY 59 (4) pp. 248-249 KARGER
Epelbaum J, Viollet C, Winsky-Sommerer R (2013) Somatostatin/Cortistatin, pp. 933-942
Huitron-Resendiz S, Winsky-Sommerer R, Sanchez-Alavez M, Wills DN, Xu Y, Civelli O, Henriksen SJ, Criado JR, Reinscheid RK, de Lecea L (2004) Effects of neuropeptide S in the regulation of sleep-wake cycle, SLEEP 27 pp. 32-33 AMER ACADEMY SLEEP MEDICINE
Winsky-Sommerer R, Vesely M, Tobler I (2006) Effects of the GABA-A receptor agonist THIP on the sleep EEG of GABA-A receptor delta subunit knockout mice, SLEEP 29 pp. A21-A21 AMER ACADEMY SLEEP MEDICINE
Dijk DJ, Winsky-Sommerer R (2012) Sleep: The way we snooze now, New Scientist 213 (2850)
Light bulbs, television, computers and shift work have all altered sleeping habits. This has huge implications for sleep deprivation and our health. © 2012 Reed Business Information Ltd, England.
Winsky-Sommerer R, Huitron-Resendiz S, Sanchez-Alavez M, Slaght K, Henriksen SJ, Criado JR, de Lecea L (2003) Effect of the endogenous GPR7/8 ligand (neuropeptide W) on sleep/wakefulness, SLEEP 26 pp. A49-A49 AMER ACADEMY SLEEP MEDICINE
Orexins have a role in sleep regulation, and orexin receptor antagonists are under development for the treatment of insomnia. We conducted a randomised, double-blind, placebo-controlled, four-period crossover study to investigate the effect of single doses of the dual orexin receptor antagonist SB-649868 (10 or 30 mg) and a positive control zolpidem (10 mg), an allosteric modulator of GABA(A) receptors. Objective and subjective sleep parameters and next-day performance were assessed in 51 healthy male volunteers in a traffic noise model of situational insomnia. Compared with placebo, SB-649868 10 and 30 mg increased total sleep time (TST) by 17 and 31 min (p
Abásolo D, Winsky-Sommerer R (2013) Investigating the possible usefulness of Lempel-Ziv complexity for the characterisation of electroencephalogram sleep recordings, Final Programme and Book of Abstracts of BioDynamics 2013 pp. 24-25
Dijk DJ, Winsky-Sommerer R (2012) Sleep: How much we need and what keeps us awake, New Scientist 213 (2850)
Recent research has brought new insights into our sleep requirements - from the amount we need to when, where and how we do it. © 2012 Reed Business Information Ltd, England.
Urena JM, La Torre A, Martinez A, Lowenstein E, Franco N, Winsky-Sommerer R, Fontana X, Casaroli-Marano R, Ibanez-Sabio MA, Pascual M, Del Rio JA, de Lecea L, Soriano E (2005) Expression, synaptic localization, and developmental regulation of Ack1/Pyk1, a cytoplasmic tyrosine kinase highly expressed in the developing and adult brain, JOURNAL OF COMPARATIVE NEUROLOGY 490 (2) pp. 119-132 WILEY-LISS
There is increasing evidence that sleep facilitates memory acquisition and consolidation. Moreover, the sleep-wake history preceding memory acquisition and retention as well as circadian timing may be important. We showed previously that sleep deprivation (SD) following learning in OF1 mice impaired their performance on an object recognition task. The learning task was scheduled at the end of the 12 h dark period and the test 24 h later. To investigate the influence of the prominent circadian sleep-wake distribution typical for rodents, we now scheduled the learning task at the beginning of the dark period. Wakefulness following immediately after the learning task was attained either by gentle interference (SD; n = 20) or by spontaneous wheel running (RW; n = 20). Two control groups were used: one had no RW throughout the experiment (n = 23), while the other group's wheel was blocked immediately after acquisition (n = 16), thereby preventing its use until testing. Recognition memory, defined as the difference in exploration of a novel and of familiar objects, was assessed 24 h later during the test phase. Motor activity and RW use were continuously recorded. Remarkably, performance on the object recognition task was not influenced by the protocols; the waking period following acquisition did not impair memory, independent of the method inducing wakefulness (i.e., sleep deprivation or spontaneous running). Thus, all groups explored the novel object significantly longer than the familiar ones during the test phase. Interestingly, neither the amount of rest lost during the SD interventions nor the amount of rest preceding acquisition influenced performance. However, the total amount of rest obtained by the control and SD mice subjected to acquisition at ?dark offset? correlated positively (r = 0.66) with memory at test, while no such relationship occurred in the corresponding groups tested at dark onset. Neither the amount of running nor intermediate rest correlated with performance at test in the RW group. We conclude that interfering with sleep during the dark period does not affect object recognition memory consolidation.
Paneda C, Winsky-Sommerer R, Boutrel B, de Lecea L (2005) The corticotropin-releasing factor-hypocretin connection: Implications in stress response and addiction, DRUG NEWS PERSPECT 18 (4) pp. 250-255 PROUS SCIENCE, SA
The hypothalamic neuropeptides hypocretins (orexins) play a crucial role in the stability of arousal and alertness. Recent data have raised the hypothesis that hypocretin neurons are also part of the circuitries that mediate the hypothalamic stress response. In particular, we have recently demonstrated that corticotrophin-releasing factor (CRF)immunoreactive terminals make direct synaptic contacts with hypocretin-expressing neurons and that numerous hypocretinergic neurons express the CRF-R1/2 receptors. Furthermore, CRF excites hypocretinergic cells ex vivo through CRF-R1 receptors. Activation of hypocretinergic neurons in response to acute stress is severely impaired in CRF-R1 knockout mice. Moreover, the stress response is impaired in hypocretin-deficient mice. We propose that upon stressor stimuli, CRF stimulates the release of hypocretins, and this circuit contributes to activation and maintenance of arousal associated with the stress response and addiction. (c) 2005 Prous Science. All rights reserved.
Kovacs Z, Tobler I, Winsky-Sommerer R (2009) Role of the GABAA Alpha4-Subtype in Sleep and Sleep Regulation, NEUROPSYCHOBIOLOGY 59 (4) pp. 267-267 KARGER
Hasan S, van der Veen DR, Winsky-Sommerer R, Dijk DJ, Archer SN (2011) Altered sleep and behavioral activity phenotypes in PER3-deficient mice., Am J Physiol Regul Integr Comp Physiol
Sleep homeostasis and circadian rhythmicity interact to determine the timing of behavioral activity. Circadian clock genes contribute to circadian rhythmicity centrally and in the periphery, but some also have roles within sleep regulation. The clock gene Period3 (Per3) has a redundant function within the circadian system and is associated with sleep homeostasis in humans. This study investigated the role of PER3 in sleep/wake activity and sleep homeostasis in mice by recording wheel running activity under baseline conditions in wild-type (WT; n = 54) and in PER3-deficient (Per3(-/-); n = 53) mice, as well as EEG-assessed sleep before and after 6 hours of sleep deprivation in WT (n = 7) and Per3(-/-) (n = 8) mice. Whereas total activity and vigilance states did not differ between the genotypes, the temporal distribution of wheel running activity, vigilance states, and EEG delta activity was affected by genotype. In Per3(-/-) mice, running wheel activity was increased and REM sleep and NREM sleep were reduced in the middle of the dark phase, and delta activity was enhanced at the end of the dark phase. At the beginning of the baseline light period, there was less wakefulness and more REM and NREM in Per3(-/-) mice. Per3(-/-) mice spent less time in wakefulness and more time in NREM sleep in the light period immediately after sleep deprivation and REM sleep accumulated more slowly during the recovery dark phase. These data confirm a role for PER3 in sleep/wake timing and sleep homeostasis.
Conti B, Sugama S, Lucero J, Winsky-Sommerer R, Wirz SA, Maher P, Andrews Z, Barr AM, Morale MC, Paneda C, Pemberton J, Gaidarova S, Behrens MM, Beal F, Sanna PP, Horvath TL, Bartfai T (2005) Uncoupling protein 2 protects dopaminergic neurons from acute 1,2,3,6-methyl-phenyl-tetrahydropyridine toxicity, JOURNAL OF NEUROCHEMISTRY 93 (2) pp. 493-501 BLACKWELL PUBLISHING LTD
Bettica P, Squassante L, Groeger JA, Gennery B, Winsky-Sommerer R, Dijk D-J (2012) Differential effects of a dual orexin receptor antagonist (SB-649868) and zolpidem on sleep initiation and consolidation, SWS, REM sleep, and EEG power spectra in a model of situational insomnia, Neuropsychopharmacology 37 (5) pp. 1224-1233
Winsky-Sommerer R, Yamanaka A, Sakurai T, Roberts AJ, Kilduff TS, de Lecea L (2004) Interaction between the corticotropin-releasing-factor system and hypocretins: Components mediating the stress response, SLEEP 27 pp. 23-23 AMER ACADEMY SLEEP MEDICINE
Winsky-Sommerer R, Tobler I (2006) Evidence for mechanism of action of the GABA-A receptor agonist THIP in GABA-A receptor delta subunit knockout mice, JOURNAL OF SLEEP RESEARCH 15 pp. 238-238 BLACKWELL PUBLISHING
Lazarus M, Shen HY, Cherasse Y, Qu WM, Huang ZL, Bass CE, Winsky-Sommerer R, Semba K, Fredholm BB, Boison D, Hayaishi O, Urade Y, Chen JF (2011) Arousal effect of caffeine depends on adenosine A2A receptors in the shell of the nucleus accumbens., J Neurosci 31 (27) pp. 10067-10075
Society for Neuroscience
Caffeine, the most widely used psychoactive compound, is an adenosine receptor antagonist. It promotes wakefulness by blocking adenosine A(2A) receptors (A(2A)Rs) in the brain, but the specific neurons on which caffeine acts to produce arousal have not been identified. Using selective gene deletion strategies based on the Cre/loxP technology in mice and focal RNA interference to silence the expression of A(2A)Rs in rats by local infection with adeno-associated virus carrying short-hairpin RNA, we report that the A(2A)Rs in the shell region of the nucleus accumbens (NAc) are responsible for the effect of caffeine on wakefulness. Caffeine-induced arousal was not affected in rats when A(2A)Rs were focally removed from the NAc core or other A(2A)R-positive areas of the basal ganglia. Our observations suggest that caffeine promotes arousal by activating pathways that traditionally have been associated with motivational and motor responses in the brain.
Levine AS, Winsky-Sommerer R, Huitron-Resendiz S, Grace MK, de Lecea L (2005) Injection of neuropeptide W into paraventricular nucleus of hypothalamus increases food intake, AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY 288 (6) pp. R1727-R1732 AMER PHYSIOLOGICAL SOC
Zanos P, Georgiou P, Gonzalez LR, Hourani S, Chen Y, Kitchen I, Kieffer BL, Winsky-Sommerer R, Bailey A (2016) Emotional Impairment and Persistent Upregulation of mGlu(5) Receptor following Morphine Abstinence: Implications of an mGlu(5)-MOPr Interaction, INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY 19 (7) OXFORD UNIV PRESS
While several methods have been used to restrict the sleep of experimental animals, it is often unclear whether these different forms of sleep restriction have comparable effects on sleepwake architecture or functional capacity. The present study compared four models of sleep restriction, using enforced wakefulness by rotation of cylindrical home cages over 11-hours in male Wistar rats. These included an electroencephalographic (EEG)-driven ?Biofeedback? method and three non-invasive methods where rotation was triggered according to a ?Constant?, ?Decreasing?, or a random protocol based upon the ?Weibull? distribution fit to an archival Biofeedback dataset. The sleep-wake architecture was determined using polysomnography and functional capacity was assessed immediately post-restriction with a simple response latency task (SRLT), as a potential homologue of the human psychomotor vigilance task. All sleep restriction protocols resulted in sleep loss, behavioural task disengagement and rebound sleep, although no model was as effective as real-time EEG-biofeedback. Decreasing and Weibull protocols produced greater recovery sleep than the Constant protocol, mirrored by comparably worse SRLT performance. Increases in urinary corticosterone levels following Constant and Decreasing protocols suggested that stress levels may differ between protocols. Overall, these results provide insights into the value of choosing a specific sleep restriction protocol, not only from the perspective of animal welfare and the use of less invasive procedures, but also translational validity. A more considered choice of the physiological and functional effects of sleep restriction protocols in rodents may improve correspondence with specific types of excessive daytime sleepiness in humans.
To test the hypothesis that sleep can reverse cognitive impairment during Alzheimer?s disease, we enhanced sleep in flies either co-expressing human amyloid precursor protein and Beta-secretase (APP:BACE), or in flies expressing human tau. The ubiquitous expression of APP:BACE or human tau disrupted sleep. The sleep deficits could be reversed and sleep could be enhanced when flies were administered the GABA-A agonist 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol (THIP). Expressing APP:BACE disrupted both Short-term memory (STM) and Long-term memory (LTM) as assessed using Aversive Phototaxic Suppression (APS) and courtship conditioning. Flies expressing APP:BACE also showed reduced levels of the synaptic protein discs large (DLG). Enhancing sleep in memory-impaired APP:BACE flies fully restored both STM and LTM and restored DLG levels. Sleep also restored STM to flies expressing human tau. Using live-brain imaging of individual clock neurons expressing both tau and the cAMP sensor Epac1-camps, we found that tau disrupted cAMP signaling. Importantly, enhancing sleep in flies expressing human tau restored proper cAMP signaling. Thus, we demonstrate that sleep can be used as a therapeutic to reverse deficits that accrue during the expression of toxic peptides associated with Alzheimer?s disease.
The process of neurogenesis has been demonstrated to occur throughout life in the subgranular zone (SGZ) of the hippocampal dentate gyrus of several mammals, including humans. The basal rate of adult hippocampal neurogenesis can be altered by lifestyle and environmental factors. In this perspective review, the evidence for sleep as a modulator of adult hippocampal neurogenesis is first summarized. Following this, the impacts of sleep and sleep disturbances on hippocampal-dependent functions, including learning and memory, and depression are critically evaluated. Finally, we postulate that the effects of sleep on hippocampal-dependent functions may possibly be mediated by a change in adult hippocampal neurogenesis. This could provide a route to new treatments for cognitive impairments and psychiatric disorders.
Specific patterns of brain activity during sleep and waking are recorded in the electroencephalogram (EEG). Time-frequency analyses methods have been widely used to analyse the EEG and identified characteristic oscillations for each vigilance state (VS) i.e., wakefulness, rapid-eye movement (REM) and non-rapid-eye movement (NREM) sleep. However, other aspects such as change of patterns associated with brain dynamics may not be captured unless a non-linear-based analysis method is used. In this pilot study, Permutation Lempel-Ziv Complexity (PLZC), a novel symbolic dynamics analysis method, was used to characterise the changes in the EEG in sleep and wakefulness during baseline and recovery from sleep deprivation. The results obtained with PLZC were contrasted with a related non-linear method, Lempel-Ziv complexity (LZC). Both measure the emergence of new patterns. However, LZC is dependent on the absolute amplitude of the EEG, while PLZC is only dependent on the relative amplitude due to symbolisation procedure and thus, more resistant to noise. We showed that PLZC discriminates activated brain states associated with wakefulness and REM sleep, which both displayed higher complexity, compared to NREM sleep. Additionally, significantly lower PLZC values were measured in NREM sleep during the recovery period following SD compared to baseline, suggesting a reduced emergence of new activity patterns in the EEG. These findings were validated using PLZC on surrogate data. By contrast, LZC was merely reflecting changes in the spectral composition of the EEG. Overall, this study implies that PLZC is a robust non-linear complexity measure, which is not dependent on amplitude variations in the signal, and which may be useful to further assess EEG alterations induced by environmental or pharmacological manipulations.
Sleep is an essential physiological phenomenon which is regulated by fundamental sleep-wake cycles. Sleep is formed of non-rapid-eye-movement (NREM) and REM stages where NREM and REM sleep stages alternate with wakefulness in a whole night sleep (i.e., typically consists of several sleep-wake cycles). During sleep, brain is active and the activity also alters with changing vigilance states (VS). Furthermore, physiological or external changes in the brain structure might influence brain activity during sleep. Effects of ageing, sex differences, and pharmacological manipulations have been widely investigated in sleep research using Fourier Transform. However, the use of non-linear analysis techniques might be more suitable in analysing non-linear and non-stationary signals (e.g., electroencephalogram (EEG)). Therefore, non-linear analysis has been used within this PhD with the hypothesis that these methods might reveal hidden characteristics in the changing brain signals that are difficult to detect with traditional EEG power spectral density analysis. The use of non-linear analysis techniques (e.g., symbolic dynamic analysis (SDA)) will allow to further dissect the physiological significance of activity-dependent changes of neuronal networks across sleep-wake cycles, as well as the significance of brain activity patterns during waking, sleep, sleep deprivation (SD), or induced by sleep-promoting drugs and pharmacological treatments.
In this PhD, rodent and human sleep EEG recordings were analysed using SDA methods: Lempel-Ziv complexity (LZC), Permutation Entropy (PE) and Permutation Lempel-Ziv complexity (PLZC). All the methods were able characterise different VS with wakefulness and REM sleep resulting in higher measures of complexity compared to NREM sleep suggesting an active state of the brain in these VS. This was measured in all datasets assisting the hypothesis on the usefulness of these techniques in sleep research by providing the minimum requirement for sleep analysis. In addition to this, SD significantly reduced complexity in the following sleep period supporting the compensation process for the lost sleep by the increased in slow wave activity which was reflected as reduced complexity in this study. Furthermore, a low dose tiagabine administration?s sleep compensation promoting effect was found in mice.
Moreover, ageing was identified as a main effect on changes in brain activity. These changes were more pronounced in the old age where complexity was significantly lower compared to young age. On the one hand, this was found with all three methods and contributing to the hypothesis that these techniques reveal structural dynamic changes due to physiological alterations. On the other hand, no significant differences in complexity across genders were found suggesting the underlying mechanisms to maintain sleep-wake cycles are similar for men and women. This finding with further investigation might corroborate to question the need to use both genders in drug trials. Furthermore, significant changes in brain activity were found at different times of the sleep period highlighting the changes occurring within VS as sleep progresses. This also has an impact on the way sleep stages are scored and investigated which are influenced by different brain activity levels within each VS throughout the entire sleep.
All in all, this study achieved to support its hypothesis of determining the changes in brain activity as a complexity measure by characterising sleep under physiological and pharmacologically induced EEG datasets in mice and in humans. The study was a novel application to analyse sleep in these conditions. However, with further analysis performed on larger datasets, its findings together with surrogate data analysis proved SDA techniques? robust usability which can complement the gold standard FT analysis in sleep research.
Human and rodent vigilance states have evolutionarily conserved control mechanisms, which suggests that measures of sleep can translate from the laboratory to the clinic. Continuity is an essential aspect of sleep architecture that facilitates the restoration of both body and mind. Current measures of vigilance state continuity do not align well between species and this prevents accurate translation. Throughout this thesis, survival and transition probability analyses were evaluated for their ability to quantify vigilance state continuity in humans and rats. These techniques produced more effective quantification of sleep architecture than metrics such as wake after sleep onset, number of awakenings and average bout lengths.
Two methods for defining a bout were first investigated. In both humans and rats, statistical properties of bouts were characterized using different bout-duration thresholds. It was found that bouts are best modelled with distributions that include a time component. Biological relevance of sleep continuity was also investigated in rats, where bouts of NREM sleep as short as 20 seconds reduced the homeostatic pressure, yet awakenings as short as 10 seconds were enough to disrupt the restorative processes of sleep. Short bouts were therefore an important component of sleep architecture and must be considered when evaluating continuity. Continuity metrics were next used to evaluate sleep restriction in rats and circadian rhythmicity in humans. Both homeostatic and circadian influences exerted significant control of NREM sleep continuity, whilst REM continuity was mostly unaffected. Finally, pharmacological agents were tested and their impact on state continuity effectively translated between species. NREM sleep continuity was not altered by the REM sleep inhibition of SSRI?s which differed to the deficits induced by REM sleep restriction. The main contribution of this thesis is to demonstrate that accurate quantification of vigilance state continuity can improve understanding of sleep architecture and the evaluation of pharmacological agents to deliver better patient outcomes.
Symbolic dynamic analysis (SDA) methods have been applied to biomedical signals and have been proven efficient in characterising differences in the electroencephalogram (EEG) in various conditions (e.g., epilepsy, Alzheimer?s and Parkinson?s diseases). In this study, we investigated the use of SDA on EEGs recorded during sleep. Lempel-Ziv Complexity (LZC), Permutation Entropy (PE), Permutation Lempel-Ziv Complexity (PLZC), as well as power spectral analysis based on the fast Fourier transform (FFT), were applied to 8-h sleep EEG recordings in healthy men (n=31) and women (n=29), aged 20-74 years. The results of the SDA methods and FFT analysis were compared and the effects of age and sex were investigated. Surrogate data were used to determine whether the findings with SDA methods truly reflected changes in non-linear dynamics of the EEG and not merely changes in the power spectrum. The surrogate data analysis showed that LZC merely reflected spectral changes in EEG activity, whereas PE and PLZC reflected genuine changes in the non-linear dynamics of the EEG. All three SDA techniques distinguished the vigilance states (i.e. wakefulness, REM sleep, NREM sleep and its sub stages: stage 1, stage 2 and slow wave sleep). Complexity of the sleep EEG increased with ageing. Sex on the other hand did not affect the complexity values assessed with any of these three SDA methods, even though FFT detected sex differences. This study shows that SDA provides additional insights into the dynamics of sleep EEG and how it is affected by ageing.
Symbolic dynamic analysis (SDA) methods have been applied to biomedical signals and have been proven efficient in characterising differences in the electroencephalogram (EEG) in various conditions (e.g., epilepsy, Alzheimer?s, and Parkinson?s diseases). In this study, we investigated the use of SDA on EEGs recorded during sleep. Lempel-Ziv complexity (LZC), permutation entropy (PE), and permutation Lempel-Ziv complexity (PLZC), as well as power spectral analysis based on the fast Fourier transform (FFT), were applied to 8-h sleep EEG recordings in healthy men (n=31) and women (n=29), aged 20-74 years. The results of the SDA methods and FFT analysis were compared and the effects of age and sex were investigated. Surrogate data were used to determine whether the findings with SDA methods truly reflected changes in nonlinear dynamics of the EEG and not merely changes in the power spectrum. The surrogate data analysis showed that LZC merely reflected spectral changes in EEG activity, whereas PE and PLZC reflected genuine changes in the nonlinear dynamics of the EEG. All three SDA techniques distinguished the vigilance states (i.e., wakefulness, REM sleep, NREM sleep, and its sub-stages: stage 1, stage 2, and slow wave sleep). Complexity of the sleep EEG increased with ageing. Sex on the other hand did not affect the complexity values assessed with any of these three SDA methods, even though FFT detected sex differences. This study shows that SDA provides additional insights into the dynamics of sleep EEG and how it is affected by ageing.
Nollet Mathieu, Hicks Harriet, McCarthy Andrew P., Wu Huihai, Moller-Levet Carla S., Laing Emma E., Malki Karim, Lawless Nathan, Wafford Keith A., Dijk Derk-Jan, Winsky-Sommerer Raphaelle (2019) REM sleep: unique associations with corticosterone regulation, apoptotic pathways and behavior in chronic stress in mice, Proceedings of the National Academy of Sciences 116 (7) pp. 2733-2742
National Academy of Sciences of the United States of America
One of sleep?s putative functions is mediation of adaptation to waking experiences. Chronic stress is a common waking experience, however, which specific aspect of sleep is most responsive, and how sleep changes relate to behavioral disturbances and molecular correlates remain unknown. We quantified sleep, physical, endocrine and behavioral variables, as well as the brain and blood transcriptome in mice exposed to nine weeks of unpredictable chronic mild stress (UCMS). Comparing 46 phenotypical variables revealed that rapid-eye-movement sleep (REMS), corticosterone regulation and coat state were most responsive to UCMS. REMS theta oscillations were enhanced whereas delta oscillations in non-REMS were unaffected. Transcripts affected by UCMS in the prefrontal cortex, hippocampus, hypothalamus and blood were associated with inflammatory and immune responses. A machine learning approach controlling for unspecific UCMS effects identified transcriptomic predictor sets for REMS parameters which were enriched in 193 pathways, including some involved in stem cells, immune response, apoptosis and survival. Only 3 pathways were enriched in predictor sets for non-REMS. Transcriptomic predictor sets for variation in REMS continuity and theta activity shared many pathways with corticosterone regulation, in particular pathways implicated in apoptosis and survival, including mitochondrial apoptotic machinery. Predictor sets for REMS and anhedonia shared pathways involved in oxidative stress, cell proliferation and apoptosis. These data identify REMS as a core and early element of the response to chronic stress, and identify apoptosis and survival pathways as a putative mechanism by which REMS may mediate the response to stressful waking experiences.